ERECTILE

DYSFUNCTION
EDITORS
A. JARDIN - G. WAGNER - S. KHOURY -
F. GIULIANO - H. PADMA-NATHAN - R. ROSEN

1st International Consultation on Erectile Dysfunction - July 1- 3, 1999, Paris

Co-Sponsored by
World Health Organization (WHO) - International Society for Impotence Research

Société Internationale d’Urologie

2
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3
4
 FOREWORD

In the field of sexuality, the end of the second millennium was marked by:
- a better understanding of sexual physiology, especially the physiology of erection,
- the availability of easy to administer and effective treatments for erectile insufficiency,
- recognition of the need for multidisciplinary collaboration to further our knowledge and to
improve patient management.
All of these elements naturally led the directors of the ICUD to organize a consultation on erec-
tile dysfunction.
This consultation was conducted according to the model of previous successful consultations in
the fields of benign prostatic hyperplasia, prostatic cancer, incontinence, etc.
The vast subject of erectile dysfunction was divided into 18 chapters, analysing all aspects and
even included a chapter on FSD, due to the importance of the female in male sexuality, and to
encourage research in the field of FSD, which is somewhat behind that of male sexual dysfunc-
tion.
These 18 committees met on several occasions and each developed a text comprising recom-
mendations which were discussed at the meeting held in Paris in July 1999.
This book is the sum of all these texts and presents a summary of the recommendations develo-
ped by the Scientific Committee.
This book therefore represents a unique body of knowledge and discussion, as it reflects the opi-
nions of specialists from all continents.
Like all books, it will become obsolete and will need to be updated by future consultations, but it
nevertheless has a sound future.
It was a great honour and a pleasure for me to be Chairman of this consultation. I would like to
thank all those who, by their hard work, their very serious comments and their talent, contributed
to the elaboration of the conclusions and recommendations presented in this book, which will cer-
tainly become rapidly indispensable to all those working in the field of sexual dysfunction.

A. Jardin

5
Some of the members of the International Committees
Paris - July 1 - 3, 1999

6
7
 EDITORS

A. Jardin, France
G. Wagner, Denmark
S. Khoury, France
F. Giuliano, France
H. Padma-Nathan, USA
R. Rosen, USA

MEMBERS OF THE COMMITTEES

(Alphabetical order - Chairmen in bold print)

2 ALEXANDRE L France 18 FERGUSON D.M USA

6 ANDERSSON K-E Sweden 2 FITZPATRICK J Ireland
13 ALTHOF S USA 8 FOURCROY J USA
2 BAY NIELSEN H. Denmark 4 FUGL MEYER A Sweden
9 BECHER E Argentina 16 GIAMI A France
4 BEJIN A France 16 GINGELL J.C. UK
18 BENNETT A.H USA 8 GIULIANO F France
13 BENSON G.S. USA 4 GLINA S Brazil
15 BONDIL P. France 14 GOLDSTEIN I USA
1 BOYLE P Italy 3 GONZALEZ CADAVID N USA
17 BRACKETT N USA 7 GOOREN L NDL
8 BROCK G Canada 9 GOVIER F USA
5 BRODERICK G.A. USA 14 GRAZIOTTIN A Italy
6 BURNETT A.L. USA 12 GUEGLIO G Argentina
7 BUVAT J France 13 HAENSEL SM NDL
9 CARRIER S Canada 1 HATZICHRISTOU D Greece
7 CARSON C. C USA 3 HEATON J Canada
15 CARTMILL R Australia 3 HEDLUND H Norway
17 CHARTIER-KASTLER E France 14 HEIMAN J USA
6 CHEN K-K China 13 HENDRY B UK
16 CHOI H.K. Korea 18 HIRSCH M. S. USA
6 CHRIST G USA 13 HULL E.M. USA
17 DENYS P France 8 HUTTER A.M. USA
8 EARDLEY I UK 7 JAROW J USA
10 EVANS C U.K. 14 JOHANNES C USA

8
16 JOHNSTON B Canada 9 PORST H Germany
10 JONAS U Germany 12 PRYOR J UK
12 JORDAN G USA 7 RAJFER J USA
13 KIHARA K Japan 12 RALPH D U.K.
7 KIM Y.C. Korea 6 RAMPIN O France
4 KIMOTO Y. Japan 18 ROSEN R USA
15 KNOLL D USA 11 SACHS B USA
8 KRANE R USA 3 SAENZ DE TEJADA I Spain
10 KRISHNAMURTI S India 16 SAMKANGE C.A. Zimbabwe
1 LAUMAN E USA 10 SARRAMON J. P France
14 LEVIN R.J UK 16 SCHMIDT A S. Africa
12 LEVINE L USA 11 SEGRAVES T USA
1 LEWIS R USA 2 SHABSIGH R USA
4 LO PICCOLO J USA 5 SHARLIP I USA
12 LUE T USA 3 SIMONSEN U Denmark
4 LUKACS B. France 17 SOENKSEN J Denmark
17 LUNDBERG P.O. Sweden 10 SOHN M Germany
14 MC KENNA K USA 15 STACKL W Austria
1 MC KINLAY J USA 3 STEERS W USA
9 MC VARY K USA 6 STIEF C Germany
9 MCMAHON C Australia 5 TAN H.M Malaysia
2 MELCHIOR H. Germany 8 TELOKEN C Brazil
11 MELMAN A USA 16 UGARTE F Mexico
5 MEULEMAN E NDL 11 VAN DRIEL M.F. NDL
10 MONTAGUE D USA 5 VARDI Y Israel
5 MONTORSI F Italy 16 VELA RODRIGUEZ L Spain
16 MORALES A Canada 7 VERMEULEN A Belgium
12 MORELAND R.B. USA 8 VICKERS M USA
4 MULCAHY J. J USA 9 VIRAG R France
3 NEHRA A USA 17 VODUSEK D Slovenia
4 O’LEARY M USA 4 WAGNER G Denmark
13 OPSOMER R.J. Belgium 10 WESPES E Belgium
18 PADMA-NATHAN H USA 10 WESSELLS H USA
16 PASINI W Switzerland 16 WILLIAMS G U.K.
15 PESCATORI E. S. Italy 18 WYLLIE M. G U.K.
3 PICKARD RS. U.K. 12 YACHIA D Israël

9
 MEMBERS OF THE COMMITTEES (by Committee)
1. EPIDEMIOLOGYAND NATURAL HISTORY 6. CURRENT RESEARCH AND FUTURE
AND RISK FACTORS INCLUDING THERAPIES
IATROGENIC AND AGEING ANDERSSON K.E. Sweden
BOYLE P. Italy BURNETT A.L. USA
HATZICHRISTOU D. Greece CHEN K-K R.China
LAUMAN E. USA CHRIST G. USA
LEWIS R. USA RAMPIN O. France
MC KINLAY J. USA STIEF C. Germany

2. ECONOMICALASPECTS 7. ENDOCRINE AND METABOLIC ASPECTS

ALEXANDRE L. France INCLUDING TREATMENT
BAY NIELSEN H. Denmark BUVAT J. France
FITZPATRICK J. Ireland CARSON C.C USA
MELCHIOR H. Germany GOOREN L. NDL
SHABSIGH R. USA JAROW J. USA
KIM Y.C. Korea
3. PATHOPHYSIOLOGY RAJFER J. USA
GONZALEZ CADAVID N. USA VERMEULEN A. Belgium
HEATON J. Canada
HEDLUND H. Norway 8. ORAL NON ENDOCRINE TREATMENT
NEHRA A. USA BROCK G. Canada
PICKARD R.S. U.K. EARDLEY I. UK
SAENZ DE TEJADA I. Spain FOURCROY J. USA
SIMONSEN U. Denmark GIULIANO F. France
STEERS W. USA HUTTER A.M. USA
KRANE R. USA
4. SYMPTOM SCORE AND QUALITY OF LIFE TELOKEN C. Brazil
BEJIN A. France VICKERS M. USA
FUGL MEYER A. Sweden
9. LOCAL PHARMACOLOGICALTREATMENT
GLINA S. Brazil
MODALITIES
KIMOTO Y. Japan
BECHER E. Argentina
LUKACS B. France
CARRIER S. Canada
MULCAHY J.J USA
GOVIER F. USA
O’LEARY M. USA
MC VARy K. USA
WAGNER G. Denmark
MCMAHON C. Australia
PORST H. Germany
5. CLINICAL EVALUATION : PRACTICAL
VIRAG R. France
AND ETHICALASPECTS AND DOCTOR/
PATIENT DIALOGUE
10. SURGICALTREATMENT AND
BRODERICK G. A. USA MECHANICAL DEVICES
MEULEMAN E. NDL EVANS C. U.K.
MONTORSI F. Italy JONAS U. Germany
SHARLIP I. USA KRISHNAMURTI S. India
TAN H.M. Malaysia MONTAGUE D. USA
VARDI Y. Israel SARRAMON J. P. France
SOHN M. Germany
WESPES E. Belgium
WESSELLS H. USA

10
11. PSYCHOLOGICAL ISSUES IN DAGNOSIS 15. PRIAPISM
AND TREATMENT BONDIL P. France
LEVINE S.B. USA CARTMILL R. Australia
MELMAN A. USA KNOLL D. USA
SACHS B. USA PESCATORI E.S. Italy
SEGRAVES T. USA STACKL W. Austria
VAN DRIEL M.F. NDL
16. EDUCATION AND ETHICS AND SOCIO-
12. PEYRONIE’S DISEASE AND OTHER CULTURALASPECTS
PENILE ABNORMALITIES CHOI H.K. Korea
GELBARD M. U.S.A. GIAMI A. France
GUEGLIO G. Argentina GINGELL J.C. UK
JORDAN G. USA JOHNSTON B. Canada
LEVINE L. USA MORALES A. Canada
LUE T. USA PASINI W. Switzerland
MORELAND R.B. USA SAMKANTE C.A. Zimbabwe
PRYOR J. UK SCHMIDT A. S.Africa
RALPH D. U.K. UGARTE F. Mexico
YACHIA D Israël VELA RODRIGUEZ L. Spain
WILLIAMS G. U.K.
13. MALE ORGASMIC AND EJACULATORY
DISORDERS 17. CENTRAL NERVOUS SYSTEM DISORDERS
ALTHOF S. USA AND ERECTILE EJCULATORY
BENSON G.S. USA DYSFUNCTION
HAENSEL SM NDL BRACKETT N. USA
HENDRY B. UK CHARTIER-KASTLER E. France
HULL E. M. USA DENYS P. France
KIHARA K. Japan LUNDBERG P.O. Sweden
OPSOMER R.J. Belgium SOENKSEN J. Denmark
VODUSEK D. Slovenia
14. FEMALE SEXUALDYSFUNCTION
GOLDSTEIN I. USA 18. STANDARDS FOR CLINICALTRIAL :
GRAZIOTTIN A. Italy DESIGN AND ASSESSMENT-CRITERIA
HEIMAN J. USA OF RESPONSE
JOHANNES C. USA BENNETT A. H USA
LAAN E. NDL FERGUSON D.M USA
LEVIN R.J. UK HIRSCH M.S. USA
Mc KENNA K. USA PADMA-NATHAN H. USA
ROSEN R. USA
WYLLIE M. G U.K.

11
 Professor G. Wagner
Honorary chairman of the
Ist International Consultation
on Erectile Dysfunction

Gorm Wagner has since he graduated from University of Copenhagen, Denmark and finished his
internship in USA worked within reproductive and sexual medicine. Starting as guest investiga-
tor in George Corners Laboratory at Rockefeller University in New York with animal experiments
followed by clinical training in gynecology and obstetrics at Copenhagen University Hospital.
These were years with clinical research of induction of labour and studies of mechanisms of myo-
metrial activity. During these years he worked closely with Anna-Riitta Fuchs, D. M. Sc. and they
described the role of oxytocin in lactation and parturition with an early observation published in
NATURE on the inhibitory effect of alcohol on the liberation of oxytocin. On a later study visit
at Washington University, St. Louis, in the lab. of A.Csapo he continued the work with in vitro
smooth muscle physiology now in relation to progesterone.
This was followed by years in Copenhagen where he developed a rabbit model grafting small
pieces of myometrium into a pre-inserted ear chamber and through electrodes and implantation
of a radiotransmitter was able to map out the activity pattern during different reproductive phases,
in the freely moving rabbit.
This was a pioneering breakthrough in use of telemetry in biological studies.
At this point he became assoc. professor at the Department of Medical Physiology, University of
Copenhagen and began making teaching courses in reproductive physiology. After his first mee-
ting with Bill Masters in St. Louis he got fascinated by the many intriguing and unsolved ques-
tions in genital physiology. With a group of colleagues from other disciplines he constructed a 35
hs long course in sexology for medical students and produced two educational films on the phy-
siological responses to sexual stimulation in the laboratory. This period was followed by high

12
activity in research of vaginal function in his lab. in close collaboration with the British physio-
logist Roy Levin and later with Bent Ottesen, who conducted studies of VIP and its activity in
genitals of the female.
But soon penile erection and erectile dysfunction came into focus. Description of a series of new
investigations: dynamic cavernosography with stimulation, Xenon wash out, vibration test ect.
were done in collaboration with Ebbehøj, Uhrenholdt and later Metz. A major step was taken
when he and Brindley tried out the effect of atropine, propanolol, phenoxybenzamine and metyl-
dopa on normal erection and thereby started the thinking of pharmacological intervention.
With Richard Green he published the first monography on Impotence in 1981, studied the effect
of tampons on vaginal milieu showing that oxygen could be one of the causes for development
of Toxic Shock Syndrome and published anatomical studies of the penis.
He gradually became involved in organisational work as a consultant to WHO, within the Inter-
national Academy of Sex Research as president, the formation of International Society for Impo-
tence Research (ISIR) and its president from 1988 to 1994.
In 1989 he became founding co-editor-in-chief of the International J. Impotence Research (IJIR)
and still serves the journal.
Extensive international connections made him a valued speaker and educator and industry has
made use of his deep knowledge of the field of erectile dysfunction.
He has his Ph.D from San Francisco in sexology and co-authored a book on injection therapy with
Helen Kaplan.
Beside his academic endeavours he was an early activist in the fight against torture and part of
the Danish Medical group who pushed this issue into the international political scene.
Together with his wife Helle Larsen, Ph.D, an extensive work with torture victims and rehabili-
tation has been carried out internationally especially with sexually tortured persons. Recently he
has started up a new clinical and experimental division of Sexual Physiology in collaboration with
the Sexology Clinic at the University Hospital in Copenhagen.
Although a citizen of the world he sticks to his roots and nourishes his creativity on his remote,
peaceful farm in Jutland - breeding cattle.

ALAIN JARDIN
SAAD KHOURY

13
 CONTENTS

FOREWORD BY A. JARDIN 5

PR G. WAGNER President of the Ist International Consultation on Erectile Dysfunction 12

1 Epidemiology and Natural History of Erectile Dysfunction ;

Risk Factors including Iatrogenic and Aging 19
R. L EWIS, D. HATZICHRISTOU, E. LAUMANN, J. MCKINLAY

2 Economical Aspects of Erectile Dysfunction 53

R.SHABSIGH, L. ALEXANDRE,, H. BAY NIELSEN,, J. FITZPATRICK,,
H. MELCHIOR

3. Anatomy, Physiology and Pathophysiology of Erectile Function 65

I. SAENZ DE TEJADA, N. GONZALES CADAVID, J. H EATON, H. H EDLUND,
A. N EHRA, R.S. P ICKARD, U. S IMONSEN, W. STEERS

4 Symptom Score and Quality of Life 103

G. WAGNER, A. BÉJIN, A. R. F UGL-MEYER, S. G LINA, Y. KIMOTO,
C.S.B LUKACS, J. M ULCAHY, M. O’L EARY,

5 Clinical Evaluation and the Doctor-Patient Dialogue 115

E. MEULEMAN, G.BRODERICK, F. MONTORSI, I.SHARLIP, H.MENG TAN, Y.VARDI

6 Current Research and Future Therapies 139

K-E ANDERSSON, AL BURNETT, KK C HEN, GJ C HRIST, O R AMPIN, C STIEF

7 Endocrine and Metabolic Aspect including Treatment 205

Y. C. KIM, J. BUVAT, C.C CARSON, L.J G OOREN, J. J AROW,
J. RAJFER, A.VERMEULEN

8. Oral non endocrine treatment 241

R. KRANE, G. BROCK, I. EARDLEY, F. FOURCROY, A.GIULIANO,
C.HUTTER, M.TELOKEN, M. VICKERS

9 Local Pharmacological Treatment Modalities 305

R.Virag, E. BECHER, S. CARRIER, F. GOVIER, K. MC VARY,
H.C. MCMAHON, H. P ORST

14
10 Surgical Treatment and Mechanical Devices 355
U. JONAS, C. EVANS, S. K RISHNAMURTI, D. M ONTAGUE,
J. P. SARRAMON, M. SOHN, E. W ESPES, H. W ESSELLS

11 Psychological Issues in Diagnosis and Treatment 405

A. MELMAN, S. LEVINE, B. SACHS, T. SEGRAVES, M.F. VAN DRIEL

12 Peyronie’s Disease 437

T.F. LUE, M.K. GELBARD, G.GUEGLIO, G.H. J ORDAN, L. A. L EVINE,
R. MORELAND, J. P RYOR, D. R ALPH, D. YACHIA

13 Male Orgasmic and Ejaculatory Disorders 477

W.F. HENDRY, S.E. ALTHOF, G.S. B ENSON, S.M. H AENSEL,
E.M. HULL, K. K IHARA , R.J. O PSOMER

14 Female Sexual Dysfunction 507

I.GOLDSTEIN, A. GRAZIOTTIN, J. R. HEIMAN, C. J OHANNES,
E . L AAN, R. L. L EVIN, K. E. MCKENNA,

15 Priapism 557
W. STACKL, P. BONDIL, R. C ARTMILL, D. KNOLL, E.S. P ESCATORI

16 Socio-Cultural, Educational and Ethical Aspects of

Erectile Dysfunction 573
A. MORALES, H. CHOI, A. GIAMI, C. G INGELL, B. J OHNSTON, W. PASINI,
L. VELA-RODRIGUEZ, C. SAMKANGE, A. SCHMIDT, F. UGARTE, G. W ILLIAMS

17 Neurological Disorders: Erectile and Ejaculatory Dysfunction 591

P.O. LUNDBERG, N.L. BRACKETT, P. DENYS, E. C HARTIER-KASTLER,
J. SØNKSEN, D. B. V ODUSEK

18 Standards for Clinical Trials in Erectile Dysfunction:

Research Designs and Outcomes Assessment 647
R. ROSEN, A. BENNETT, D. F ERGUSON, M. H IRSCH,
H. PADMA-NATHAN, M. W YLLIE.

Illustrated Atlas 679

D. HATZICHRISTOU

Recommendations of the 1st International Consultation on Erectile Dysfunction 709

15
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 ERECTILE
DYSFUNCTION
EDITORS

A. JARDIN - G. WAGNER - S. KHOURY -

F. GIULIANO - H. PADMA-NATHAN - R. ROSEN

17
18
 Committee 1

Epidemiology and Natural History of

Erectile Dysfunction ;
Risk Factors Including Iatrogenic
and Aging

Chairman
R. LEWIS

Members
D. HATZICHRISTOU,
E. LAUMANN,
J. MCKINLAY

19
 CONTENTS

6. C ARDIOVASCULAR DISEASE AND

I. INTRODUCTION HYPERTENSION

7. M EDICATIONS AND RECREATIONAL DRUGS

II. WORLDWIDE PREVALENCE OF
8. S URGERY AND TRAUMA
ERECTILE DYSFUNCTION
9. THE EFFECT OF MODIFICATION OF RISK
1. UNITED STATES AND OTHER NORTH AMERI- FACTORS
CAN STUDIES
V. CONCLUSIONS
2. EUROPEAN STUDIES
3. ASIAN STUDIES
4. AUSTRALIAN STUDIES VI. RECOMMENDATIONS

III. NATURAL HISTORY AND APPENDIX A

INCIDENCE STUDIES

APPENDIX B
IV. RISK FACTORS

1. G ENERAL RISK FACTORS APPENDIX C

2. HORMONAL OR ENDOCRINE (INCLUDING
“ANDROPAUSE”) APPENDIX D
3. SMOKING OR OTHER TOBACCO USE
4. DIABETES MELLITUS
5. O THER CHRONIC DISEASE REFERENCES

20
 Epidemiology and Natural History of
Erectile Dysfunction ; Risk Factors
Including Iatrogenic and Aging
R. LEWIS
D. HATZICHRISTOU, E. LAUMANN, J. MCKINLAY
I. INTRODUCTION
The 1993 National Institutes of Health (NIH)
Consensus Conference on Impotence suggested
erectile dysfunction as the appropriate term for
this male sexual dysfunction rather than impoten-
ce [1]. The disorder is defined as the following: the
inability to obtain and/or maintain penile erection
sufficient for satisfactory sexual performance.
Consistency and degree are important words mis-
sing in this definition. Adding these words pro-
vides a flexibility that has resulted in attempts to
assign erectile dysfunction further into minor,
moderate, and severe categories. However, by
adding consistency, the duration of time for the
disorder is mandatory, since there are instances of
temporary failures that spontaneously resolve.
Erectile dysfunction can be further classified as
primary (life-long) or secondary. Thus, differences
in definition affect the ability to compare different
articles on epidemiology of erectile dysfunction.
In fact, Boyle states in his recent chapter on the
epidemiology of erectile dysfunction that the lack
of a unifying definition is a fundamental problem
for this disorder that requires resolution.[2]. He
states further that it should be a priority to establi-
sh a system of classification after determination of
the severity and ‘cause’ of erectile dysfunction.
The two components of epidemiology, descriptive
epidemiology (incidence and prevalence by per -
sons, place and time) and analytical epidemiolo -
gy (the search for disease risk that may serve to
increase prospects for prevention) are the key
components of this chapter [2].
The occurrence rates of erectile dysfunction are
21
calculated in two ways – prevalence and inciden -
ce [3]. The former refers to the number of people
who have the disorder at a given time and can be
further characterized as current or lifetime preva-
lence. Prevalence rates, in fact, can be determined
for any time duration but are commonly expressed
as years or lifetime. Current prevalence reveals
the percentage of people experiencing the disor -
der at the time of the assessment. Lifetime preva -
lence measures the percentage of people ever
experiencing the disorder, even if they are no lon -
ger experiencing it. Incidence refers to the num -
ber of new cases of a disorder occurring in a spe -
cific population during a discrete period of time.
These concepts are discussed in more detail in the
introduction section of a critical review of empiri-
cal literature regarding incidence and prevalence of
sexual dysfunction in men and women published in
1990 by Spector and Carey [3]. Twenty-three stu-
dies appearing over the fifty years prior to that
publication are included in their report.
Another consideration in developing this chapter
is the source of the populations studied. Discus-
sions of medical disease consist of people seen for
the disorder in a hospital, clinical offices or those
in community-based populations screened for the
disorder by questionnaires or other methods. Both
are potentially useful for different reasons but
community studies are more popular recently for
the definition of the potential number of patients
who suffer from this disorder who might benefit
from treatment. A community sample should be
truly representative with social, cultural, and
health status data available to validate the repre -
sentative nature of the group sampled. The fre-
quency of the disorder generated from self reports
is suspect and consequently will bias any epide-
miological study that would investigate the etiolo-
gy of the phenomenon [2]. To more clearly define
the natural history of this disorder and to examine
the effects of aging on erectile dysfunction, longi-
tudinal studies as opposed to cross-sectional stu-
dies are needed. Longitudinal studies allow better
definition of incidence of the disorder and facili -
tate sorting out confounding effects.
Studies of erectile dysfunction draw their sample
populations in two fundamentally different ways.
Each method has definite strengths and weak-
nesses that should be kept clearly in mind when
assessing information in hand. The first method,
clinical studies, recruits samples from patients
who attend clinics because they have or suspect
they have a particular health problem. Boyle has
reviewed some of the data on erectile dysfunction
from such sources [2]. Constituting the vast pre-
ponderance of available empirical studies on erec-
tile dysfunction, such studies can reveal a great
deal about the nature of erectile dysfunction in
particular patients, even with concomitant disease
processes like hypertension or diabetes. These stu-
dies offer the opportunity to collect carefully
monitored physiological and biologically relevant
tests, physical examinations and case histories that
permit the exploration of complex etiologies and
courses of dysfunction. One must realize, howe-
ver, that these samples, drawn from the population
at large in highly biased or selective ways, are dif-
ficult or impossible to gauge or evaluate. They
can tell us little about the incidence or prevalence
of the problem in the population at large.
The second method, probability-based surveys,
recruits representative (cross-section) samples of
well-defined populations at large. These samples
are defined independently from the health condi-
tion of interest – that is, both healthy and afflicted
persons are included in the sample in direct pro -
portion to their prevalence in that population
universe. A central problem in these types of stu-
dies is the validity and reliability of identification
of those who have the health condition and those
who do not. The problem arises because the rich
array of diagnostic techniques available in clinical
studies are not practicable in most population sur-
veys which forces reliance on self-reports. Self
reports have a well-known biases of under-repor-
ting due to concerns about social stigmatization or
22
due to lack of awareness because the condition is
asymptomatic or undiagnosed. Moreover, self
reports vary in their ability to tap accurately the
health condition of interest since these indicators
may also capture alternate causes. There are only
three population-based surveys of erectile dys-
function known in the literature, but only two of
these use modern probability-based sampling stra-
tegies. Alfred Kinsey (1948) reported on erectile
dysfunction based on his large and broadly selec-
ted sample, but he explicitly rejected the notion
that randomly drawn samples could be drawn to
study sensitive sexual phenomena and thus relied
on volunteer samples from an ill-defined region of
northern Indiana and the Chicago area plus addi-
tions [4]. It is well known that volunteer samples
are biased in favor of those specially interested in
the phenomena under investigation – in this case
sexual behavior, and are therefore likely to overes-
timate the incidence and prevalence of various
behaviors and conditions related to sexuality [5].
Estimates from Kinsey’s work can only be taken
as suggestive and cannot reliably be used in syste-
matic, over-time comparisons.
The other two surveys are recent and use modern
probability sampling techniques. The Massachu -
setts Male Aging Study (MMAS), consisting of
1,709 free-living, non-institutionalized men bet -
ween the ages of 40 and 70 living in the greater
Boston area in 1987 to 1989 at base line, gathe-
red extensive physiological measures, demogra-
phic information, and self-reported erectile func-
tional status [6]. Because of the rigorous require-
ments for collecting blood samples from the
respondents early in the morning, the length of
time required, and the usual difficulties of recrui-
ting male respondents, the sample completion rate
is only 53%, raising some concerns about possible
biases in participation. Another important feature
of the MMAS is its longitudinal character, the
followup sample succeeded in re-interviewing
1,290 persons some 8 years later, thus affording
an opportunity to estimate incidence as well as
prevalence rates. The National Health and Social
Life Survey (NHSLS) is a national probability
survey of 1,410 men and 1,749 women between
the ages of 18 and 59 years living in households
throughout the United States in 1992 [5,7]. It
accounts for about 97% of the population in this
age range – roughly 150 million Americans. It
excludes people living in group quarters such as
barracks, college dormitories, and prisons as well
as those who do not know English well enough to
be interviewed. The sample completion rate was
greater than 79%. While the central focus of the
MMAS was on impotence among aging males,
the NHSLS is principally directed to a broad-
ranging inquiry into US sexual practices and
beliefs among younger adults. Consequently, it
collected only limited information on sexual dys-
function broadly defined and physical heath
conditions. The two surveys complement one
another rather nicely. The MMAS provides detai-
led opportunities to investigate the relevance of
changing hormonal levels across ages on erectile
functioning but with a limited capacity to genera-
lize to the country as a whole. In contrast, the
NHSLS has limited information on erectile dys-
function per se but has the capacity to place infor-
mation in a much broader perspective of US
demographics and sexual dysfunction. When the
findings of these two studies overlap, they are
remarkably consistent.
II. WORLDWIDE PREVALENCE OF
ERECTILE DYSFUNCTION
1. UNITED STATES AND OTHER NORTH AME-
RICAN STUDIES
Before the MMAS and NHSLS reports, the most
extensive population-based source of normative
data on male sexual behavior in the United States
was the forty year old Kinsey report [4,8]. In Kin-
sey’s report, erectile dysfunction was reported in
42% of a sample of 5460 white and 177 black
males and negatively correlated with age, that is
the older the participant the higher the prevalence
of erectile dysfunction. However, only 306 of the
15,781 men reported in this study were older than
55 years and only 4,108 were older than 25 years.
In contrast, Spector and Carey’s review of articles
published in the English language up to 1990, the
prevalence of erectile difficulties in community
studies was estimated to be between 3% and 9%
[3]. In all such studies, prevalence increased with
age. Another study of a community population 60
years or older in Michigan showed a prevalence of
erectile dysfunction of 38.3% in married men and
51.2% in the other marital categories, 40.3% ove-
rall [9]. Eighty-eight percent of the 92 married
23
men who responded positively to the question of
impotency estimated the percent of the erection
achieved. Thirty-nine point eight percent had no
erection at all, 26.1% had 1% to 50%, and 21.5%
had 51% to 75% of a normal erection. Twelve
point five percent were able to achieve 75% to
100% of a normal erection, but were unable to
maintain their erection [9]. The Baltimore Longi-
tudinal Study of Aging reported that, by the age of
55 years, impotence was present in 8% of healthy
men. For 65, 75, and 80 year old men, the preva-
lence of impotence was 25%, 55%, and 75% res-
pectively [10].
The MMAS study was the first cross-sectional,
community-based, random-sample multidiscipli -
nary epidemiological survey on impotence and its
physiological and psychosocial correlates in
men. The design of the study, with four groups of
intervening variables (sociodemographic and psy-
chosocial characteristics, health status and lifesty-
le characteristics), permitted precise estimation of
key parameters while controlling for potentially
important confounders [6]. The ages of men stu-
died in the MMAS study ranged from 40 years to
70 years of age. The MMAS sexual activity ques-
tionnaire included 9 items related to potency
(Appendix A.) with 1,290 of the 1,709 male sub-
jects (75%) providing a complete response. (See
Table 1 for characteristics of the population stu-
died.) In the MMAS study, the prevalence of
impotence of all degrees was 52% (minimal at
17.2%, moderate at 25.2%, and complete at
9.6%) (Figure 1a). Extrapolating these numbers,
it was estimated that about 18 million men are
impotent in the United States. The MMAS instru-
ment was linked to a direct assessment of potency
by means of a separate calibration study in a sub-
set of 303 men to categorize impotency as mini-
mal, moderate, complete, or the participant as not
impotent. [11] (Table 2). Between the ages of 40
and 70, the probability of complete impotence
increased from 5.1% to 15% and moderate impo -
tence from 17% to 34%. Over the same age
range, the probability of minimal impotence
remained constant at about 17%. An estimated
60% of the men were not impotent at age 40 years,
decreasing to 33% at age 70 (Figure 1b).
The recently published report by Laumann et al
identified prevalence and predictors of erectile
dysfunction along with other sexual dysfunction in
Table 1: Physical, medical and socio-demographic characteristics of 1,290 MMAS subjects included in study of impotence

PHYSICAL MEASURES:* MEDICATIONS: #

Age (yrs.) 53.8± 8.5 Cardiac 112 (9)
Ht. (inches) 69.1± 3.0 Antihypertensive 140 (11)
Wt. (pounds) 186.7± 31.5 Lipid-lowering 21 (2)
Body mass index (kg/m 2) 27.5± 4.4 Hypoglycemic agents 49 (4)
Serum cholesterol (mg/dl) 209±49 Vasodilator 53 (4)
Physical activity (kcal/kg/day) 48.2±15.2 Sympathetic 28 (2)
CIGARETTE SMOKING: SOCIO-DEMOGRAPHICS: #
Current smokers # 286 (22) Married 1,082 (84)
Cigarettes/day (smokers only)* 25.0± 15.1 Have sexual partner‡ 1,290 (100)
Passive smoking at work # 475 (38) Living alone 112 (9)
Passive smoking at home # 366 (28) Employed 1,061 (82)
MEDICAL CONDITIONS: # Depressed 120 (9)
Diabetes: Belonging to social groups 706 (55)
Not treated 36 (3) Emotional support available 1,196 (93)
Treated 52 (4) RACE: #
Heart disease: White 1,240 (96)
Not treated 65 (5) Black 28 (2)
Treated 90 (7) Other 22 (2)
Hypertension: EDUCATION:
Not treated 176 (14) Below high school 125 (10)
Treated 200 (16) Completed high school 205 (16)
Arthritis: Beyond high school 377 (29)
Not treated 228 (18) Bachelor’s degree 174 (13)
Treated 76 (6) Graduate study or degree 409 (32)
Allergy:
Not treated 261 (20) *Mean « standard deviation
Treated 67 (5) # Number of patients (%)
Ulcer: ‡ Criterion for inclusion in impotence substudy
Not treated 98 (8) From: Feldman et al. J Urol 1994, 151: 54-61.
Treated 31 (2)

Table 2: Self-rated impotence in calibration sample (303 subjects) related to sexual activity questions from MMAS

Not Minimally Moderately Completely

Impotent Impotent Impotent Impotent

No. subjects 116 41 92 54

Sexual activity• 8 7 3 0
Full erection • 30 30 4 0
Awaken with erection • 10 10 3 0
No activity within last 6 mos. (%)* 2 7 20 61
Trouble getting erection (%)* 5 50 85 90
Trouble keeping erection(%)* 5 63 95 96
Satisfaction with frequency of
activity (%) 65 46 15 17
Satisfaction with sex life# 1.6 3.0 4.1 4.6
Satisfaction with partner# 1.3 2.2 3.2 3.7
Partner satisfaction 1.5 2.6 3.5 4.1
•Median frequency/month
*Among those reporting some sexual activity within last 6 months
# Mean on scale from 1 (extremely satisfied) through 5 (extremely dissatisfied)
From: Feldman et al. J Clin Epidem 1994: 47:457-467.
24
Figure 1 a: Prevalence of erectile dysfunction
Figure 1 b: Association between age and prevalence of erectile dysfunction
American men and women [7]. This report ana -
lyzes data on sexual dysfunction from the Natio -
nal Health and Social Life Survey (NHSLS)
conducted in 1992 [5]. (Tables 3a-c and Appendix
B) This is a national probability sample of 1410
men and 1749 women between the ages of 18 and
59 years living in households through the United
States. In response to questions regarding
trouble maintaining or achieving an erection, the
following prevalence rates for age categories
were reported: 7% for ages 18-29 years, 9% for
30-39 years, 11% for 40-49 years, and 18% for
50-59 years. While martial status affected preva-
25
lence rate (those married having a lower risk for
erectile dysfunction), educational level did not
affect the rate, although there was a slightly grea-
ter prevalence in those with an education level less
than high school. The prevalence rate for erectile
problems was less in Hispanics (5%) than White
(10%), Black (13%), or other race or ethnic group
(12%). (See Table 3c) Men who experience emo-
tional or stress problems, urinary tract symptoms,
and have poor health are more likely to have erec-
tile dysfunction. Deterioration in economic posi-
tion, indexed by falling household income, is asso-
ciated with a higher prevalence of erectile difficul-
Table 3a: Prevalence of dysfunction items by demographic characteristics (Men)*
PREDICTORS LACKED INTEREST IN SEX UNABLE TO ACHIEVE ORGASM
Adjusted OR Adjusted OR
No. (%) (95% CI) No. (%) (95% CI)
TOTAL 1249 1246

AGE

18-29 56 (14) Referent 28 (7) Referent

30-39 52 (13) 1.52 (0.95-2.42)‡ 28 (7) 1.31 (0.71-2.40)

40-49 45 (15) 2.11 (1.23-3.64)# 26 (9) 1.79 (0.90-3.55)‡

50-59 30 (17) 2.95 (1.60-5.44)# 15 (9) 1.74 (0.79-3.83)

MARITALSTATUS

Married 77 (11) Referent 49 (7) Referent

Never married 71 (19) 2.75 (1.74-4.36)# 31 (8) 1.55 (0.86-2.79)

Divorced, separated, widowed 31 (18) 1.69 (1.05-2.73)# 15 (9) 1.29 (0.69-2.39)

EDUCATION

Less than high school 30 (19) Referent 18 (11) Referent

High school graduate 42 (12) 0.61 (0.35-1.05)‡ 25 (7) 0.62 (0.31-1.21)

Some college 65 (16) 0.88 (0.53-1.47) 32 (8) 0.68 (0.35-1.30)

College graduate 44 (14) 0.71 (0.40-1.24) 22 (7) 0.55 (0.27-1.12) ‡

RACE OR ETHNICITY

White 134 (14) Referent 68 (7) Referent

Black 27 (19) 1.30 (0.67-1.90) 13 (9) 1.14 (0.57-2.26)

Hispanic 12 (13) 0.94 (0.47-1.86) 8 (9) 1.24 (0.54-2.83)

Other 10 (24) 2.02 (0.94-4.32)‡ 8 (19) 2.83 (1.24-6.50) #

*Data from National Health and Social Life Survey. Estimated ratio of odds of reporting a given symptom for members of the
specific group to odds for reference group. Derived from logistic regression models performed on respondents with at least 1 part-
ner during the 12 month period prior to the survey. The model includes all predictor variables as well as controls for religious
affiliation and residence in rural, suburban, or urban areas. Percentages are derived from respondents in each category, and the
total number represents those who responded to the questions. OR indicates odds ratio; CI is confidence interval. (Laumann et
al. JAMA 1999, 281(6):540) [7]
# P≤ .05
‡ P≤ .10

26
Table 3b: Prevalence of dysfunction items by demographic characteristics (Men)*
PREDICTORS CLIMAX TOO EARLY SEX NOT PLEASURABLE
Adjusted OR Adjusted OR
No. (%) (95% CI) No. (%) (95% CI)
TOTAL 1243 1246

AGE

18-29 121 (30) Referent 39 (10) Referent

30-39 122 (32) 1.01 (0.72-1.42) 30 (8) 0.95 (0.54-1.69)

40-49 83 (28) 0.88 (0.60-1.30) 25 (9) 1.04 (0.54-2.01)

50-59 55 (31) 0.95 (0.61-1.49) 10 (6) 0.73 (0.31-1.69)

MARITALSTATUS

Married 214 (30) Referent 41 (6) Referent

Never married 111 (29) 0.95 (0.68-1.33) 40 (11) 1.80 (1.02-3.18)#

Divorced, separated, widowed 54 (32) 1.12 (0.77-1.62) 21 (13) 2.27 (1.27-4.04)

EDUCATION

Less than high school 61 (38) Referent 22 (14) Referent

High school graduate 125 (35) 0.91 (0.61-1.35) 21 (6) 0.35 (0.17-0.68)#

Some college 106 (26) 0.58 (0.39-0.87)# 39 (9) 0.59 (0.32-1.08)‡

College graduate 87 (27) 0.65 (0.42-1.00)# 21 (6) 0.44 (0.22-0.88)#

RACE OR ETHNICITY

White 290 (29) Referent 70 (7) Referent

Black 49 (34) 1.14 (0.75-1.72) 23 (16) 2.33 (1.29-4.20) #

Hispanic 25 (27) 0.78 (0.46-1.31) 7 (8) 0.95 (0.40-2.29)

Other 17 (40) 1.63 (0.86-3.09) 4 (9) 1.29 (0.44-3.82)

*Data from National Health and Social Life Survey. Estimated ratio of odds of reporting a given symptom for members of the
specific group to odds for reference group. Derived from logistic regression models performed on respondents with at least 1
partner during the 12 month period prior to the survey. The model includes all predictor variables as well as controls for reli-
gious affiliation and residence in rural, suburban, or urban areas. Percentages are derived from respondents in each category,
and the total number represents those who responded to the questions. OR indicates odds ratio; CI is confidence interval. (Lau-
mann et al JAMA1999, 281 (6):540-541 [7].
#P≤.05
‡ P≤ .10

27
Table 3c: Prevalence of dysfunction items by demographic characteristics (Men)*
ANXIOUS ABOUT PERFORMANCE TROUBLE MAINTAINING OR ACHIEVING
AN ERECTION
Adjusted OR Adjusted OR
PREDICTORS No. (%) (95% CI) No. (%) (95% CI)
TOTAL 1247 1244

Age

18-29 77(19) Referent 30 (7) Referent

30-39 65 (17) 0.98 (0.65-1.48) 35 (9) 1.46 (0.84-2.57)

40-49 55 (19) 1.09 (0.68-1.75) 31 (11) 1.84 (0.97-3.47)‡

50-59 25 (14) 0.87 (0.49-1.54) 31 (18) 3.59 (1.84-7.00) #

MARITALSTATUS

Married 98 (14) Referent 65 (9) Referent

Never married 78 (21) 1.71 (1.14-2.56) # 37 (10) 1.73 (1.00-2.97) #

Divorced, separated, widowed 45 (26) 2.29 (1.51-3.48) # 24 (14) 1.61 (0.96-2.71)‡

EDUCATION

Less than high school 37 (23) Referent 21 (13) Referent

High school graduate 65 (18) 0.68 (0.42-1.10) 32 (9) 0.64 (0.34-1.18)

Some college 77 (19) 0.70 (0.44-1.13) 43 (10) 0.76 (0.42-1.38)

College graduate 41 (13) 0.49 (0.28-0.83)# 31 (10) 0.66 (0.35-1.26)

RACE OR ETHNICITY

White 173 (18) Referent 98 (10) Referent

Black 35 (24) 1.22 (0.76-1.95) 19 (13) 1.21 (0.67-2.17)

Hispanic 5 (5) 0.24 (0.09-0.61)# 5 (5) 0.53 (0.20-1.39)

Other 9 (21) 1.33 (0.61-2.90) 5 (12) 1.17 (0.44-3.12)

*Data from National Health and Social Life Survey. Estimated ratio of odds of reporting a given symptom for members of the
specific group to odds for reference group. Derived from logistic regression models performed on respondents with at least 1 part-
ner during the 12 month period prior to the survey. The model includes all predictor variables as well as controls for religious
affiliation and residence in rural, suburban, or urban areas. Percentages are derived from respondents in each category, and the
total number represents those who responded to the questions. OR indicates odds ratio; CI is confidence interval. (Laumann et
al. JAMA1999, 281(6):541 [7]

#P≤.05

‡ P≤ .10

28
ties. Interestingly, men who were victims of adult-
child contact and men who have sexually assaul-
ted women were 3.3 times as likely to report erec-
tile dysfunction. Men with erectile dysfunction
experience diminished quality of life as measured
by multiple indicators, including happiness, physi-
cal health status, and physical and emotional satis-
faction with sexual partners.
Sexual dysfunction was indexed in the NHSLS
according to 7 dichotomous response items, each
measuring presence of critical symptoms or pro-
blems during the past 12 months. Response items
included:
1) lack of desire for sex;
2) arousal difficulties (i.e. erection problems in
men, lubrication difficulties in women);
3) inability to achieve climax or ejaculation;
4) anxiety about sexual performance;
5) climaxing or ejaculating too rapidly;
6) physical pain during intercourse; and
7) not finding sex pleasurable.
(The NHSLS measure of erectile dysfunction,
because it asks the respondent to identify a pro -
blem of at least several months duration, seems
roughly equivalent to the MMAS’ definition of
complete impotence. For the men aged 40 to 59 in
both samples, self-reported erectile dysfunction
rates are roughly comparable).
Table 3 outlines the prevalence of six male dys-
function items by demographic characteristic,
including age, marital status, education, and race
or ethnicity. The adjusted odds ratios in the table
take into account all the demographic predictors
plus controls for religious affiliation and residence
in rural, suburban or urban areas. Note that,
except for marital status and age, the other demo-
graphic characteristics are unrelated to the preva-
lence of erectile dysfunction. For comparative
purposes, it is worth noting that there are differen-
tial distributions of the other sexual dysfunctions
across demographic categories. It is also worth
noting that while erectile dysfunction is clearly
related to age, the crude prevalence of erectile dys-
function among 18 to 29 year olds stands at 7%.
This is likely to be under-estimated because of the
strong social concerns about stigmatization among
the younger men.
29
For comparative purposes, it is worth knowing
how the five other dysfunctions co-exist with erec-
tile dysfunction. The respondent checked as many
dysfunctions as applied to him. Thus, the condi-
tional probability of having a particular dysfunc-
tion can be determined, given that the man also
has an erectile dysfunction. Accounting for the
prevalence of the other dysfunction in question
allows the computation of the odds of having
sexual dysfunction A and erectile dysfunction
against the odds of having erectile dysfunction
alone (Table 4).
Table 4: Odds ratios of both sexual dysfunction A and erec -
tile dysfunction versus erectile dysfunction.
Climax too early 4.06
Lack of interest in sex 4.58
Experienced pain during sex 7.46
Sex not pleasurable 7.69
Anxious about performance 10.53
Unable to achieve orgasm 14.24
From Laumann et al 1999[7]
Jonler and colleagues used a self administered
questionnaire for assessing potency during a free
screening program of prostate cancer in three dif-
ferent locations in the United States - Madison,
WI, New York, NY, and New Orleans, LA.[12]
1517 of 1680 men responded to the questionnaire
(90.3%). Of the men responding, 70.4% were
Caucasian, 24.9% African-American, 3.1% Hispa-
nic, 1.2% Arabic and 0.4% reported as other races.
One hundred twenty-nine (7.7%) of the respon-
ding men had not had any erections during the pre-
vious 12 months. The 1388 men who reported an
erection in the previous 12 months were asked a
second question requesting more detail of their
ability to have erections during the past month.
12.4% of these had erections on less than one
occasion in five. The percentage of this response
increased with age with 10% of those age 50-59
having erections on less than one occasion in five
to 40% of men age 70-79 with the same answer.
Vice versa, 60% of men age 50-59 usually had
erections with sexual stimulation while only 20%
of men age 70-79 gave a similar response. Ano-
ther 7.3% of the entire group reported inability to
have an erection less than half of the time when
sexually stimulated in any way. There was no
demonstrable difference between ethnicity and
response to the two questions regarding potency.
2. EUROPEAN STUDIES
In a small sample of 109 men in a British survey
(representing 25% of solicited population, predo-
minately biased toward the better educated social
classes) published in 1996, 32% reported some
problem in obtaining an erection during foreplay
with their partner [13]. Twenty per cent had some
difficulty maintaining an erection long enough to
have intercourse with their partner ( see Table 5).
In 1993, a Danish study of 411 men aged 51
years, the prevalence of erectile dysfunction was
determined by a questionnaire. One hundred of
these same men were subsequently interviewed
[14]. In the questionnaire, 16 (4%) of the 411
men reported having suffered from erectile dys -
function on more than a few occasions during
the previous year. Another 61 (15%) reported
only occasional erectile dysfunction. None of the
16 men had a subsequent interview. Although
none of the 100 men interviewed reported suffe -
ring from erectile dysfunction on more than a
few occasions during the previous year on the
questionnaire, 7 reported erectile dysfunction on
more than one occasion at the time of the inter -
view. At the time of the interview, another 16
reported impaired erection of other kinds, such as
“too soft”, “too slowly erecting”, or “too fast
decreasing”. In this survey, almost 40% of the men
felt that they suffered from some sort of sexual
dysfunction. However, only 7% considered the
problem abnormal for their age, only 5% plan -
ned to consult a therapist and only 2% conside -
red their sexual problem to be part of a disease.
In 1997, in an epidemiological study in Goteberg,
Sweden, 10,458 men were invited to respond to a
Table 5: Erectile functioning (n = 93; missing data = 16) *
PERCENTAGE
TOTAL
Do you get an erection during
foreplay with your partner
Never 0 Never
Occasionally 3 Occasionally
Half of the time 1 Half of the time
Most of the time 28
All of the time 68
*From: Spector and Boyle. British J Med Psych, 1996, 59: 3510-3518. [3]
questionnaire that included general data and ques-
tions regarding urinary incontinence and other
urologic symptoms, including impotence [15].
The source of the population sample consisted of
men born on odd dates every five years from
1912-1947. The response rate varied from a low
of 69% for the birth cohort 1907 to a high of 80%
for the birth cohort 1922. Overall response rate
was 74.2%. There was an overall impotence pre-
valence rate of 7.6% ranging from 1.5% for age 45
yrs. to 17.8% for age 80 yrs. with a steady increa-
se for each succeeding five years of age. There
was also a linear decrease in sexual activity with
increasing age with 76.1% reporting being sexual-
ly active for age 45 to 16.7% for age 80. Reported
prevalence of regular sexual activity overall was
50.1%.
In 1999, Fugl-Meyer and Sjogren Fugl-Meyer pre-
sented data from a Swedish study on sexual disa-
bilities in 2810 respondents aged 18 to 74 (1,475
who were men). This study used structured ques-
tionnaires and check-lists with structured face-to-
face interviews conducted by trained professional
interviewers [16] (See Table 6). Of the 4,781
patients chosen to participate in the study 1,971
declined to participate or could not be located
(approximately 100 of the 1,971) for a 41% dro-
pout rate. Only 5% of the 1,288 men responding to
questions regarding erectile function reported
sexual disability (in the categories of quite often,
nearly all the time, or all the time for erectile disa-
bility). Erectile disability was age dependent
(Table 6). The authors reported that in the 5% of
men with erectile disability, 69% felt that this was
a problem for them and of those with this percep-
tion, 75% were not sexually satisfied. In the dis-
PERCENTAGE
TOTAL
Can you keep an erection long enough
to have intercourse with your partner
0
1
1
Most of the time 18
All of the time 80
30
Table 6: Prevalence of erectile dysfunction in a nationally representative swedish population by Age-Cohorts*
AGE
COHORTS
18 – 24
25 – 34
35 – 49
50 – 65
66 – 74
* From: Fugl-Meyer and Sjogren Fugl-Meyer. Scandinavian Journal of Sexology 1999, 2:79-105. [16]
cussion section of this report, the authors present
prevalence rates of 7.5% for erectile dysfunction
in French men between the ages of 18 and 69. The
French study, conducted by Giami, was reported to
be in press. The authors also mention two other
Scandinavian studies of erectile dysfunction, one
from Finland and one from Denmark, with similar
prevalence rates for erectile dysfunction.
Bejin evaluated questions regarding premature eja-
culation and erectile dysfunction from analysis of a
larger survey of sexual lifestyles conducted in Fran-
ce that had been reported in 1992. The original sur-
vey was applied to 20,055 people aged 18-69 years.
The prevalence rate for erectile dysfunction repor-
ted “often” was 7%, for erectile dysfunction repor-
ted as “often”, “sometimes”, or “quite seldom” was
47%. In men age 18-24 years, 11% reported erecti-
le dysfunction alone and 22% reported erectile dys-
function and premature ejaculation. For those men
60-69 years of age, similar rates reported were 27%
and 41% respectively [17].
3. ASIAN STUDIES
Shirai et al estimated the prevalence rate of erecti-
le dysfunction to be 26% in Japan. This rate is
based upon a compilation of data regarding the
number of men affected with conditions associated
with erectile dysfunction and the estimated preva-
lence of erectile dysfunction in these populations
[18].
4. AUSTRALIAN STUDIES
Astudy to determine erectile dysfunction prevalen-
ce by a questionnaire distributed to consecutive
adult male attendees at 62 general medical practices
was conducted in the metropolitan Perth area [19].
The mean age of participants was 56.4 years in the
1240 men completing the questionnaire. Thirty-
RESPONDENTS ERECTILE DISABILITY
N %
251 3
331 2
435 2
339 7
119 24
eight of the practices recorded the number of the
questionnaires distributed and of the 1697 distribu-
ted, 1100 were returned to the institute conducting
the study for a response rate of 64.8%. The other
309 questionnaires were received from 24 partici-
pating doctors who did not record the number of
questionnaires distributed. Prevalence data were
similar in both sources of questionnaires. Of these
1409 returned questionnaires, 169 men opted not to
participate in the study producing a participation
rate of 88%. 39.4% of those returning the ques-
tionnaires reported erectile dysfunction in the follo-
wing categories: 119 (9.6%) occasionally, 110
(8.9%) often, and 231 (18.6%) all the time with 30
men (2.3%) giving no indication of severity.
Among the 707 men aged 40-69 the prevalence of
erectile dysfunction was 33.9% (240 men) and
11.9% had complete impotence. The prevalence of
erectile dysfunction increased with age from 2% in
those 40-49 years of age to 44.9% in those in the
70-79 year age group. Only 11.6% of those repor-
ting erectile dysfunction on this questionnaire had
received treatment for the disorder. Hypertension,
ischemic heart disease, peripheral vascular disease,
and diabetes mellitus were frequently associated
with erectile dysfunction.
III. NATURAL HISTORY AND
INCIDENCE STUDIES
There is a paucity of data due to the lack of lon -
gitudinal studies. However, data has recently
become available from the Massachusetts Male
Aging Study [20]. Analyses were performed on
847 men without erectile dysfunction at baseline
(1987-89) and with complete follow-up informa -
tion (1995-97) using a random, population-based
survey. The baseline average age of the 847 men
31
was 52.2 years (range 40-69). The crude inciden -
ce rate for erectile dysfunction was 25.9
cases/1000 man-years (95% confidence interval
[CI], 22.5-29.9). The annual incidence rate
increased with each decade of age (CI of 95% for
all): 12.4 cases/1000 (9.0-16.9), 29.8 cases/1000
(24.0-37.0), and 46.4 cases/1000 (36.9-58.4) res-
pectively for men aged 40-49, 50-59, and 60-69.
Age-adjusted risk of erectile dysfunction was
higher for men with lower education, diabetes
(50.7 cases/1000 man-years), treated heart disea -
se (58.3 cases/1000) and treated hypertension
(42.5 cases/1000). [20] Applying the MMAS inci-
dence estimates to the population of men aged 40-
69 at risk in Massachusetts resulted in an expected
17,718 new cases of erectile dysfunction annually.
The corresponding estimate for U.S. white men in
the same age range is 617,715 new cases annually.
Using data from the MMAS, the likely worldwide
increase in erectile dysfunction between 1995
and 2025 has been published [21].
The lone published estimate of the incidence of
erectile dysfunction is based on data from a conve-
nience sample of 3,250 men aged 26-83 (mean 51)
seen at a preventive medicine clinic at least twice
between 1987 and 1991 [22]. The incidence for
erectile dysfunction after 6-48 months follow-up
(median 22 months) was 12 cases/1000 man years
and was age-related. Incidence rates were 2.4
cases/1000 man years among men less than 45 to
52.3 cases/1000 man years among men over the
age of 65. This population was healthier, younger,
and followed for less time than the MMAS study.
Erectile dysfunction was measured differently in
the two studies - this study by one question in a
lengthy medical history questionnaire and the
MMAS study by discriminate analysis of 13 ques-
tions and a single global question. Both measures
were self-reported.
IV. RISK FACTORS
1. G ENERAL RISK FACTORS
A latent class analysis (LCA) of the NHSLS data
was used to evaluate the syndromal clustering of
individual sexual dysfunctions or symptoms. (See
Appendix C).
Latent class analysis is a statistical method used to
group categorical data into latent classes [23,24]
32
and has a number of medical applications, such as
evaluation of diagnostic systems [25,26,27] and
generation of epidemiological estimates using
symptom data [28,29]. Latent class analysis tests
whether a latent variable, specified as a set of
mutually exclusive classes, accounts for observed
covariation among manifest, categorical variables.
By accounting for observed covariation among
dysfunctional items, LCA, in essence, attempts to
improve on construct validity that is more proble-
matic when using information from only one sur-
vey indicator. These categories, then, represent a
typology of disorders for sexual dysfunction found
in the US population, indicating both prevalence
and types of symptoms.
Only those respondents reporting at least 1 part -
ner in the prior 12 month period were included in
the LCA. This procedure may limit the results
because excluded respondents may have avoided
sex because of sexual problems. However, this
procedure was necessary to ensure that each
respondent answered all the symptom items since
only three items were asked of sexually active
respondents. One hundred and thirty-nine men
were excluded on this basis. The excluded men
were more likely to be single and have lower
levels of education. We expect that this will bias
the estimates of prevalence of sexual dysfunction
downward since sexually inactive men generally
reported higher rates of symptoms. With respect to
erection problems, 14% of the excluded men
reported this problem in comparison to 10% pre-
valence among men included in the analysis.
The results of the LCA allow for analyzing risk
factors and quality-of-life concomitants in rela -
tion to categories of sexual dysfunction, rather
than individual symptoms. These results indicate
that the clustering of symptoms according to syn-
drome can be represented by 4 categories of men.
Latent class analysis also estimates the size of
each class as a proportion of the total sample, a
result corresponding to sexual dysfunction catego-
ry prevalence in the US population. Finally, LCA
identifies symptoms for each class, indicating the
likelihood that respondents in that class will exhi-
bit a given symptom, thus providing researchers
with information about what elements characteri-
ze each category. Although not equivalent to cli-
nical diagnosis, this approach offers a statistical
representation of sexual dysfunction.
A large proportion of men (70% prevalence)
constitutes an unaffected population. The remai-
ning three classes consist of premature ejacula-
tion (21% prevalence), erectile dysfunction (5%
prevalence), and low sexual desire (5% prevalen-
ce). The LCA procedure estimates 5% overall
prevalence rate for erectile dysfunction, a figure
that is lower than the 10% estimate using the
single indicator. The difference, explained by the
lower validity of the latter, is likely to include
other causes of the indicator unrelated to erectile
dysfunction. Tables 7 and 8 present multinomial
logistic regressions on categories of sexual dys-
function. Adjusted Odds Ratios (OR) indicate the
relative risk of experiencing a given category of
sexual dysfunction versus reporting no problems
for each risk factor, while controlling for other
characteristics.
Table 8 classifies risk factors into three sets:
health and lifestyle, social status, and sexual expe-
rience. Regarding health and lifestyle risk factors,
those who experience emotional or stress-related
problems are more likely to experience sexual
dysfunctions defined in each of the categories.
Men with poor health have elevated risk for all
three categories of sexual dysfunction. The pre-
sence of urinary tract symptoms appears to impact
premature ejaculation and erectile dysfunction.
However, having a history of a sexually transmit-
ted infection, moderate to high alcohol consump-
tion, and circumcision generally do not result in
increased odds of experiencing sexual dysfunc-
tion.
Social status variables, which measure an indivi-
dual’s socioeconomic and normative position rela-
tive to other persons, assess how sociocultural
position affects sexual function. Deterioration in
economic position, indexed by falling household
income, doubles the likelihood of erectile dys-
function but has no association with the other two
categories of male dysfunction. Men with liberal
attitudes about sex are approximately 1 1/3 times
more likely to experience erectile dysfunction and
1 3/4 more likely to experience premature ejacula-
tion.
Finally, various aspects of sexual experience results
in an increased risk of sexual dysfunction. Sexual
history, indicated by having more than five lifetime
partners and by masturbation practices, does not
increase relative risk for men. Men reporting any
33
same sex activity are more than twice as likely to
experience premature ejaculation and low sexual
desire. Male victims of adult-child contact or for-
ced sexual contact are 3 times as likely to expe-
rience erectile dysfunction and approximately twice
as likely to experience premature ejaculation and
low sexual desire than those who have not been vic-
tims of adult-child contact. Finally, men who have
sexually assaulted women are 3 times as likely to
report erectile dysfunction. Indeed, traumatic
sexual acts continue to exert profound effects on
sexual functioning, some effects lasting many years
beyond the occurrence of the original event.
2. HORMONAL OR ENDOCRINE (INCLUDING
“ANDROPAUSE”)
Androgens influence the growth and develop -
ment of the male reproductive tract as well as
secondary sexual characteristics [30]. Their
effect on libido and sexual behavior is well esta -
blished but the effect of androgens on the erecti -
le mechanism remains unclear [31,32]. The
controversy is mainly due to the lack of a large
study on hormones in a healthy aging male popu-
lation. Serum levels of testosterone, prolactin,
FSH and LH at various ages of man have been fre-
quently studied in the literature [33,34]. Spark et al
found neuroendocrine dysfunction in 1% of impo-
tent men, while Slag et al reported hypogonadism
in 19%, hypothyroidism in 5%, hyperthyroidism
in 1% and hyperprolactinemia in 4% of 188 impo-
tent patients with mean age of 60 years [35,36].
The MMAS constitutes the largest male endocri -
ne database presently available. It includes
reliable measurement of 17 hormones, a complete
hormonal profile [6,32]. Interestingly, testostero -
ne – either free, albumin-bound, total or DHT,
was not statistically significantly correlated with
impotence. This may be explained by the fact that
any decline in testosterone with age may be due in
large part to ill health, rather than a natural phy-
siologic phenomenon [6].
No correlation with impotence was found for any
of 17 hormones measured, including FSH, LH,
prolactin, androtenedione, androstanediol and
estrogens, with the exception of the adrenal
androgen metabolite dehydroepiandrosterone
sulfate (DHEAS) [6]. DHEAS levels of 0.5 mg/ml
were associated with a high probability of com-
plete impotence (16%), comparing to DHEAS
Table 7: Quality of life concomitants by latent classes of sexual dysfunction *
SATISFACTION WITH PRIMARY PARTNER AND HAPPINESS
LATENT CLASS LOW PHYSICAL LOW EMOTIONAL LOW GENERAL HAPPINESS
SATISFACTION SATISFACTION
Men (n=1218) (n=1219) (n=1238)
No problems Referent Referent Referent
Premature ejaculation 0.79 (0.47-1.32) 0.97 (0.63-1.48) 1.28(0.75-2.18)
Erectile dysfunction 4.38 (2.46-7.82)# 2.40 (1.33-4.33)# 2.48 (1.22-5.05) #
Low desire 3.14 (1.74-5.69)# 1.57 (0.85-2.90) 2.61 (1.28-5.31) #
* Data from National Health and Social Life Survey and presented as adjusted odds ratio (95% confidence interval). Estimated
ratio of odds of respondents of each latent class having negative concomitant outcomes. Derived from logistic regression models
performed on respondents with at least 1 partner during the 12-month period prior to the survey. The dependent variables are the
concomitant outcomes and the predictors variables, modeled simultaneously, includes latent classes as well as controls for age,
marital status, education, race and ethnicity, religion, and place of residence. (Laumann et al. JAMA1999, 281(6):543 [7]).
# P≤.05

Table 8: Latent classes of sexual dysfunction by risk factors (men)*

ADJUSTED OR (95%CI)
PREMATURE ERECTILE
PREDICTORS EJACULATION DYSFUNCTION LOW DESIRE
Health and lifestyle (n=1202)
Daily alcohol consumption 0.79 (0.36-1.69) 1.63 (0.61-4.34) 2.24 (0.89-5.64)‡
STD ever 1.10 (0.70-1.73) 1.29 (0.64-2.59) 1.05 (0.51-2.15)
Urinary tract symptom 1.67 (0.95-2.93)‡ 3.13 (1.48-6.63)# 1.68 (0.71-3.97)
Poor to fair health 2.35 (1.40-3.95)# 2.82 (1.26-6.33) # 3.07 (1.38-6.81)#
Circumcised 0.87 (0.58-1.31 1.30 (0.63-2.70) 1.64 (0.75-3.58)
Emotional problems or stress 2.25 (1.58-3.20) 3.56 (2.00-6.34)# 3.20 (1.81-5.67) #
SOCIAL STATUS (N=1232)
HOUSEHOLD INCOME (1988-91)
% CHANGE
1-20 increase Referent Referent Referent
0-20 decrease 1.09 (0.74-1.61) 1.49 (0.79-2.82) 1.23 (0.65-2.34)
> 20 decrease 1.41 (0.87-2.29) 2.11 (1.01-4.38) # 1.38 (0.62-3.07)
Liberal attitudes about sex 1.72 (1.17-2.53)# 1.33 (0.72-2.46) 1.07 (0.57-2.00)
Sexual experience (n=1039)
≥5 lifetime partners 0.96 (0.64-1.45) 1.02 (0.50-2.05) 1.26 (0.61-2.60)
Sex frequency no more than
once monthly 0.94 (0.58-1.52) 1.20 (0.55-2.63) 1.57 (0.79-3.12)
Thinks about sex less than
once weekly 0.99 (0.49-2.02) 0.77 (0.25-2.42) 3.63 (1.57-8.40)#
Masturbation at least once
monthly 1.09 (0.73-1.64) 0.66 (0.33-1.33) 1.72 (0.86-3.42)
Any same sex activity ever 2.11 (1.15-3.86)# 0.72 (0.23-2.33) 2.51 (1.10-5.74)#
Partner had an abortion ever 1.83 (1.15-2.90)# 0.63 (0.24-1.61) 1.98 (0.92-4.23)‡
Sexually forced a woman ever 1.74 (0.70-4.30) 3.52 (1.03-11.98) # 0.49 (0.06-4.08)
Sexually harassed ever 1.43 (0.97-2.11)‡ 1.27 (0.66-2.47) 1.31 (0.69-2.48)
Sexually touched before puberty 1.80 (1.12-2.90)# 3.13 (1.49-6.59) # 2.23 (1.10-4.56)#

*Data from National Health and Social Life Survey. Estimated ratio of odds of membership in a given latent class for members
of the specified group to odds for reference group in the default latent class of having no problems. Derived from multinomial
logistic regression models performed on respondents with at least 1 partner during the 12-month period prior to the survey. Three
models run separately for each sex (health and lifestyle, social status, and sexual experience). Predictor variables, in addition to
those listed for health, lifestyle, and sexual history included age, marital status, education, race and ethnicity, religion, and place
of residence. OR indicates odds ratios, CI is confidence interval and STD sexually transmitted disease. (Laumann et al. JAMA
1999, 281 (6):543 [7].
# P≤.05 ‡P≤ .10

34
levels 5 and 10 mg/ml (6.5% and 3.4% respective-
ly). Conversely, probabilities of complete impo -
tence increased as DHEAS levels decreased
while the overall and moderate impotence proba -
bilities remained unchanged. Such patterns sup-
port the hypothesis that minimally impotent men
may become complete impotence if their DHEAS
levels decreased from 10 to 0.5 mg/ml. It should
be noted that as the MMAS data were adjusted for
age, the rapid decline of serum DHEAS concen-
tration with age was not the cause of this finding.
It is possible that the described pattern expresses
the vascular health status of the sample. DHEAS
levels have been proposed in the literature as a
predictor for cardiovascular disease [37].
Certainly, in most cases of hypogonadism both
libido and sexual function are adversely affected.
However, medical or surgical castration does not
necessarily lead to the loss of erectile function.
The adrenal glands in man may produce all the
androgens that are necessary for corpora caverno-
sal function [38]. Rat models show much more
androgen dependency for erectile activity [39].
Treating hypogonadal men with exogenous testos-
terone has been shown to increase both number of
and degree of rigidity of nocturnal erection events
[40]. Other authors show that testosterone treat-
ment in normal eugonadotrophic men did not
increase the frequency but did increase the rigidi-
ty of nocturnal erections suggesting an end organ
effect [41]. The level of free testosterone may be
more important than total serum testosterone
levels in maintaining erections in the hypogonadal
male [42]. Other studies have shown a differential
androgen effect on erectile dysfunction in sexual
situations and nocturnal erectile events but an
independence of this effect on erotic visual sex sti-
mulated erections [43-45]. Prolactin secreting
tumors of the pituitary gland usually are associa-
ted with markedly decreased serum testosterone
levels, but there are exceptions to this.
Lisa Tenover recently addressed two important
questions: whether many older men experience
an age-associated decline in androgens and if
this has a negative impact on their sexual func -
tion. To answer the first question, she summarized
the recent literature which shows that there is a
decline in androgen levels and production due to a
number of factors [46]. In a later review article,
Bhasin added other age-related changes which are
35
included in Table 9 [47]. Tenover cautions that
most of this information has been reported only in
Caucasian men with a paucity of data for other
ethnic populations [46]. She also cautions that the
magnitude of the decline in testosterone with
aging is poorly documented and that there is also
a lack of longitudinal population-based sampling.
In response to the question of whether age exerts a
negative impact on sexual function, Dr. Tenover
reports that there is a mixed picture from the lite -
rature and that there may be a relationship bet -
ween declining testosterone and sexual activity
and/or sexual desire but such a relationship with
this decline and erectile dysfunction, is not wide -
ly supported [46]. It has recently been reported
that hypo-testosteronemia may be more clearly
related to other adverse effects of age in men such
as osteoporosis, decreased body mass, lower red
cell counts and hemoglobin, alterations in sexual
response, mood, and cognitive functions and that
these conditions may respond to testosterone sup-
plementation.[48] However, the connection bet-
ween hypo-testosteronemia and erectile dysfunc-
tion has not been confirmed [46,48].
In a clinical review based on a Medline search of
English language literature published between
1975 and 1992, Mulligan and Schmitt examined
Table 9: Male reproductive hormone changes with normal
aging
Decreased testosterone production; decreased testosterone
clearance
• decrease in testicular Leydig cell numbers
• decreased enzymes in metabolic pathways
governing testosterone production
• diminished testicular response to pituitary LH
Decreased levels of serum total and free testosterone
Increased sex hormone-binding globulin: Decreased “bio-
available testosterone”
No change in serum levels of dihydrotestosterone
Increased serum estradiol levels
Small increase in serum gonadotropin (LH and FSH) levels
Partial impairment of the hypothalamic GnRH pulse genera-
tor
Decreased LH pulse amplitude
Increased hypothalamic sensitivity to sex steroid feedback
More asynchronous production of LH and testosterone
Table generated from data from references [46 and 47]
the association between testosterone and erectile
failure [49]. They were able to draw three conclu-
sions:
- testosterone enhances sexual interest (libido,
sexual thoughts and perceived sexual arousal)
- testosterone led to increase frequency of sexual
acts (the success rate for vaginal intercourse
was not reported)
- testosterone increased the frequency of sleep-
related erections but had little or no effect on
fantasy or visually induced erections.
3. SMOKING OR OTHER TOBACCO USE
The use of tobacco is clearly a risk factor for
erectile dysfunction [50,51]. This risk has been
substantiated in animal models [52,53]. Cigarette
smoking is reported as an independent risk factor
in the development of atherosclerotic lesions in
the internal pudendal and common penile arteries
of young impotent men [54]. In the MMAS group
of patients, cigarette smoking exacerbated the
risks of impotence associated with cardiovascu -
lar disease and medication [6]. Among subjects
with treated heart disease the age-adjusted proba-
bility of complete impotence was 56% for current
smokers, compared with 21% in current non-smo-
kers. Among treated hypertensives, those who cur-
rently smoked had an elevated probability of com-
plete impotence (20%), whereas the non-smokers
(8.5%) were comparable to the general sample
(9.4%). Smoking exacerbated drug effects on erec-
tile dysfunction, which increased the age-adjusted
probability of complete impotence in those taking
cardiac medication (from 14% to 41%), antihyper-
tensive medications (from 7.5% to 21%), and
vasodilators (from 21% to 52%). However, in the
MMAS study an overall effect of current smo -
king was not determined, with complete impoten -
ce present in 11% of smokers and 9.3% of non-
smokers. The probability of impotence demons-
trated no dose dependency with current smoking
or lifetime cigarette consumption among current
smokers [6]. In a small group of patients, NPT
measurements showed improvement in patients
avoiding cigarettes for 24 hours [55]. Another
report showed that smoking interfered with the
erection response to intracavernosal pharmacolo-
gical injection [56].
36
4. D IABETES MELLITUS
Erectile dysfunction has been reported to occur
in at least 50% of men with diabetes mellitus,
with the onset of the impotence occurring in an
earlier age than those without diabetes mellitus
[57,58]. Also the prevalence rate of erectile dys-
function is higher for each decade of diabetic men
compared to non-diabetics [2]. Hatzichristou et al
have reported that the prevalence of impotence in
diabetics has been estimated between 35-75% in
the literature [59].
Whitehead and Klyde reviewed a large amount of
the reported associations between erectile dysfunc-
tion and diabetes mellitus present in the literature in
a 1990 article on diabetes-related impotence in [58].
Their observations include the following: in greater
than 50% of patients with impotence and diabetes,
impotence is noted within ten years of the onset of
diabetes. Impotence occurs at an earlier age in Type
I insulin dependent diabetic patients (IDDM) com-
pared to type II non-insulin dependent diabetic
patients (NIDDM), although it probably occurs in
equal frequency in the two types. Impotence may
present as the first sign of diabetes in 12% of
patients. Temporary impotence may be due to poor-
ly controlled diabetes although this point is deba-
table. Impotence is present in almost all patients
with diabetes who have manifestations of diabetic
neuropathy such as bladder dysfunction or decrea-
sed testicular sensation. Diabetic macrovascular
complications are reported as related to age, while
duration of diabetes and degree of glycemic control
affect microvascular complications. Lehman and
Jacobs reported that 83% of the type I diabetics had
vascular abnormalities compared to 57% of the type
II diabetics [60].
In Boyle’s epidemiologic review chapter, he pro-
vides the following data [2]. Prevalence surveys in
diabetics found rates of erectile dysfunction ran-
ging from 35% to 59%. Erectile dysfunction in
diabetic men had been reported to be associated
with severe diabetic retinopathy, a history of peri-
pheral neuropathy, cardiovascular disease, a
higher glycosylated hemoglobin, use of antihyper-
tensive drugs and a higher body mass index. In the
MMAS report, the age-adjusted probability of
complete impotence was three times higher in men
who reported having treated diabetes than in those
without diabetes [6].
Each of the pathologic effects of diabetes melli -
tus on tissue, such as small arterial and arterio -
lar effects, neurologic demyelinization, and sinu -
soïds smooth muscle deterioration, have all been
implicated as the etiologic factor likely associated
with erectile difficulty. Metro and Broderick have
reviewed these different areas of pathophysiology
in erectile dysfunction in a recent report [61]. In
that study, 105 diabetic men (79/105 NIDDM and
26/105 IDDM) underwent duplex Doppler evalua-
tion of cavernosal arteries for the evaluation of
erectile dysfunction. The authors reported the pre-
sence of coronary artery disease in IDDM patients
was associated with lower peak systolic velocity
than in those with NIDDM. However, the type of
diabetes itself, smoking, or hypertension showed
no difference in cavernosal artery peak systolic
velocity between IDDM or NIDDM groups [61].
de Tejada et al reported impaired autonomic
nerve-mediated and endothelium-dependent
relaxation of corporal smooth muscle in diabetic
patients with maintenance of autonomic nerve-
mediated contraction [62]. The longer the duration
of diabetes, the less pronounced the neurogenic
relaxation. No difference was seen between men
who were treated and those not treated with insu-
lin. Nor were there differences in those diabetics
controlled for hypertension and smoking. Relaxa-
tion was normal in diabetics when induced by
endothelium-independent vasodilators, sodium
nitroprusside, and papaverine [62].
Sullivan et al demonstrated a significant increase
in endothelin B (ETB) receptor binding sites on
the rabbit corpus cavernosum six months after the
induction of diabetes mellitus by alloxan [63].
They suggested that this could represent a patho-
physiological pathway in diabetic erectile dys-
function (up regulation of smooth muscle constric-
tion and initiation of cellular proliferation) or a
compensatory response to impaired nitric oxide
(NO) or prostacyclin (PGI2) release which has
been reported in diabetic animal models [63].
Indeed, elevated plasma concentration of endothe-
lin-1 in peripheral vein blood was significantly
increased in non-diabetic and diabetic men with
impotence compared to control men and also
significantly higher in diabetic patients compared
to non-diabetic patients [64].
There is much to be learned about the pathological
37
effects of diabetes on the corporal tissue, and by
understanding these processes, clues to the patho-
physiology of erectile dysfunction in the aging
male may be forthcoming. Since this is such a
prevalent disorder in the diabetic male, the Natio-
nal Institute of Health has recently announced a
major research effort for the study of impotence in
diabetics.
5. OTHER CHRONIC DISEASE
Chronic neurologic disease correlated with a
high risk for impotence include cerebrovascular
accidents, temporal lobe epilepsy, multiple sclero-
sis, Arnold-Chiari syndrome, Guillain-Barre syn-
drome, autonomic neuropathy associated with
AIDS or diabetes mellitus, Alzheimer’s disease,
tumors, and infection [57]. Vardi and others repor-
ted a 38% coincidence of polyneuropathy and
impotence in diabetics and a 10% coincidence rate
in non-diabetics [65]. Sexual dysfunction is very
common in Parkinson’s disease. The prevalence
of erectile dysfunction is reported to be about 60%
[66,67]. Multiple system atrophy, a syndrome that
encompasses several conditions such as Shy-Dra-
ger syndrome, has also been associated with impo-
tence in 96% of the cases; in 37% of them, erecti-
le dysfunction was the first symptom [68].
In a recent review article on urological condi -
tions associated with multiple sclerosis, the asso -
ciation with erectile dysfunction was discussed
[69]. The following summary is largely drawn
from that article. Some have reported a prevalen -
ce of erectile dysfunction in 40% of the males
afflicted with the disease while others have repor -
ted it as high as 80% in patients suffering from
multiple sclerosis [70,71]. Impotence onset is
rarely seen early in the disease, generally occur-
ring a decade after onset but has been reported 3.7
to 9 years after diagnosis [72,73]. There is
approximately another five years from the time of
the first symptoms of erectile dysfunction and see-
king medical attention [70]. The effect of this
disease on erectile dysfunction can be predomi-
nantly central (psychogenic) or the result of a neu-
rological lesion of the spinal cord. Certain tests
such as nocturnal tumescence monitoring (NPT)
often do not clearly distinguish the two. [70] Some
authors report that the sexual dysfunction parallels
the disability while others report that the erectile
problems are independent of the disability status
of the patient but is more closely related to bladder
and pyramidal dysfunction [71,72-77].
Men suffering from depression have a greater
risk for impotence possibly related to decreased
testosterone levels [6,57]. Medications used to
treat depression are also a risk factor for impoten-
ce as discussed below. In the MMAS, the psycho-
logical factors strongly associated with impotence
include depression, low levels of dominance, and
anger, either expressed outward or directed inward
[6].
Chronic renal failure is associated with impoten -
ce in up to 40% of those affected [57]. Hyperpro-
lactinemia, hypogonadism, hyperparathyroidism
and zinc deficiency have been suggested as etiolo-
gic factors in the face of renal disease [57]. An
excellent review of the hemodynamic pathophy-
siology in impotence associated with renal failure
was prepared in 1994 by Kaufman and associates
[78]. In patients with hepatic failure, there is an
increased risk from impotence, particularly in
alcoholic cirrhosis [57].
Chronic obstructive lung disease (perhaps asso-
ciated with oxygen dependency for nitric oxide
synthase) has been implicated as a risk for erec -
tile dysfunction [79]. In fact, three patients in this
report were given home oxygen for resting or noc-
turnal hypoxemia and two had improvement of
erectile function on therapy [79].
Other diseases that may account for an increased
risk for erectile dysfunction include Peyronie’s
disease, other disease or injury leading to scarring
or fibrosis of the tunica albuginea of the corpora,
injury to the intracavernosal tissue (such as post-
priapism seen with sickle cell disease and other
states), chronic brucellosis, other infective or para-
sitic disease, and widower’s syndrome [57]. Scle -
roderma has been reported as a risk factor for
erectile dysfunction and impotence has been
reported in 12% to 60% of cases [80]. Impotence
has been the presenting symptom of systemic scle-
roderma in 12% to 21% of the cases [80].
6. C ARDIOVASCULAR DISEASE AND
HYPERTENSION
Cerebrovascular accidents, coronary bypass sur -
gery, myocardial infarction, heart disease, hyper -
tension, hyperlipidemia, low serum levels of high
38
density lipoproteins, arteriosclerosis, and per -
ipheral vascular disease are all cardiovascular
factors that have high correlation with erectile
dysfunction. Wabrek and Burchell reported that
64% of 131 males, aged 31-86 years, hospitalized
for an acute myocardial infarction were impotent
[81]. In 130 impotent men, the incidence of myo-
cardial infarction was found to be 12% and 1.5%
in patients with abnormal and normal penile
hemodynamics respectively [10]. Heaton and his
colleagues discuss some of the problems of asses-
sing risk pre- and post- operatively in patients
undergoing coronary artery bypass graft surgery
[82]. In their introduction and discussion section,
the authors remind us of psychological factors
affecting erection in cardiac patients such as fear
of angina, death with intercourse and fear of
damaging chest wounds during intercourse in post
operative bypass graft patients. Significant phy-
siological effects such as high sympathetic drive
seen in patients with congestive heart failure or
significant coronary artery disease oppose the
vasodilitation that is necessary for erection [82]
.The authors appropriately call for prospective stu-
dies to clearly define risk factors for erectile dys-
function in the patient with cardiovascular disease
[82].
Several reports emphasize the association of
hypertension with erectile dysfunction. Oaks and
Moyer reported that 8-10% of untreated hyperten-
sive patients were impotent at the time of diagno-
sis of the disease [83]. Muller et al found caverno-
sal artery insufficiency in 85% of 117 hyperten-
sives tested [84].
Treated heart disease (worse in smokers), treated
hypertension (again, worse in smokers), and low
serum levels of high density lipoproteins were
significantly correlated with impotence in the
MMAS report [6]. As discussed below, erectile
dysfunction is frequently reported in association
with drugs used to treat a variety of cardiovascular
disorders.
Wei et al found that a high level of total choleste-
rol and a low level of HDL are important risk fac-
tors for erectile dysfunction [22]. In the MMAS,
the impotence probability pattern varied signifi-
cantly with HDL-cholesterol, in a manner interac-
tive with age [6]. The first pattern represents
changes in younger men (aged 38-55 years) and
the second in older men (aged 56-70 years). The
probability of moderate impotence for the younger
group increased from 6.7% to 25.5% when the
HDL values decreased from 90 to 30 mg/dL.
Considering that minimal impotence diminished
from 27.7% at HDL levels of 90 mg/dL to 14.1%
at HDL levels of 30 mg/dL, it was assumed that
men with minimal impotence may increase to the
moderate category. Values more than 90 mg/dL
were associated with 0% probability of complete
impotence. When the HDL values dropped to 30
mg/dL, the probability of complete impotence
increased to 16.1%. These data, along with the fin-
ding that total serum cholesterol was not correla-
ted with impotence probabilities, support HDL
levels as a strong determinant of impotence.
Certainly, the presence of cardiovascular disease
and its treatment is clearly a risk factor for erecti-
le dysfunction. Similarly, impotence may be an
indication of arterial disease in the coronary
arteries although this has not been substantiated.
More research into the relationship between disea-
se in the cavernosal arteries and disease in the
coronary arteries is highly recommended.
7. MEDICATIONS AND RECREATIONAL DRUGS
Erectile dysfunction due to prescription medica-
tions is underreported. Slag et al reported a 25%
incidence of drug-associated impotence in a medi-
cal outpatient population [36]. In the MMAS, a
statistically significant correlation between impo -
tence and vasodilators, antihypertensives, car -
diac and hypoglycemic agents was noticed [6].
This topic has been discussed summarily by Lund-
berg and Biriell [85]. Meinhardt et al have revie-
wed the influence of medication on erectile dys-
function recently in some detail [86]. In Table 1
from that article, the authors list some 332 medi-
cations that are associated with erectile dysfunc-
tion. Major classes of prescription drugs com -
monly reported to be associated with erectile dys -
function are histamine-2 receptors antagonist,
hormones, anticholinergics, and certain cyto -
toxic agents.
Certainly, anti-hypertensive drugs appear to
represent a major risk factor for erectile dys -
function. Lundberg and Biriell report that erecti-
le dysfunction is more likely seen with alpha or
alpha/beta blocking agents and guanidine deriva-
39
tives than with calcium blocking agents, conver-
ting enzyme inhibitors or diuretics [85]. All anti-
hypertensives lower blood pressure and this
mechanism is probably the main reason that most
are a risk to cause erectile dysfunction. However,
reported decreases in libido with certain anti-
hypertensives indicate that there may be a central
effect as well from these medications. Based on
Lundberg and Biriell’s commentary and the article
by Meinhardt et al, it would appear that selective
or non-selective beta-blocking agents are more
likely to cause erectile dysfunction than other anti-
hypertensives [85,86]. As suggested by Meinhardt
et al, this side effect may result due to a change in
the balance between alpha and beta sympathetic
influence which results in insufficient antagonism
of alpha-1 vasoconstriction [86]. Other authors
have suggested that diuretics, particularly thiazide
diuretics, are the most common cause of impoten-
ce from prescription drugs due to their common
usage [57]. However, Prisant et al examined the
short term usage of various antihypertensives in a
media analysis of self-reported sexual dysfunc-
tion. There was no higher increase in erectile dys-
function from single agent use compared to those
patients on a combination of a diuretic and a beta-
blocker [87]. It seems reasonable to think that cal-
cium re-entry blocking agents would be less like-
ly to cause erectile dysfunction. However, com-
mentary by Lundberg and Biriell shows that it is
not uncommon for erectile dysfunction to be asso-
ciated with this class of drugs as well, again pro-
bably due to the central lowering of blood pressu-
re [85]. Reserpine, alphamethyldopa, and ACE-
antagonists may not only be a risk factor for erec-
tile dysfunction because of their blood pressure
lowering effect but also because of hormonal
influences [57,86]. There may be some central
effect of a few of these agents as well [57,85].
Every clinician who deals with erectile dysfunc-
tion has anecdotal data to suggest that changing
the type of anti-hypertensive for the patient will
often reverse erectile dysfunction. Calcium chan -
nel blockers and alpha adrenergic blockers may
be theoretically the best alternative in attempting
to reverse erectile dysfunction when associated
with other anti-hypertensive agents.
Patients on psychotropic drugs such as pheno-
thiazine and butyrophenone tranquilizers, antide-
pressants including tricyclics, monamine oxidase
inhibitors, lithium, fluoxetine (Prozac) and other
selective serotonin reuptake inhibitors (SSRI),
benzodiazepines, and antipsychotics are definitely
at greater risk of erectile dysfunction. An article
published by Rosen and others in 1999 reviews
sexual dysfunction problems associated with the
SSRIs [88]. In that article, they report an inciden-
ce of erectile dysfunction with fluoxetine of 1.7%,
with sertraline (100 mgm/day) of 2.5%, with
paroxetine (30 mgm/day) of 6.4%. An antidepres-
sant less likely to cause erectile dysfunction is tra-
zodone, however, there is a risk for priapism. This
agent could be considered as an alternate antide-
pressant drug when others produce the side effect
of erectile dysfunction [86]. In general, it is sug -
gested that antipsychotics with strong alpha-1
receptor affinity properties be considered as sub -
stitutes for other prescription psychotropic drugs
associated with erectile dysfunction.
Histamine-2-receptor antagonists have a high
risk for erectile dysfunction, particularly cimeti -
dine [85]. More modern anti-ulcer drugs do not
appear to present the same risk factor. Hormones
and enzymes affecting hormones, including estro-
gens, progesterone, corticosteroids, cyproterone
acetate, flutamide, finasteride, and gonadotropin-
releasing hormone agonists, as well as non-hor-
monal drugs such as spironolactone and ketocona-
zole, lower testosterone and therefore have a signi-
ficant risk factor for erectile dysfunction [57,86].
Digoxin may be associated with erectile dysfunc-
tion from a hormonal etiology, however, it has
been suggested that the underlying mechanism for
digoxin-associated impotence may be an inhibi-
tion of the Na+/K=-ATPase pump [57,86].
Life style related risk factors for erectile dysfunc-
tion include chronic alcoholism and chronic use of
marijuana, codeine, meperidine, methadone, and
heroin [57]. There was a recent case report when a
chronic alcoholic suffering from Vitamin B1 defi-
ciency had a reversal of his erectile dysfunction
two weeks after receiving 25mg of oral thiamine
daily [89].
8. S URGERY AND TRAUMA
Spinal cord injury patients obviously are at an
increased risk for erectile dysfunction with psy -
chogenic induced erection possible in those with
lower spinal cord injury and reflexogenic erec -
tion possible in those with upper cord injury.
40
Certain sports-related activities, such as bicycle
riding, gymnastics involving bars or projections on
gymnastic equipment, water ski and water jet ski
accidents, as well as football-related trauma may
cause site-specific blunt trauma to the perineum
which could lead to erectile dysfunction [90].
Reports from the same institution have also recent-
ly been in the lay press suggesting that the current
design of bicycle seats may be a source of chronic
injury to the perineum and therefore a risk factor
for erectile dysfunction. This has not been reported
in peer reviewed scientific literature as yet.
Surgery or trauma affecting any level of neuro -
logic control of erection or interfering with the
arterial supply to the corpora cavernosal tissue
are unquestionably risk factors for erectile dys -
function. This includes head trauma and brain
surgery. Spinal cord injury, lumbar disc surgery,
non-nerve sparing retroperitoneal lymph node dis-
section, and abdominal aneurysmectomy are all
risk factors for erectile dysfunction [57]. Pelvic
trauma and surgery (particularly radical bowel and
genitourinary cancer surgery) are obvious poten-
tial risk factors for erectile dysfunction. The use
of nerve-sparing surgery for radical genitourinary
cancer has increased in order to lessen the high
incidence of impotence previously reported from
this type of surgery. The variability of the reports
of successfully preserving sexual function with
nerve-sparing techniques has been well discussed
by Benet and Melman [57]. Radiation therapy for
prostate malignancy is a risk factor for erectile
dysfunction with delayed symptoms appearance
compared to the immediate presentation of symp-
toms seen with surgery [91]. Both membranous
urethral injury and surgical procedures designed to
repair the strictures resulting from such injury are
risk factors for erectile dysfunction. Transurethral
surgery for benign prostatic hyperplasia (TURP)
and stricture disease have been reported as minor
risk factors for erectile dysfunction. However, an
excellent prospective study done recently serious-
ly questions equating retrograde ejaculation with
erectile dysfunction [92].
DePalma recently reviewed the impact of vascular
surgery on impotence [93]. Aortic and aortoingui-
nal bypass surgery are procedures that carry a risk
for erectile dysfunction. Sixty percent of 23 men
obtained spontaneous erections in the author’s
own study [93].
9. THE EFFECT OF MODIFICATION OF RISK
FACTORS
Using data from the reassessment of a portion of
the population sampled in the original MMAS
study, an attempt was made to assess the effect of
modification of certain risk factors associated with
erectile dysfunction [94]. Until then, spontaneous
recovery seemed rare and occurred only in cases
with resolution or dramatic improvement of asso-
ciated medical or psychiatric diseases. After exclu-
ding men without erectile dysfunction, men trea-
ted for heart disease or diabetes, men with history
of prostate cancer and those with incomplete data
on risk factors, 593 men were identified for this
study. These men, who were free of moderate or
severe erectile dysfunction at baseline, were the
basis of the analysis of the effect of modifying risk
factors performed eight years later. Risk factors
studied were cigarette smoking, alcohol use, obe-
sity, and sedentary life style. The limitations of
this study are that only two time points were stu-
died and the small sample size within each catego-
ry of risk factor change.
The majority of these men exhibited healthy beha-
viors at baseline and follow-up. Half of the smo-
kers at baseline had quit and half of the heavy
drinkers had reduced their alcohol consumption.
Eighteen per cent of those obese at baseline had
lost weight and 55% of those sedentary were less
sedentary at follow-up. The results of this analysis
showed that a change in smoking status or change
in heavy drinking was not associated with decrea-
sed risk of erectile dysfunction. This analysis sug-
gests that smoking cessation or a change in alco-
hol consumption in middle age do not significant-
ly reduce the risk for erectile dysfunction. Men
obese at baseline appeared to have a higher inci-
dence of erectile dysfunction regardless of follow-
up status. This suggests that by the fifth and sixth
decade of life, the long-term pathophysiologic
effects of obesity are difficult to reverse. Sedenta -
ry behavior status was associated with developing
erectile dysfunction with the highest risk of dys -
function for those who remained sedentary. The
lowest level of risk for erectile dysfunction, for all
factors analyzed, was in those subjects who ini -
tiated physical activity after qualifying as seden -
tary at baseline. Increasing physical activity is
effective for reversing other cardiovascular
41
disease risk factors and this study seems to
demonstrate a similar benefit for developing
erectile dysfunction. Given the limitations of this
study, the findings highlight the need for future
longitudinal studies of preventable risk factors.
One important point of this study is that modi -
fiable risk factors may require earlier interven -
tion than middle age.
V. CONCLUSIONS
There is a difference in the reporting of erectile
dysfunction prevalence from the different
regions of the world. These differences are explai-
ned by a number of different reasons. First, there
is no standard adopted method for asking popu -
lations studied if and to what degree they have
erectile dysfunction. Groups studied have ranged
from patients seen in a clinical setting to random
population studies. The population studies had
varying degrees of success in the samples that
used questionnaires or skilled questioning during
face to face encounters. The perception of erecti -
le dysfunction depends on the surveyed popula -
tion’s understanding that their inability to obtain
an erection is a sexual problem and if it interferes
with their quality of life or satisfaction with their
sex life. Two American studies, rigorously adhe-
ring to established epidemiologic standards, sug-
gest that erectile dysfunction prevalence is higher
than previously reported in other studies, particu-
larly in the moderate and severe categories. Most
studies have shown an increase in the prevalen -
ce of erectile dysfunction with aging. Epidemio-
logic studies establishing incidence rates are parti-
cularly lacking in the literature. Longitudinal stu -
dies were almost non-existent until the recently
reported data from the Massachusetts Male
Aging Study. Data from other regions of the
world is sparse. This information could be impor -
tant in distinguishing cultural factors that may
play a role in prevalence and incidence of erecti -
le dysfunction. The data could also be utilized for
clarification of overlapping risk factors that may
vary greatly among different regions of the world.
Erectile dysfunction affects the quality of life for
any patient. Other male sexual dysfunction pro-
blems, such as premature ejaculation, do not have
the same impact on the person’s sex life and gene-
ral quality of life. Men who suffer from erectile
dysfunction, particularly if the condition is com -
plete or severe, are depressed by this condition.
Relationships with sexual partners are disrupted
and strained by this disorder.
There are clearly identified risk factors for erecti -
le dysfunction but the interaction and interplay of
one risk factor on another or clustering of risk
factors must be confirmed by more rigorous stu -
dies. Particularly relevant is the emerging eviden -
ce that erectile dysfunction and cardiovascular
disease are highly intertwined. Smoking or other
tobacco use compounds other risk factors associa-
ted with erectile dysfunction. Modification of cer-
tain risk factors, such as consumption of alcohol or
cigarette smoking, at a later age in life may not
result in a change in the erectile dysfunction but
may produce improvement in the erectile status of
the individual if addressed at an earlier age. Chro-
nic disease states, particularly diabetes mellitus, are
clear risk factors for erectile dysfunction. Other
chronic disease states may be independent risk fac-
tors for erectile dysfunction but an individual’s
general disability may be a component of the asso-
ciated erectile dysfunction rather than a direct risk
effect. Certain medications are clearly associated
with an increased prevalence of erectile dysfunc-
tion, particularly antihypertensives and psychotro-
pics. The effect of testosterone levels is a contro-
versial issue. Clearly established clinical hypogo-
nadism is associated as a risk factor for erectile dys-
function but the idea of andropause, a condition of
decreasing androgens with aging, is not an establi-
shed cause of erectile dysfunction, but may play a
role in fat deposition, loss of muscle and bone mass.
VI. RECOMMENDATIONS
1. S UBSTANTIVE RECOMMENDATIONS
a. To clarify the comparison of epidemiologic
studies of prevalence and incidence rates,
there is an immediate need to standardize
the definition of erectile dysfunction and to
include an allowance for degree and/or per-
sistence in that definition.
b. A meta-analysis, performed by an establi-
shed scientific body devoted to the study of
erectile dysfunction, of published and peer-
42
reviewed literature regarding the worldwide
prevalence of ED is imperative.
c. To establish the effect of a particular disease
on erectile dysfunction, it is necessary to
separate treated from untreated patients for
analysis of populations affected with the
given disease.
d. There are certain social and cultural bar-
riers hindering access to data for epidemilo-
gic analysis and/or medical care that must
be address to promote the relevance of erec-
tile dysfunction as a medical condition
worldwide.
e. There is a pressing need to study the presen-
ce of erectile dysfunction as a sentinel event
indicative of coronary artery disease.
2. M ETHODOLOGICAL RECOMMENDATIONS
a. Future epidemiological studies should:
• be community based and randomized
• be of significant size
• cover broad age groups (30 years to death)
• be longitudinal whenever possible so that
incidence data can be more clearly esta-
blished which will allow elucidation of
temporal relationships to diseases and
other risk factors.
b. Standardized questions for determination of
erectile dysfunction should be developed, at
least for epidemiologic surveys. ( See Appen-
dix D)
c. People who do not have access of health care
systems should be included in epidemiologic
surveys.
d. There is an immediate need for international
comparative studies.
 APPENDIX A
Sexual activity questions related to potency, from self-administered instrument included in MMAS. [6]
1. I N AN AVERAGE WEEK, HOW OFTEN DO YOU USUALLY HAVE SEXUAL INTERCOURSE OR ACTIVITY?
(Enter number in box)
2. D URING AN AVERAGE 24-HOUR DAY, HOW OFTEN DO YOU HAVE A FULL HARD ERECTION?

(Enter number in box)

3. DURING THE LAST 6 MONTHS HAVE YOU EVER HAD TROUBLE GETTING AN ERECTION BEFORE INTERCOURSE BEGINS?
a. No
b. Yes
c. Have not had sexual intercourse within last 6 months

4. D URING THE LAST 6 MONTHS HAVE YOU EVER HAD TROUBLE KEEPING AN ERECTION ONCE INTERCOURSE HAS BEGUN?
a. No
b. Yes
c. Have not had sexual intercourse within last 6 months

5. HOW FREQUENTLY DO YOU AWAKEN FROM SLEEP WITH A FULL ERECTION?

a. Daily
b. 2 or 3 times per week
c. Once a week
d. 2 or 3 times per month
e. Once a month
f. Less than once per month
g. Not at all within the last 6 months

6. HOW SATISFIED ARE YOU WITH YOUR SEX LIFE?

a. Extremely satisfied
b. Somewhat satisfied
c. Neither satisfied nor dissatisfied
d. Somewhat dissatisfied
e. Extremely dissatisfied

7. HOW SATISFIED ARE YOU WITH YOUR SEXUAL RELATIONSHIP WITH YOUR PRESENT PARTNER OR PARTNERS?
a. Extremely satisfied
b. Somewhat satisfied
c. Neither satisfied nor dissatisfied
d. Somewhat dissatisfied
e. Extremely dissatisfied

8. HOW SATISFIED DO YOU THINK YOU PARTNER(S) IS (ARE ) WITH YOUR SEXUAL RELATIONSHIP?
a. Extremely satisfied
b. Some satisfied
c. Neither satisfied nor dissatisfied
d. Somewhat dissatisfied
e. Extremely dissatisfied

9. HAS THE FREQUENCY OF YOUR SEXUALACTIVITY WITH A PARTNER BEEN:

a. as much as your desire?
b. less than you desire?
c. more than you desire?
43
 APPENDIX B
Description Of Variables
The variables used in the analysis of the NHSLS data were constructed using answers provided by respondents to the
questions present in the Appendix. For further information about the questionnaire, Laumann et al. (1994). [5]
DEMOGRAPHIC CHARACTERISTICS
Age : We grouped age into 10 year intervals, except for the youngest group, which was expanded to include respon-
dents below 20 years.
Marital status : We grouped respondents who were, at the time of the survey, divorced, separated from their spouse
or widowed.

Education : “What was the highest grade or year of schooling you completed?” The possible answers include: 8 th
grade or less, Some high school, Finished high school or equivalent, Vocational/trade/business school, Some college
or 2 year degree, Finished college, 4 to 5 year degree, Master’s degree or equivalent, and Other advanced degree.
We collapsed 8th grade or less with Some high school. Vocational/trade/business school was combined with Some
college or 2 year degree and combined all respondents with at least a four year college degree.
Race/ethnicity : Respondents who identified themselves as Hispanic were coded with this ethnicity rather than with
a racial category. Asian/Pacific Islander and Alaskan Native/Native American and Other were grouped into a single
category called Other.
Religion : The primary components of our religious classification are as follows: Mainline Protestant consists of
Methodists, Presbyterians, Lutherans, and Episcopalians. Conservative Protestant includes Baptists, Pentecostals,
and a number of smaller denominations. Other includes Jews, Greek Orthodox, Muslims, Hindus, Eastern religions,
and small Protestant groups and other religions.
RISK FACTORS
Drinks alcohol daily : “During the past 12 months, about how regularly did you drink alcoholic beverages?” Pos-
sible responses include Daily, Several times a week, Several times a month, Once a month or less, and Not at all. We
contrasted those answering with Daily against all the other categories.
STD ever : “There are several diseases or infections that are transmitted during sex. These are sometimes called
venereal diseases or VD. We will be using the term sexually transmitted disease or STDs. As I read each STD, tell
me whether you have ever been told by a doctor that you had it.” (Yes/No) If respondents answered Yes to any of
the following diseases, they were coded as having an STD: gonorrhea, syphilis, herpes, chlamydia, genital warts,
hepatitis, AIDS or HIV, pelvic inflammatory disease (women only), nongonococcal urethritis (men only), and any
other STD.
Urinary tract symptoms : “During the past 12 months, have you ever experienced any of the following symptoms:”
(Yes/No) If the respondents answered yes to any of the following: painful or difficult urination, painful intercour-
se, lesions or sores in the genital area, intense chronic itching of genital area, and vaginal discharge (women only).
Poor/Fair Health : “In general, would you say your health is. . .” Possible responses include Excellent, Good, Fair,
and Poor. We created a dichotomous variable, grouping Fair with Poor and Excellent with Good.
Circumcised – “Are you circumcised?” (Yes / No)
Emotional problems/stress : This dichotomous variable was constructed from two questions. “(A) During the past
12 months, how much of the time have emotional problems interfered with your sexual activities? (B) During the
past 12 months, how much of the time has stress or pressures in your life interfered with your sexual activities?” Pos-
sible answers for both questions include All of the time, Most of the time, Some of the time, A little of the time, and
None of the time. If respondents answered, All of the time, Most of the time or Some of the time to either question,
we indicated that the respondent suffered from emotional or stress related problems.
Household income : “Compare your total household income from all sources in 1991 with your total household
income four years ago (in 1988).” Possible answers include: Risen a lot (e.g. by 20% or more), Risen somewhat,
Remained about the same, Fallen somewhat, Fallen a lot (e.g. by 20% or more). We grouped Risen a lot with Risen
somewhat and Remained about the same with Fallen somewhat.

44
Liberal attitudes toward sex : Respondents were asked whether they Strongly agree, Agree, Disagree or Strongly
Disagree with three statements. “(A) Any kind of sexual activity between adults is okay as long as both persons free-
ly agree to it. (B) I would not have sex with someone unless I was in love with them. (C) My religious beliefs have
shaped and guided my sexual behavior.” The responses of (A) were reversed and then (A), (B), and (C) were ave-
raged. We then dichotomized the average response.
5 or more lifetime partners – See Laumman et al. (1994) [5.]for the variable Page 18.
Sex frequency less than monthly : “ About how often did you have sex during the past 12 months?” Responses
include Not at all, Once or twice, About once a month, Two or three times a month, About once a week, Two or three
times a week and Four or more times a week. We dichotomized this variable by grouping Not at all and Once or twice
with About once a month and then collapsed the remaining categories together.
Thinks about sex less than weekly : “On the average, how often do you think about sex?” Possible answers inclu-
de More than once a day, Everyday, Several times a week, Once a week, 2-3 times a month, Once a month, Every
other month, 3-5 times a year, 1-2 times a year, and 0 times this year. We grouped Every other month, 3-5 times per
year, 1-2 times per year, and 0 times this year together and then collapsed the remaining categories.
Masturbation more than monthly : “On average, in the past 12 months, how often did you masturbate? “ Possible
answers include More than once a day, Everyday, Several times a week, Once a week, 2-3 times a month, Once a
month, Every other month, 3-5 times a year 1-2 times a year and 0 times this year. We grouped Every other month,
3-5 times a year, 1-2 times a year and 0 times this year together and then collapsed the remaining categories.
Any same sex activity ever : For male respondents, if they answered Yes to any of the following questions “(A) Have
you ever performed oral sex on a man? (B) Has a man ever performed oral sex on you? (C) Have you ever had anal
intercourse with a man where you were the inserting partner? (D) Have you ever had anal intercourse with a man
where you were the receiving partner? (E) Have you ever done anything else sexual with a man? “ (YES / NO)
For female respondents, if they answered Yes to any of the following questions: “(A) Have you ever performed oral
sex on a woman? (B) Has a woman ever performed oral sex on you? (C) Have your every done anything else sexual
with another woman?” (YES / NO)
Abortion ever : For women, “Have you ever had an abortion?” (YES / NO)
For men, “Have you ever had a sexual partner who became pregnant by you and ended that
pregnancy by abortion?“ (YES / NO)
Sexually harassed ever : “Sometimes at work women (men) find themselves the object of sexual advances, propo-
sitions, or unwanted sexual discussions from co-workers or supervisors. The advances sometimes involve physical
contact and sometimes just involve sexual conversations. Has this ever happened to you?” (YES / NO)
Forced a woman ever : “Have you ever forced a woman to do something sexual that she did
not want to do? “ (YES / NO)
Forced by a man ever : “Have you ever been forced by a man to do something that you
did not want to do? “ (YES / NO)
Sexually touched before puberty : “Before your were (age of puberty, or if respondent doesn’t know
12 or 13 years old), did anyone touch you sexually? “ (YES / NO)
QUALITY OF LIFE CONCOMITANTS
Low physical satisfaction : “How physically pleasurable did you find your relationship with (PARTNER) to be? “
Possible answers include Extremely, Very, Moderately, Slightly, and Not at all. We dichotomized this variable by
grouping Extremely and Very together and collapsing the remaining variables.
Low emotional satisfaction : “How emotionally satisfying did you find your relationship with (PARTNER) to be? “
Possible answers include Extremely, Very, Moderately, Slightly and Not at all. We dichotomized this variable by
grouping Extremely and Very together and collapsing the remaining variables.
Low general happiness : “Generally, how happy have you been with your personal life during the past 12 months?”
Possible answers include: Extremely happy, Very happy most of the time, Generally satisfied, pleased, Sometimes
fairly unhappy, and Unhappy most of the time. We grouped Sometimes fairly unhappy and Unhappy most of the
time and collapsed the remaining categories.
HELP-SEEKING BEHAVIOR
Seeking medical help : “Sometimes people have problems like this, they go to someone for help such as a doctor
or a counselor of some sort. In the past 12 months, have you gone to any of the following people for help with the
sexual problem(s) you have experienced: a private psychiatrist or psychologist, a psychiatrist or psychologist in a
clinic, another type of private doctor, or another type of doctor in a clinic?” (YES / NO)

45
 APPENDIX C
Latent Class Analysis

This appendix provides a brief overview of LCA, its application to NHSLS symptom data, and the results of our ana-
lysis. Our information regarding LCAis abridged and focuses on its applicability to sexual dysfunctions. For an in-
depth description of latent class model, see Rehm et al. (1995) [95] or McCuthcheon (1987). [24]
THE LATENT CLASS MODEL
The latent class model (LCM) is a statistical method that tests whether a set of mutually exclusive latent classes
accounts for observed association in a cross-classification of manifest, categorical variables. A central assumption
in the LCM is local independence. In short, this assumption means that a T-class solution should explain all the asso-
ciations between manifest variables, making them statistically independent of one another. Let variables A, B,. . .,E
denote observed, categorical variables that take values i, j, . . ., m, respectively, and let variable X denote a T-class
latent variable. The general form of the latent class model states:

Where the left term indicated the probability that a randomly selected case will be located in the I, j, . . ., m cell for
the t th latent class. The final term indicates the probability than an individual will be in class t of latent variable X.
The remaining terms denote the probabilities than an individual in class t of latent variable X will be located at level
i, j, …, m of variables A, B, …, E, respectively.
A number of researchers have noted the utility of LCA in medical diagnosis. Applications of LCAhave focused on
rater agreement on diagnostic criteria, validation of diagnostic indicators, and the generation of epidemiological esti-
mated using symptom data.
Table c1: Latent classes and conditional probabilities of sexual dysfunction

WOMEN NO LOW AROUSAL SEXUAL

LATENT CLASS PROBLEMS DESIRE DISORDER PAIN
LC Probability 0.58 0.22 0.14 0.07
Conditional probabilities of symptoms
Lacked interest 0.04 0.74 0.83 0.19
Unable to orgasm 0.05 0.49 0.84 0.04
Pain during sex 0.03 0.07 0.56 0.63
Sex not pleasurable 0.01 0.38 0.80 0.36
Anxious about performance 0.04 0.12 0.40 0.29
Trouble lubricating 0.08 0.16 0.63 0.50

MEN NO PREMATURE ERECTILE LOW

LATENT CLASS PROBLEMS EJACULATION DYSFUNCTION DESIRE
LC probability 0.70 0.21 0.05 0.05
Conditional probabilities of symptoms
Lacked interest 0.04 0.16 0.64 1.00
Unable to orgasm 0.00 0.10 0.71 0.37
Climax too early 0.16 0.68 0.60 0.38
Sex not pleasurable 0.00 0.17 0.51 0.41
Anxious about performance 0.03 0.49 0.75 0.31
Trouble maintaining erection 0.01 0.24 0.97 0.00

Source: National Health and Social Life Survey

LCA excluded the climax too early item for women and the pain item for men in order to avoid sparse data problems.

46
RESULTS OF LCA
Table C.1 shows latent class and conditional probabilities for the best fitting models and indicates the prevalence of
a category of sexual dysfunction and the likelihood that a class member will exhibit a given symptom.
The procedures used to generate our final latent class models consisted of three stages: (1) selection and cross-clas-
sification of manifest variables, (2) generation of best-fitting models, and (3) assignment of individual cases to latent
classes. For both women and men, we used six manifest, dichotomous variables generating a corresponding cross-
classification table with 26 = 64 cells. The mean frequency of women per cell is 23.2, and for men this figure is
19.7. For each sex, we excluded one symptom variable: orgasm too early for women and pain with sex for men. This
is justified based on partly theoretical and partly empirical grounds. Both of these symptoms are the least prevalent
for each respective gender and are not considered critical symptoms of sexual dysfunction. If we included these
variables in our analysis, it would have dropped our mean frequency per cell counts to 11.6 for women and 9.8 for
men. Using all seven symptoms caused a number of cells with a frequency of 0 which generated sparse data pro-
blems in our analysis. One important implication of this strategy is that women and men are not completely com-
parable since they match on only five of the six indicators.
Next, we generated a series of models for women and men. Typically, goodness of fit tests utilize df calculations that
are reclaimed when conditional probabilities are found to be zero or one. However, while this is a convenient stra-
tegy, it is not, strictly speaking, correct. Instead, we performed goodness of fit tests that did not reclaim df. As shown
in Table C.2, the best fitting model for women was the four-class model. Although the five-class model misalloca-
ted fewer cases (2.6% versus 3.4%), it is not as parsimonious, so we decided to go with the four-class model.

Table C 2: Fit statistics for latent class models of female dysfunction

NUMBER OF LATENT CLASSES LIKELIHOOD- INDEX OF
RATIO X 2 DF P VALUE DISSIMILARITY
One-class model 1256.44
Two-class model 145.79 50 0.000 0.079
Three-class model 92.23 43 0.000 0.059
Four-class model 45.76 36 0.128 0.034
Five-class model 34.89 29 0.208 0.026
Four vs. Five 10.87 7 0.144 0.008
The best fitting model for men was also a four-class solution. Here, the five-class solution did not have any advan -
tages over the four-class, and the latter was the most parsimonious model. Table B.3 shows these results.

Table C 3: Fit statistics for latent class models of male dysfunction

NUMBER OF LATENT CLASSES LIKELIHOOD- INDEX OF
RATIO X 2 DF P VALUE DISSIMILARITY

One-class model 77.36

Two-class model 114.17 50 0.000 0.066
Three-class model 76.42 43 0.001 0.045
Four-class model 42.09 36 0.224 0.032
Five-class model 31.53 29 0.341 0.032
Four vs. Five 10.57 7 0.159 0.000
Finally, in assigning individual cases to the latent classes, the procedure correctly allocated 84.8% of the women and
87.1% of the men.

47

APPENDIX D
Global Question for Self-Rating of ED
IMPOTENCE means being able to get and keep an
erection that is rigid enough for satisfactory sexual
activity. How would you describe yourself?
(Circle one letter)
A) NOT IMPOTENT:
always able to get and keep an erection good
enough for sexual intercourse
B)MINIMALLY IMPOTENT:
usually able to get and keep an erection good
enough for sexual intercourse
C)MODERATELY IMPOTENT:
sometimes able to get and keep an erection good
enough for sexual intercourse
D)COMPLETELY IMPOTENT:
never able to get and keep an erection good
enough for sexual intercourse
Submitted by JB McKinlay
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______________________
52
 Committee 2

Economical Aspects of
Erectile Dysfunction

Chairman
R. SHABSIGH

Members
L. ALEXANDRE,
H. BAY NIELSEN,
J. FITZPATRICK,
H. MELCHIOR

53
 CONTENTS

I. INTRODUCTION V. THE EMERGING GUIDELINES

II. THE ECONOMIC SIGNIFICANCE
OF THE EPIDEMIOLOGY OF ED
III. THE IMPACT OF ED ON
QUALITY OF LIFE AND
RELATIONSHIP AND ITS
ECONOMIC SIGNIFICANCE
IV. UTILIZATION OF HEALTH CARE
SERVICES AND THERAPIES FOR ED
1. RECENT INCREASE IN THE UTILIZATION OF
ED TREATMENTS
2. IMPACT OF INTRODUCTION OF ORAL
THERAPY
3. PENILE IMPLANTS
4. VACUUM CONSTRICTION DEVICES
5. ALTERNATIVE MEDICINE
FOR THE DIAGNOSTIC EVALUA-
TION AND TREATMENT OF ED AND
THEIR ECONOMIC SIGNIFICANCE
VI. INCREASED EXPENDITURE OF
THE INDUSTRY ON R&D IN ED
VII. THE ACCUMULATIVE ECONO-
MIC IMPACT OF ED ON SOCIETY,
PATIENTS, HEALTH CARE
PROVIDERS, INSURANCE,
INDUSTRY, ACADEMIA, ETC
VIII. THE UNKNOWNS ABOUT THE
ECONOMIC IMPACT OF ED
IX. CONCLUSIONS
X. RECOMMENDATIONS
XI. ACKNOWLEDGEMENTS

6. REIMBURSEMENT
REFERENCES
7. ED MANAGEMENT COST IN THE UK

54
 Economical Aspects of
Erectile Dysfunction
R.SHABSIGH,
L. ALEXANDRE, H. BAY NIELSEN, J. FITZPATRICK, H. MELCHIOR
I. INTRODUCTION
A brief introduction into the general principles of
economics is helpful. The study of the economics
of a certain medical condition may be performed
in different steps or levels. These steps include:
descriptive economics, analytic economics and
interventional economics. The first and most fun-
damental step is descriptive economics. At this
level the condition under study, i.e. ED is defined.
The definition is very important because it permits
accurate identification of the human subjects, i.e.
patients (or in some economic terms consumers).
In addition to definition, the epidemiology of ED
is an indispensable part of this level of the study of
economics. Descriptive data are collected and
summed. The next step is analytic economics,
where data are analyzed for recognition of trends,
correlations, predictors and other statistical indica-
tors. This analysis usually leads to the understan-
ding of consumer/market behavior and the identi-
fication of factors influencing such behavior. At
this step models and hypotheses are created and
theories may emerge. The most advanced step in
the study of economics is planning an intervention
and investigating the consumer/market response.
This chapter on the economics of ED at the first
international consultation on ED, is limited most-
ly to descriptive and to a lesser extent to analytic
economics.
II. THE ECONOMIC SIGNIFICANCE
OF THE EPIDEMIOLOGY OF ED
Health care providers, economic planners and the
public are concerned about the economic impact
of the development of efficacious and safe phar-
55
macotherapy for erectile dysfunction including
oral medications. The answer to this important
question lies in the understanding of the epide-
miological and medico-economic factors related
to erectile dysfunction. Four facts have been
repeatedly demonstrated: erectile dysfunction is
highly prevalent; its incidence is age-related, it is
a progressive condition, and it is currently signi-
ficantly undertreated. The Massachusetts Male
Aging Study (MMAS) suggests the number of
men in the USA with erectile dysfunction to be 10-
20 million [1]. Inclusion of patients with partial
erectile dysfunction may increase the estimate to
30 million [1]. Erectile dysfunction has been
found to be associated with age [1-4]. Data on see-
king medical help for erectile dysfunction reveals
that erectile dysfunction is undertreated [5]. It is
estimated approximately 15% of patients with
erectile dysfunction might ultimately seek treat-
ment annually. In one study, 50% of patients with
erectile dysfunction refused evaluation and treat-
ment [3]. This data underscores the fact that erec-
tile dysfunction is undertreated.
The data from the MMAS showed that ED was not
only age related but also suggested that ED was a
progressive condition (fig. 1). New data from a
follow up study of the MMAS showed that in the
USA approximately 921,000 new ED cases are
expected annually [6]. The population growth
compounded by the population aging will clearly
result in acceleratingly increasing number of men
with erectile dysfunction. The introduction of new
oral medications and the intensified public aware-
ness and education will result in a higher rate of
seeking and utilizing treatment. The combined
effects of population growth (fig. 2) and aging
(fig. 3, 4) with the increased utilization of treat-
ment will simply lead to a larger patient base.
Such a larger patient base will naturally include all
levels of severity of erectile dysfunction. Erectile
dysfunction has evolved to follow a step-care
health delivery model. Oral therapy has become
the first line treatment. Intracavernous injection
therapy and intraurethral therapy have become
second line treatment and penile implants have
become a third line treatment. Vacuum constric-
tion devices can be used at any step of the process.
Hormonal therapy and penile revascularization are
indicated in a small number of patients with speci-
fic requirements. Sex therapy can be utilized alone
in specific cases or as an adjunct in other cases.
III. THE IMPACT OF ED ON
QUALITY OF LIFE AND RELATION-
SHIP AND ITS ECONOMIC
SIGNIFICANCE
The economic impact of a disease or a medical
condition is not only limited to the cost of diagno-
sis and treatment. Medico-economic analysis has
been used to determine other economic impact of
a disease or a medical condition on society. Such
impact may include lost time at work, decreased
productivity, effect on partner, wife, family and
coworkers. Erectile dysfunction has many corre-
lates with known high economic impact such as
atherosclerosis, myocardial infarction, hyperten-
sion and diabetes. However, it should be clear that
it is not ED that causes these conditions, nor does
it worsen them. Nevertheless, depression and rela-
tionship issues might well be negatively affected
by ED and consequently have a negative econo-
mic impact. The MMAS has shown that ED was
highly correlated with depression. Another study
comparing patients presenting with ED alone,
BPH alone and ED + BPH showed that the inci-
dence of ED was twice as high in those with ED
alone or ED + BPH as compared to BPH alone
(fig. 5) [7]. A recently completed multicenter cli-
nical trial on the treatment of ED in patients with
ED and comorbid depressive symptoms (fig. 6)
showed that improvement of erectile function in
men with ED who responded to treatment was
associated with a significant improvement in their
symptoms of depression. Results from this study
also showed that successful treatment of ED with
sildenafil significantly improved 5 out of 8 gene-
ral quality of life parameters. One could hypothize
56
that the improvement of symptoms of depression
and the positive effect on quality of life of the suc-
cessful treatment of ED, may ultimately result in a
positive economic effect. Such hypothesis defini-
tely justifies further socio-economic research.
IV. UTILIZATION OF HEALTH CARE
SERVICES AND THERAPIES FOR ED
1. RECENT INCREASE IN THE UTILIZATION OF
ED TREATMENTS:
Comparing the number of prescriptions and the
drug sales of 1995 with 1998 shows very clearly
that the utilization of treatment increased dramati-
cally in such a short time (fig. 7 and 8) [8]. During
this short period the number of total prescription
grew 650% and the ED drug sales grew 3,127%.
This increase is an indisputable evidence that ED
has been an undertreated medical condition with a
big room for expansion in utilization of therapies.
The growth in the utilization of drug therapy for
ED was not only in the USA but similarly world-
wide (fig. 9). Just in 1 year between 1997 and
1998, the world wide ED drug sales increased
187%. With the exception of Japan, all world
regions experienced significant increases in the
utilization of drug therapy for ED (fig. 10). These
increases ranged from a low of 147% in Asia to
344% in the USA. The main driver for the growth
in drug therapy has been the development and
registration of new safe and efficacious drugs.
Tracking the number of prescriptions (fig 11) and
the drug sales (fig. 12) from 1995 to 1999 in the
USA clearly shows that the introduction of new
drugs increased the number of total prescriptions
and new prescriptions, consequently increasing
drug sales. Aside from major «blips» prescriptions
are stable at approximately 300,000 new
Rx/month and 800,000 total Rx/month. Drug sales
are stable at approximately $ 55,000,000.
2. IMPACT OF INTRODUCTION OF ORAL THERAPY
The strongest impact was the introduction of oral
therapy, i.e. sildenafil (Viagra). Indeed, between
1995 and 1998 there was a major shift toward oral
therapy with this new drug (fig. 13-15). Current-
ly, oral drugs make up the highest percentage of
number of prescriptions as well as drug sales (fig.
16 and 17). In 1995, oral drug sales (Yohimbine)
Figure 1: MMAS Erectile dysfunction is highly prevalent, Figure 2: Growth of the male population of the world
age-related and progressive.

Figure 3: Increase in average male life expectancy of the Figure 4: Aging of the male population of the world
world

Figure 5: Erectile dysfunction is associated with increased Figure 6: Successful treatment of ED improves comorbid
incidence of depression depressive symptoms

57
Figure 7: Increased number of prescriptions for ED bet- Figure 8: Increased ED drug sales between 1995 and 1998
ween 1995 and 1998 in USA in USA

Figure 9: Increased ED drug sales between 1997 and 1998 Figure 10: Increased ED drug sales between 1997 and 1998
worldwide in the various regions of the world

Figure 11: Effect of introduction of new drugs on number Figure 12: Effect of introduction of new drugs on ED drug
of prescriptions for ED in USA sales USA

58
Figure 13: Change in type of ED treatment in the past 4 Figure 14: Change in type of ED treatment in the past 4
years in USA years in USA

Figure 15: Change in type of ED treatment in the past 4 Figure 16: Oral drugs make up the highest percentage of
years in USA number of prescriptions and drug sales for ED in the USA

Figure 17: Oral drugs make up the highest percentage of

number of prescriptions and drug sales for ED in the USA

59
constituted 68.7% of the total ED drug sales. In
1998, oral drug sales (mostly Viagra with some
Yohimbine) constituted 82% of the total ED drug
sales in the USA. This trend was also evident in
other regions of the world (fig. 18-23).
3. PENILE IMPLANTS
Although penile implants decreased in the past 4
years, this trend appears to have stabilized (fig.
24).
4. VACUUM CONSTRICTION DEVICES
Although vacuum devices decreased in the past 2
years, this trend appears to have stabilized (fig.
25).
5. ALTERNATIVE MEDICINE
Use of alternative medicine for treatment of ED
has been known for a long time all over the world.
This may include herbs, acupuncture, etc. The
economic impact of alternative medicine for ED is
not known.
6. REIMBURSEMENT
Reimbursement of drug cost by insurance is still in
transition. Many insurance companies and even
governmental agencies are passing through confu-
sion as to what is reasonable in reimbursement of
drug cost. Concern about uncontrollable high costs
is always present. In the USA the majority of
patients pay cash for ED oral drug therapy with
Viagra (fig. 26).
7. ED MANAGEMENT COST IN THE UK
An attempt at studying the annual cost of ED to
the United Kingdom Society was recently under-
taken [9]. In 1997/98 a total of 113,000 patients
sought treatment in approximately 390,000 visits
(fig. 27). The annual total National Health Service
cost of managing ED was £43.9 million in
1997/98 (fig. 28). The burden was sensitive to the
number of outpatient visits and to a lesser extent
the number of prescriptions. The burden was
insensitive to the number of GP visits. It must be
qualified that the UK situation is unique and that
this data was prior to the introduction of sildenafil
60
(Viagra).
V. THE EMERGING GUIDELINES
FOR THE DIAGNOSTIC EVALUA-
TION AND TREATMENT OF ED AND
THEIR ECONOMIC SIGNIFICANCE
The introduction of oral therapy had a great impact
on the practice of ED, changing the pattern of
health care delivery from specialty to primary
care. Consequently, this changed the diagnostic
and therapeutic algorithm and resulted in develop-
ment of practice guidelines. One of such practice
guidelines is the process of care in the USA [10].
In addition, there are also guideline initiatives in
Europe and other regions of the world. These gui-
delines will directly and indirectly affect the eco-
nomics of ED.
The introduction of oral drug therapy has resul-
ted in a shift toward primary care at least in the
initial management of ED. This is evident in the
percentage of sildenafil (Viagra) prescriptions by
prescriber (fig 29). The step-care model of health
care delivery is becoming rapidly established in
ED with the majority of initial management by
primary care physicians and selective advanced
management by specialists. The economic signifi-
cance of such changes in health care delivery are
obvious.
VI. INCREASED EXPENDITURE OF
THE INDUSTRY ON R&D IN ED
It is very evident that the pharmaceutical industry
has dramatically increased its expenditure on
research and development of drugs for the treat-
ment of ED. This increase is driven by the fact that
ED has been an undertreated condition and also by
the fact that the first oral drug sildenafil (Viagra)
has been very successful. The next few years are
expected to witness the introduction of a number
of new oral drugs. Exact numbers of the pharma-
ceutical R&D expenditure are not available at the
Figure 18: Change in type of ED treatment from 1997 to Figure 19: Change in type of ED treatment in the past 4
1998 in the various regions of the world years in the various regions of the world

Figure 20: Change in type of ED treatment in the past 4 Figure 21: Change in type of ED treatment in the past 4
years in the various regions of the world years in the various regions of the world

Figure 22: Change in type of ED treatment in the past 4 Figure 23: Change in type of ED treatment in the past 4
years in the various regions of the world years in the various regions of the world

61
Figure 24: Worldwide change in penile implants Figure 25: Worldwide change in vacuum devices

Figure 26: Reimbursement for sildenafil (Viagra) in the Figure 27: ED annual cost to UK society 1997/98
USA

Figure 28: ED annual cost to UK society 1997/98 (cont) Figure 29: Sildenafil (Viagra) prescriptions by prescriber

62
time of the preparation of this report.
VII. THE ACCUMULATIVE ECONO-
MIC IMPACT OF ED ON SOCIETY,
PATIENTS, HEALTH CARE
PROVIDERS, INSURANCE,
INDUSTRY, ACADEMIA, ETC
Medico-economic analysts have taken a strong
interest in the projections of the ED industry or
market. One such analysis predicts that, within 4
years, the ED industry will grow more than 4
times reaching almost 5 billion dollars worldwide
Figure 30: World wide projections of ED industry 1998 to
2002.
(fig 30) [11].
VIII. THE UNKNOWNS ABOUT THE
ECONOMIC IMPACT OF ED
There are known epidemiologic data about the
prevalence and incidence of ED. However, there
are many unknown factors that contribute to the
inability to accurately measure or predict some of
the aspects of the economic impact of ED. These
include the following questions. How much will
the rate of utilization of treatment increase with
the introduction of new treatments? How long will
patients use treatment? What will the long term
drop out rate of the new oral therapies be? How
many patients will progress in the treatment algo-
rithm through the step-care model from the least
invasive treatments to more invasive treatments?
What is the negative economic impact of depressi-
63
ve symptoms and decreased quality of life asso-
ciated with ED? What is the positive economic
impact of improved depressive symptoms and
improved quality of life and relationship with the
successful treatment of ED? How justifiable, vis-
à-vis affordable are future drug combinations?
IX. CONCLUSIONS
Available limited data suggests that the economic
impact of ED has increased significantly in the past
4 years. The reasons for this increase are: increase
of patient base of this undertreated condition; intro-
duction of new drug therapies; introduction of oral
therapy; increased awareness and education. This
increasing economic impact is expected to accele-
rate with the growth and aging of the male popula-
tion of the world. There are still many unknown
important issues in the economics of ED.
X. RECOMMENDATIONS
Further extensive research is recommended
to determine the various components of the
economic impact of ED and its treatments on
groups and society. Studies should be not
only cross-sectional but also longitudinal
because of the accumulative impact of ED
and the unknown long term issues such as
drop out rates. Cost-efficacy considerations
may help in refining ED management algo-
rithms. Drug combination and drug compa-
rative studies might shed light not only on
the efficacy and safety of therapy, but also
might help in avoiding unnecessarily expen-
sive and ineffective combinations. Reaso-
nable insurance reimbursement guidelines
need to be developed.
REFERENCES
1. FELDMAN, H.A., GOLDSTEIN, I., HATZICHRISOU,
D.G., et al: Impotence and its medical and psychological
correlates: results of the Massachusetts male aging
study. J. Urol., 151: 54, 1994.
2. NIH Consensus Development Panel on Impotence.
 Impotence. JAMA; 270:83-90, 1993. 11. S G COWEN: Therapeutic Categories Outlook 3/99.
3. SLAG, M.F., MORLEY, J.E., ELSON, M.K., et al:
Impotence in medical clinic outpatients. JAMA,
249:1736, 1983.
XI. ACKNOWLEDGEMENTS
4. MULLIGAN, T., RETCHIN, S.M., CHINCHILLI,
V.M., & BETTINGER, C.B.: The role of aging and The chairman of the committee on economical
chronic disease in sexual dysfunction. JAGS, 36: 520- aspects of ED wishes to extend acknowledgement
524, 1988.
and appreciation to the following individuals,
5. SHABSIGH, R.: Editorial: Impotence on the rise as a
companies and institutions for their contribution to
urologic subspecialty. J. Urol., 155: 924-925, 1996.
this chapter in form of data and/or advice:
6. JOHANNES, C.B., ARAUJO, A.B., FELDMAN, H.A.,
et al: IJIR, 10: S55, 1998 abstract in supplement.
7. SHABSIGH, R. KLEIN, L., SEIDMAN, S., KAPLAN,
STEVE POMERANTZ
S.A., LERHOFF, B., & RITTER, J.: High incidence of Pfizer, Inc
depressive symptoms is associated with erectile dys-
function. Urol. 52: 848-852, 1998.
KENT SUMMERS
Lilly Corporation
8. IMS prescription tracking data 1999.
9. Schwarz Pharma, data on file 1999. AMBER FENSOM
10. R. ROSEN, I. GOLDSTEIN, J. HEIMAN, S. KOREN- Schwarz Pharma
MAN, M. LAKIN, T. LUE, D.K. MONTAGUE, H.
PADMA-NATHAN, R. SADOVSKY, R.T. LEON YAFFE
SEGRAVES, R. SHABSIGH: The process of care DOUGLAS TRAPP
model for evaluation and treatment of erectile dysfunc-
tion. IJIR, 11: 59-74, 1999.

64
 Committee 3

Anatomy, Physiology and Pathophysiology

of Erectile Function

Chairman
I. SAENZ DE TEJADA

Members
N. GONZALEZ CADAVID,
J. HEATON,
H. HEDLUND,
A. NEHRA,
R.S. P ICKARD,
U. SIMONSEN,
W. STEERS

65
 CONTENTS

A. ANATOMY C. PATHOPHYSILOGY OF
ERECTILE DYSFUNCTION

B. PHYSIOLOGIC REGULA- I. NEUROGENIC ERECTILE

DYSFUNCTION
TION OF PENILE SMOOTH
MUSCLE CONTRACTILITY 1. THE ETIOLOGIES OF NEuROGENIC ED CAN
BE CLASSIFIED AS:

I. PENILE SMOOTH MUSCLE 2. ERECTILE DYSFUNCTION IN SPINAL CORD

CONTRACTION INJURY
3. ERECTILE DYSFUNCTION AFTER RADICAL
PELVIC SURGERY
II. PENILE SMOOTH MUSCLE
RELAXATION II. VASCULAR ED
1. ROLE OF NITRIC OXIDE AND THE CGMP 1. ED IN ATHEROSCLEROSIS AND HYPERCHO-
PATHWAY LESTEROLEMIA
2. THE CAMP PATHWAY 2. ED IN HYPERTENSION
3. RELAXATION THROUGH HYPERPOLARIZA- 3. PELVIC/PERINEAL TRAUMA
TION OF THE MUSCULAR CELL 4. DIABETES

III. REGULATION OF THE III. ED IN END-STAGE RENAL

BALANCE BETWEEN THE DISEASE (ESRD)
DILATOR AND CONSTRICTOR
MECHANISMS
IV. PRIMARY ERECTILE
1. REGULATION OF THE ADRENERGIC ACTIVI- DYSFUNCTION
TY BY PROSTANOIDS

2. ADRENERGIC REGULATION OF NANC V. DRUG INDUCED IMPOTENCE

NERVES

3. MOLECULAR OXYGEN AS A MODULATOR REFERENCES

OF PENILE ERECTION

66
 Anatomy, Physiology and Pathophysiology
of Erectile Function
I. SAENZ DE TEJADA
N. GONZALEZ CADAVID, J. HEATON, H. HEDLUND, A. NEHRA, R.S. PICKARD,
U. SIMONSEN, W. STEERS
A. ANATOMY
The average length of the human male pendulous
penis is 8.8 cm flaccid, 12.4 cm stretched and 12.9
cm erect with neither patient age nor size of the
flaccid penis accurately predicting erectile length
[1]. In another study, erect penile length varied
from 10-20 cm with an erect thickness of 3-5 cm
[2]. The penis is composed of three bodies of erec-
tile tissue; the corpus spongiosum, encompassing
the urethra and terminating in the glans penis; and
the two corpora cavernosa which function as
blood-filled capacitors; providing structure to the
erect organ [3-5]. In this section we will discuss
the anatomical composition of the three erectile
tissues of the penis, the nerve and blood supply
and the connective tissue and fascia which toge-
ther make up the intact penis.
The corpora cavernosa are a unique vascular bed
consisting of sinuses (the trabeculae) whose arte-
rial blood supply arises from the resistance helici-
ne arteries (figure 1); which in turn are fed from
the deep penile cavernosal artery [3-5]. The trabe-
culae are drained by the subtunical venules that
coalesce to form the emissary veins which in turn
communicate with the cavernosal veins (figure 2).
The penile arterial and venous supply are discus-
sed in greater detail below. The lacunae have mea-
sured blood PO2 of 20-40 mmHg when the penis
is in the flaccid state [6-8]. This venous-like flac-
cid blood PO2 increases upon erection with dila-
tion of the helicine arteries to 90-100 mmHg, [6]
and these changes in oxygen tension directly
impact both the physiologic function and trabecu-
lar structure of the corpora cavernosa (see patho-
physiology section) [9-10]. Histologically, the
corpora are composed primarily of trabecular
smooth muscle (40%-50%) and connective tissue
67
(~50%-45%) with endothelium, fibroblasts, and
nerves [3-5,9]. The corpora are separated in the
pendulous penis by an incomplete septum and
proximally separate into two individual corpora,
terminating in the paired crura which directly atta-
ch to the ischiopubic ramus. This latter structure is
particularly susceptible to pelvic trauma1 [11] and
x-radiation during wide beam therapy for prostate
cancer (see iatrogenic causes of erectile dysfunc-
tion) [12]. Crural leakage can result in a dysfunc-
tional veno-occlusive mechanism and erectile dys-
function [11].
The tunica albuginea is a multilayered structure
of inner circular and outer longitudinal layers of
connective tissue encompassing the paired corpo-
ra cavernosa [13-15]. An incomplete septum sepa-
rates the two corpora cavernosa and anchors into
the circular inner layer of the tunica albuginea. In
the distal pendulous penis, intracavernous pillars
anchor the tunica across the corpora cavernosa at
the two- and six-o’clock positions with minor
struts branching off these pillars at the five- and
seven-o’clock positions [15]. It has been demons-
trated that tunical thickness varies from 1.5 to
3 mm thick depending on the circular position
around the tunica [13-15]. The longitudinal outer
layer which provides strength to the tunica albugi-
nea is absent at the six-o’clock position where the
corpus spongiosum fits in the indentation between
the two corpora cavernosa [15]. It has been pro-
posed that this design allows unrestricted expan-
sion of the corpus spongiosum so that ejaculation
is unimpeded during penile erection [15]. The lon-
gitudinal layer is also thinnest at the three- and
nine-o’clock positions, consistent with the greatest
number of traumatic penile fractures in those posi-
tions [14]. The tunica albuginea is composed of
fibrillar (mainly type I but also type III) collagen
in organized arrays interlaced with elastin fibers
[15]. While collagen has a greater tensile strength
Figure 1: Scanning electron microscopic study of a cast of penile microcirculation. It shows an helicine artery opening direct-
ly into a lacunar space. Helicine arteries regulate the amount of blood entering into the lacunar spaces acting as resistance
vessels. After the proper stimulus, the muscle surrounding the artery relaxes, increasing the blood flow and pressure delivered
to the lacunar spaces. (Courtesy of Dr. Yoshiaki Banya).

Figure 2: Scanning electron microscopic study of the venous system of the corpus. A dense plexus of venules that drain the
lacunar spaces can be seen beneath the tunica albuginea. This veins coalesce to form the emissary veins. (Courtesy of Dr.
Yoshiaki Banya).

68
than steel, it is unyielding. In contrast, elastin can
be stretched up to 150% of its length [15 ]. It is the
elastin content that allows the compliance of the
tunica albuginea and helps to determine stretched
penile length [16]. Disorganization of the circular
or longitudinal layers in the tunica as well as dis-
ruption of elastin or a decrease in elastin content
can result in penile deformities during erection as
well as erectile dysfunction. Further, damage to
the tunica albuginea can result in site-specific lea-
kage or undermining of the draining tunical
venules [17].
The corpus spongiosum has a similar histologic
appearance to the corpus cavernosum in that it is a
spongy erectile tissue, but this erectile tissue does
not provide structure to the erection. The intraspon-
giosal pressures are one-third to one-half that of the
corpora cavernosa; an advantage in that this lower
pressure may prevent urethral blockage during eja-
culation [5]. This may also be the reason for the
absence of longitudinal tunical fibers in the six-
o’clock position of the tunica albuginea, such that
the urethra is not restricted during ejaculation [15].
Three sets of peripheral nerves have a role in erec-
tile function: thoracolumbar sympathetic, sacral
parasympathetic, and sacral somatic (figure 3).
The pelvic plexus (occasionally referred to as the
inferior hypogastric plexus in humans) found in the
pelvic fascia on either side of the lower genitouri-
nary tract and the rectum is also a very important
site for the integration of autonomic input to the
penis via the cavernous nerves (see below). The
efferent limb originates in the parasympathetic
center in the sacral cord, which contributes fibers
to the pelvic nerve that enters the cavernosal tissue
as the cavernous nerves. Careful attention to pre-
serving these nerve tracts has gained importance in
radical pelvic cancer surgery in the potent patient.
In the brain, several regions modulate the psycho-
genic component of erection, including the thala-
mic nuclei, the rhinencephalon, and the limbic
structures, with integration of these various areas
occurring in the preoptic anterior hypothalamic
area [18]. Input from the brain involves descen-
ding spinal pathways and is relayed through both
lumbar sympathetic and sacral parasympathetic
outflows to the penis. Anti-erectile sympathetic
efferent pathways arise in paravertebral sympathe-
tic chain ganglia and course to the penis primarily
through hypogastric and pudendal nerves. Physio-
69
logic studies implicate the parasympathetic ner-
vous system as the primary effector of penile erec-
tion. The neurophysiology of erection is dealt with
in greater detail elsewhere in this volume.
Neural innervation of the penis may be divided
into autonomic (parasympathetic and sympathetic)
and somatic (sensory and motor) [3,5,18]. Parasym-
pathetic preganglionic fibers originate from the
second to fourth sacral vertebra and proceed to the
pelvic or hypogastric plexus. This plexus serves as
a relay station for preganglionic and postganglionic
fibers to the penis. The cavernous nerve begins at
the pelvic plexus and travels through the pelvic fas-
cia to the prostatic capsule where it goes across the
posterolateral aspect of the prostate. Distal to the
membranous urethra, branches of the cavernous
nerve penetrate the tunica albuginea of the corpus
spongiosum. Other branches enter the crura of the
corpora cavernosa along the pudendal artery and
exiting cavernous veins. The remaining branches
proceed down the dorsal nerve to innervate distal
portions of the penis. Sympathetic preganglionic
fibers arise preganglionic neurons from ninth thora-
cic and fourth lumbar vertebra. These neurons inter-
face with sympathetic chain neurons at the level of
the spinal cord and proceed downward to the super-
ior hypogastric plexus. This plexus divides into the
right and left hypogastric nerve. One of these
branches then interfaces with the pelvic plexus.
Sensory stimuli elicited in the glans, penile, and
other perineal and inguinal areas are originated in
sensory receptors whose nerve fibers converge to
form the dorsal nerve of the penis. This nerve joins
other pelvic nerves to become the internal pudendal
nerve, ascending to the dorsal root of the second,
third and fourth sacral vertebra. Motor innervation
of the penis derives from the second, third and four-
th sacral vertebra within the sacral nerves which
lead to the pudendal nerve that reaches the bulboca-
vernous and ischiocavernous muscles. Contraction
of the latter muscle is important in the rigid erection
phase by constriction and compression of the cor-
pora cavernosa while rhythmic contraction of the
bulbocavernous muscle is important for the expel-
ling of semen during ejaculation [3,5,18].
The arterial blood supply of the penis is primarily
via the hypogastric artery [3-5].The internal
pudendal artery branches off the hypogastric arte-
ry and proceeds through Alcock’s canal becoming
the common penile artery (figure 4). However,
 Figure 3: The pelvic plexus

Figure 4

70
accessory internal pudendal arteries arising from
the obturator or other pelvic arteries are not
uncommon. The internal pudendal artery splits
into the bulbourethral, dorsal, and cavernosal arte-
ries. The bulbourethral artery supplies the urethra
and the glans while the cavernosal arteries enter
the corpora cavernosa at a point where the two
crura converge. As the cavernosal arteries proceed
proximally, they lie in the middle of the corporal
bodies. The cavernosal arteries give rise to the
helicine resistance arteries which in turn feed the
individual trabeculae. The paired dorsal penile
arteries proceed down the penis in the eleven and
one-o’clock positions along with the dorsal nerves
and supply superficial structures in the penis as
well as potentially supplying the corpora caverno-
sa via circumflex arteries. Thus the dorsal penile
artery can supply the cavernous tissue with mul-
tiple branches along the shaft of the penis as a nor-
mal variant. There can also be rich anastomotic
networks of vessels between the arteries of the pel-
vic area, and one side may also supply both cor-
poreal spaces as a normal variant.
The venous drainage system of the penis occurs
on three levels: superficial, intermediate, and deep
[3-5]. The superficial venous system, which lies
above Buck's fascia and primarily drains the peni-
le skin, can also have anastomotic connections to
the deep dorsal vein. This superficial system
drains into the femoral vein via the saphenous and
the external pudendal veins. The intermediate sys-
tem consists of the deep dorsal and circumflex
veins. The trabeculae of the corpora cavernosa
drain into a system of sub-tunical venules that coa-
lesce on the outer surface of the cavernous tissue
just beneath the tunica albuginea of the corpus
cavernosum [3-5]. These venules form a number
of veins transversing the tunica albuginea called
emissary veins which usually drain into the cir-
cumflex veins on the outer surface of the tunica
albuginea. The circumflex veins in turn drain into
the deep dorsal vein of the penis shaft between the
dorsal arteries usually lying just laterally adjacent,
all beneath Buck's fascia. Occasionally, the deep
dorsal vein consists of more than one trunk on the
most distal shaft of the penis, and occasionally the
deep dorsal vein receives direct emissary veins
from the cavernous tissue in the dorsal midline.
The deep dorsal vein near the glans penis is also
initially constituted by numerous trunks from the
71
glans and many of the circumflex vessels anasto-
mosis with small tributaries from the spongiosum.
The deep dorsal vein in the infrapubic region
(where it can also receive tributaries from the pre-
pubic fat) usually consists of one trunk that drains
into the pelvic preprostatic venous plexus or the
internal pudendal veins. The deep penile drainage
system consists of the cavernosal and/or crural
veins that drain the deeper cavernous tissue. The
cavernosal veins are in fact extensions of emissa-
ry veins from the infrapubic cavernous tissue that
drain directly into the pelvic plexus or the deep
dorsal vein in the deep infrapubic area. The crural
veins are direct emissary veins from the antero- to
posterolateral surface of the crura of the cavernous
tissue that usually drains into the internal pudendal
veins or the pelvic plexus.
The penile skin is continuous with that of the
abdominal wall and covers the glans penis as the
prepuce to reattach at the coronal sulcus [4]. The
underlying Colles’fascia is continuous with Scar-
pa’s fascia of the lower abdominal wall. The deep
layer of penile fascia, Buck’s fascia, covers both
corpora cavernosa and the corpus spongiosum in
separate fascial compartments. This fascia layer
has a dense connective tissue structure and is atta-
ched proximally to the perineal membrane and
distally to the coronal sulcus where it fuses with
the corpora cavernosa. Buck’s fascia gives rise to
the suspensory ligament of the penis which
attaches to the pubic symphysis. Colles’ fascia
also gives rise to the fundiform ligament which,
superior to the suspensory ligament, attaches to
the public symphysis as well. Both of these liga-
ments are important in maintaining penile position
during erection. The bulbocavernosal and ischio-
cavernosal muscles are inferior to Colles’ fascia
but superior to Buck’s fascia.
Lymphatic draining of the penile skin and prepu-
ce proceeds towards the presymphyseal plexus
where it divides right and left joining the lympha-
tics from scrotum and perineum [4]. Here they tra-
vel along with the external pudendal blood vessels
to junction with the superficial inguinal lymph
nodes. The lymphatics of the penile glans and ure-
thra drain via the deep inguinal and presymphy-
seal lymph nodes and occasionally drain into the
external iliac lymph nodes [4].

B. PHYSIOLOGIC
REGULATION OF PENILE
SMOOTH MUSCLE
CONTRACTILITY
The state the contractile tone of penile smooth
muscle (arterial and trabecular) determines the
hemodynamic events that induce erection or main-
tain penile flaccidity (figure 5).
The contractile activity of the penile muscle (arte-
rial and trabecular) is regulated by several factors:
adequate levels of agonists (neurotransmitters,
hormones, and endothelium-derived substances),
adequate expression of receptors, integrity of the
transduction mechanisms, calcium homeostasis,
interaction between contractile proteins, and effec-
tive intercellular communication among smooth
muscle cells (gap-junctions) [19].
I. PENILE SMOOTH MUSCLE
CONTRACTION
The contraction of smooth muscle depends on the
rise, relatively rapid, of the intracellular concen-
tration of free calcium. This concentration must be
maintained above baseline level for the mainte-
nance of the contractile tone. Several mechanisms
are activated favoring entry of calcium from the
extracelular compartment and/or the release of
calcium accumulated in intracellular organelles;
mainly the sarcoplasmic reticulum [20].
•ALPHA-ADRENERGIC MECHANISMS
Locally, the detumescence of the erect penis is
mediated by adrenergic nerve terminals whose
neurotransmitter, norepinephrine, activates adre-
nergic receptors. Contraction of human penile
arteries and trabecular smooth muscle is largely
mediated by ? 1 adrenergic receptors [20,21]. The
? 1d and ? 1a subtypes are the ones expressed with
higher density in the trabecular muscle [22].
The ? -adrenergic receptors can also be stimulated
by circulating catecholamines (norepinephrine as
well as epinephrine) (figure 6). Contraction
mediated by ? 2-receptors depends on the entry of
calcium from the extracellular compartment while
the activation of ? 1 receptors provokes the release
of intracellular calcium, initially, with subsequent
72
extracellular calcium entry for the maintenance of
the contractile tone.
Adrenergic stimulation causes vasoconstriction of
the penile arteries and contraction of the trabecu-
lar muscle which results, respectively, in the
reduction of the arterial inflow and in the collapse
of the lacunar spaces. The contraction of the tra-
becular muscle causes decompression of the drai-
nage venules from the cavernous bodies, allowing
the venous drainage of the lacunar spaces [23-25].
Even though the role of the adrenergic neuroeffec-
tor system as mediator of detumescence of the
erect penis has been demonstrated, its role in the
maintenance of penile flaccidity is not clearly
defined. An important argument against an ? -
adrenergic mechanism in the maintenance of the
flaccidity of the penis is the observation that the
intracavernosal injection an ? -adrenergic receptor
blocker, in the absence of other stimuli, does not
cause an erection. However, ? -adrenergic bloc-
kers are effective in prolonging the duration of an
already established erection.
The peptide endothelin and some eicosanoids
(PGF2 ? , thromboxane A2) are candidates for par-
ticipation in the maintenance of penile flaccidity.
Endothelin-1 is a member of a family of three pep-
tides, discovered in 1988 [26]. This peptide is a
potent constrictor synthesized by the lacunar endo-
thelium and, possibly, by the trabecular muscle
itself [27,28]. Its presence and constrictor activity in
human cavernous tissue suggests the participation
of this peptide in the regulation of trabecular smoo-
th muscle contractility. It has been also demonstra-
ted that endothelin potentiates the constrictor
effects of catecholamines on trabecular smooth
muscle [29]. Two receptors for endothelin, ETA and
ETB, mediate the biological effects of endothelin in
vascular tissue. ETA is the principal mediator of the
contraction in response to endothelin while ETB
prevails in endothelium, mediating a endothelium-
dependent vasodilator response. The mechanism of
intracellular transduction for both receptors is the
activation of the metabolism of inositol-phosphate,
with release of intracellular calcium and activation
of protein kinase C (PKC).
Several constrictor prostanoids, including PGH2,
PGF2 ? and thromboxane A 2 (TXA2) are synthe-
sized by the human cavernous tissue. In vitro stu-
dies have demonstrated that prostanoids are res-
Figure 5: Schematic representation of the structures involved in penile erection. In flaccidity (top) constrictor tone is predo -
minant, producing a low flow and low pressure state in lacunar spaces. Penile erection (bottom) requires the vasodilatation of
cavernosal and helicine arteries and the relaxation of trabecular smooth muscle, expanding the lacunar spaces and tunica
albuginea. This fact produces an elongation of subtunical venules, reducing their diameter and increasing the resistance to
outflow (veno-occlusive mechanism).

73
Figure 6: Schematic representation of the regulation of contractile tone of penile smooth muscle by adrenergic mechanisms.
NE, norepinephrine; NO, nitric oxide; 1, -adrenergic receptor type 1; 2, -adrenergic receptor type 2; 2, -adrenergic
receptor type 2.

74
ponsible for the tone and the spontaneous activity
of isolated trabecular muscle [30]. Also it has been
observed "in vitro" that constrictor prostaglandins,
simultaneously released with nitric oxide, attenua-
te the dilator effect of this substance [31]. The cor-
relation of these in vitro findings with the physio-
logical regulation in vivo is not yet established.
II. PENILE SMOOTH MUSCLE
RELAXATION
Dilation of the penile arteries (cavernous artery
and helicine arteries), is the first event in the deve-
lopment of erection. Its consequence is the increa-
se of blood flow and pressure into the lacunar
spaces. Following arterial dilation, the trabecular
muscle relaxes increasing the compliance of the
lacunar spaces to its expansion facilitating the
accumulation of blood. The relaxation of the
muscle depends on endocrine (circulating sub-
stances), paracrine mechanisms (neurogenic and
endothelial) as well as, possibly, on autocrine
mechanisms (release of vasodilator substances
generated in the muscle) (figure 7).
1. ROLE OF NITRIC OXIDE AND THE CGMP
PATHWAY
Nitric oxide (NO) is a free radical (the molecule
has an electron in excess), therefore it is a highly
reactive and chemically unstable molecule. It is
now known that this molecule is synthesized in
different types of cells in mammals and that it is a
modulator of several biological activities inclu-
ding: endothelium-dependent dilation of blood
vessels, inhibition of platelet-aggregation, macro-
phage cytotoxic activity, and also has a role as a
neurotransmitter in the peripheral and central ner-
vous system [32].
The constitutive forms of nitric oxide synthase
(NOS), located in nerves (nNOS) and endothelium
(eNOS), use the amino acid arginine and molecu-
lar oxygen to produce nitric oxide and the amino
acid citrulline [33,34]. This reaction requires a
series of co-factors, among them NADPH, tetra-
hydrobiopterin and calcium-activated calmodulin.
The inducible form of this enzyme, whose expres-
sion in cells occurs after the stimulation with cyto-
kines, does not require calcium activated calmo-
dulin as cofactor [33,34]. While the constitutive
75
isoforms of NOS have been identified in the caver-
nous body, the presence or the possible physiolo-
gical role of the inducible form, in this tissue, is
yet to be determined.
Unlike many other regulatory substances, such as
the classic neurotransmitters (acetylcholine, nora-
drenaline) or growth factors, nitric oxide does not
have a specific receptor on the cellular membrane.
Nitric oxide crosses the plasma membrane of the
cells targeting the enzyme guanylate cyclase, pro-
ducing a conformational change in the molecule
that increases its activity. Activated guanylate
cyclase catalizes the conversion of guanosine-5"-
triphosphate (GTP) to 3', 5' cyclic guanosine
monophosphate (cGMP) (figure 8). The accumu-
lation of cGMP sets in motion a cascade of events
at the intracellular level which induce a loss of
contractile tone. These include: hyperpolarization,
closure of voltage activated calcium channels,
sequestration of calcium by intracellular organells,
decrease in intracellular calcium and, probably,
changes in the affinity of the contractile apparatus
for calcium (figure 9).
Many are the experiments that demonstrate, both
in vivo and in vitro, an essential role for nitric
oxide in the erection of the penis [6, 35-45]
2. THE CAMP PATHWAY
Vasoactive intestinal peptide (VIP), in the autono-
mic nerves, prostaglandin E (PGE1 and PGE2),
synthesized by the smooth muscle, and neural or
circulating catecholamines (norepinephrine and
epineprine), stimulate specific receptors coupled
to Gs proteins with stimulation of the adenylate
cyclase, that catalyzes the formation of cAMP
(figure 7). This is an efficient route for the relaxa-
tion of the smooth muscle of the penis, as demons-
trated by the erectogenic effect of intracavernosal
PGE1 administered for the treatment of impoten-
ce. It is probable that the coordinated activation of
both pathways, cGMP and cAMP, participate in
the physiology of erection.
During the 80's great attention was given to VIP as
the possible mediator of erection. This proposal was
based on the observation of nerve fibers that contai-
ned VIP in cavernous tissue and that exogenous VIP
was a potent relaxant of the smooth muscle of the
penis [46-48]. Furthermore, the intracavernosal
administration of VIP caused tumescence and rigid
erection in some individuals [49].
Figure 7: Schematic representation of the processes leading to penile smooth muscle relaxation. E, epinephrine; EP-R, pros -
tanoid receptor type E; Na+-pump, Na+/K+-ATPase; NE, norepinephrine; NO, nitric oxide; PGE, prostaglandin E; VIP,
vasoactive intestinal peptide; VIP-R, VIPreceptor; 2-AR, -adrenergic receptor type 2.

Figure 8: Schematic representation of nitric oxide

generation and action pathway in penile smooth muscle
and the processes involved in its regulation. NO, nitric
oxide; NOS, NO synthase; O2, superoxide anion;
PDE5, phosphodiesterase type 5, 2-AR, -adrenergic
receptor type 2.

76
The discovery of the role of nitric oxide diverted
the interest from VIP to the new molecule. Recent-
ly, the co-localization of VIP and nNOS in nerves
within the corpus cavernosum has been reported
[50]. This has revived once more the concept of
co-transmission in this tissue and the interest in
VIP. The two molecules, VIP and NO, would indu-
ce relaxation in the muscle by two different, and
potentially synergistic, pathways. Selective relea-
se of neurotransmitters depending on the stimula-
tion frequency has been demonstrated. Thus, for
example, nitric oxide would be released at low
frequencies, while the largest release of VIP would
occur with high frequencies. The precise physiolo-
gical role of this modulation in the release of neu-
rotransmitters in erection is not known. VIP recep-
tors in the cavernous body are coupled to Gs pro-
teins that stimulate the catalytic activity of adeny-
late cyclase with formation of cAMP (figure 10).
Prostaglandin E1 and E2 are the most abundant
prostanoids synthesized by the smooth muscle of
the penis. It is not known if the endogenous pros-
tanoids participate in the regulation of penile
smooth muscle contractility, although preliminary
evidence supports such a role for PGE. The recep-
tor (s) that mediates trabecular relaxation to PGE
is designated as the EP receptor. The specific sub-
type, of the four that exist in the EP family, has not
been determined. The EP2 and EP4 subtypes are
the most likely candidates, since they are coupled
to Gs proteins which stimulate adenylate cyclase.
Finally, the stimulation by catecholamines of ? -
adrenergic receptors causes relaxation of arterial
and trabecular smooth muscle. The ? 2 subtype is
probably the most important receptor mediating
these effects [51-53]. Adrenaline has a high affini-
ty for this receptor, whose stimulation counteracts
in part the constrictor effects, mediated by ? -adre-
nergic receptors, of this catecholamine. There is
evidence in the vascular system that the expres-
sion of ? 2-adrenergic receptors decreases with
age, giving way progressively in the erectile tissue
to the constrictor mechanisms (? -adrenergic)
which would prevail.
3. RELAXATION THROUGH HYPERPOLARIZA-
TION OF THE MUSCULAR CELL
One of the mechanisms by which the cyclic
nucleotides induce relaxation of the smooth
muscle is through the opening of potassium chan-
77
nels, hyperpolarizing the cell. This effect on K+-
channels can be provoked by the cAMP-depen-
dent protein kinase (PKA), by the cGMP-depen-
dent protein kinase (PKG) or by cGMP itself. The
activation of potassium channels (of the "maxi-
K+" type) by the action of the PGE1, an effect
mediated by cAMP, has been demonstrated [54]. It
has also been demonstrated that relaxation of peni-
le arteries is inhibited, in part, upon blocking of
calcium-dependent K+-channels [38]. Hyperpola-
rization causes the closure of voltage-dependent
calcium channels, therefore reducing the calcium
entry from the extracellular compartment, with
decrease in the concentration of intracellular free
calcium and subsequent relaxation of the muscle.
Independent of this mechanism, provoked by the
action of the cyclic nucleotides, it has been propo-
sed that, in arteries, nitric oxide can directly sti-
mulate the opening of potassium channels as well
as the sodium-potassium ATPase (the sodium
pump). This last mechanism has been demonstra-
ted in the trabecular muscle [55]. The sodium-
potassium ATPase pump is electrogenic due to the
fact that it extracts three positive charges from the
cell while introducing only two. Therefore, the cell
hyperpolarizes initiating the same mechanisms of
closure of calcium channels decribed after the
activation of K+-channels. This process repre-
sents, therefore, a mechanism for relaxation that
does not depend on cyclic nucleotides.
III. REGULATION OF THE
BALANCE BETWEEN THE
DILATOR AND CONSTRICTOR
MECHANISMS
• Cholinergic nerves
Erection is initiated by a sacral parasympathetic
nerve input, the preganglionic neurotransmitter of
which is acetylcholine. Because of this fact, it was
initially assumed that post-ganglionic cholinergic
nerves were the direct mediators of penile smooth
muscle relaxation. As it has already been explai-
ned, it is now known that the relaxation of the
smooth muscle is mediated by one or more nona-
drenergic, noncholinergic (NANC) neurotransmit-
ters.
Nevertheless, cholinergic nerves are present in the
cavernous body and seem to have a modulator role
Figure 9: Schematic representation of the mechanisms involved in penile smooth muscle relaxation by the cGMP pathway.
GC, guanylate cyclase; IP3, inositol triphosphate; PKA, protein kinase A; PKG, protein kinase G; PLB, phospholipase B; PLC,
phospholipase C; NO, nitric oxide.

Figure 10: Schematic representation of the mechanisms involved in penile smooth muscle relaxation by the cAMP pathway.
AC, adenylate cyclase; EP-R, type E prostanoid receptor; Gs, stimulating G-protein; IP3, inositol triphosphate; PGE, prosta -
glandin E; PKA, protein kinase A; PKG, protein kinase G; -R, -adrenergic receptor.

78
on the other neuroeffector systems. Adrenergic
nerves receive inhibitory interneuronal cholinergic
modulation. The interaction of acetylcholine with
muscarinic receptors in the adrenergic nerves
reduces their release of noradrenaline [21,56]. This
prejunctional regulation, therefore, would favor
erection through the decrease of constrictor adre-
nergic tone. Cholinergic nerves also seem to modu-
late NANC nerves but, in this case, they facilitate or
potentiate the vasodilator response mediated by
these nerves [56]. The specific underlying mecha-
nism of this facilitation remains unidentified.
In summary, cholinergic activity in the cavernous
body would have a modulatory role facilitating
erection, on the one hand reducing constrictor tone
(adrenergic) and on the other facilitating NANC-
mediated relaxation.
1. REGULATION OF THE ADRENERGIC ACTIVI-
TY BY PROSTANOIDS
The precise physiological role of the endogenous
prostanoids has not been clearly established. Pros-
tacyclin is produced by the endothelium and parti-
cipates, probably together with the nitric oxide, in
the regulation of homeostasis between the trabe-
cular wall and the blood. Prostaglandins E (E1 and
E2) are the most abundant prostanoids synthesized
by the cavernous muscle. In addition to their role
as a relaxants of trabecular muscle, previously
mentioned, and that of regulators of the collagen
synthesis [57], PGE also modulates adrenergic
nerves through a prejunctional mechanism. It has
been demonstrated in human cavernous tissue that
PGE1 inhibits the release of noradrenaline by
adrenergic nerves [58]. Prostaglandins E, therefo-
re, promote erection by their direct relaxant effect
on the muscle and by their indirect effect of reduc-
tion of adrenergic tone.
Certain prostanoids, such as PGD2, have the oppo-
site effect, since they facilitate the release of nora-
drenaline by adrenergic nerves [58].
2. ADRENERGIC REGULATION OF NANC
NERVES
In intracavernosal arteries from experimental ani-
mals, prejunctional regulation of NANC nerves by
? 2 adrenergic receptors has been demonstrated. The
activation of these adrenergic receptors inhibits
vasodilation induced by nitrergic nerves [59]. This
regulation suggests that termination of the erection
79
by the increase in adrenergic activity would have
two components: one direct, constrictor, on the
smooth muscle, mediated by ? 1 and ? 2 receptors
and other one indirect, in which the vasodilator
effect of nitrergic nerves is inhibited by a prejunc-
tional, ? 2 adrenergic-mediated mechanism.
3. MOLECULAR OXYGEN AS A MODULATOR
OF PENILE ERECTION
The partial oxygen pressure (PO2) in the blood of
the cavernous body during the flaccid state is simi-
lar to that of venous blood (~ 35 mmHg). However,
during the erection, due to the increase in arterial
blood entering the lacunar spaces, the PO2
increases to approximately 100 mmHg (i.e. the cor-
pora cavernosa are arterialized) [7]. Molecular oxy-
gen is a substrate, together with L-arginine, for the
synthesis of nitric oxide mediated by NOS. In cor-
pus cavernosum tissue, it has been demonstrated
that the synthesis of nitric oxide is directly regula-
ted by the oxygen concentration [7]. At the low
oxygen concentrations that are measured in the
cavernous body in the flaccid penis, the synthesis of
nitric oxide is profoundly inhibited, blocking, there-
fore, endothelium and neurogenic relaxation of the
trabecular muscle. This would help in the mainte-
nence of penile flaccidity since it facilitates
constrictor tone by supressing relaxation.
After arterial vasodilatation, the oxygen concentra-
tion in the cavernous bodies rises providing suffi-
cient substrate (O2) so that nitric oxide is synthesi-
zed. It has been estimated, after "in vitro" studies,
that the minimal concentration of oxygen in the
cavernous bodies necessary to reach a full activity
of the nitric oxide synthase is between 50 and 60
mmHg. Inferior concentrations would induce a par-
tial synthesis of nitric oxide with, subsequent, par-
tial relaxation of the trabecular muscle.
In a similar way to the nitric oxide synthase, the
prostaglandin H synthase (the ciclooxygenase) is
also a oxygenase and uses oxygen as substrate for
the synthesis of prostanoids. It has been demons-
trated that the oxygen concentration to which the
cavernous bodies are exposed regulates the synthe-
sis of prostanoids [60]. In the case of the PGE, the
relaxing prostaglandin of the trabecular muscle,
physiological variations in the oxygen concentra-
tion will condition its endogenous production: inhi-
bited in flaccidity and stimulated in erection.
The synthesis of the vasoconstrictor, endothelin, is
also subject to modulation by the oxygen concen-
tration. In this case low oxygen concentrations
(Venous) promote its synthesis and high levels
(arterial) inhibit it.
This capacity of the molecular oxygen for regula-
ting the synthesis of endogenous vasoactive sub-
stances, make of it an important modulator of the
erectile activity of the penis.
C. PATHOPHYSILOGY OF
ERECTILE DYSFUNCTION
Normal erectile function requires the involvement
and coordination of multiple regulatory systems
and is thus subject to the influence of psychologi-
cal, hormonal, neurological, vascular and caverno-
sal factors. An alteration in any of these factors
may be sufficient to cause ED, but in many cases
a combination of several factors is involved.
I. NEUROGENIC ERECTILE
DYSFUNCTION
Erection can be initiated in the brain (central erec-
tion) and/or follow genital stimulation (reflex
erection). The combination of both is probably
involved in sexual activity.
Events that disrupt central neural networks or the
peripheral nerves involved in sexual function can
cause ED. This form of ED has been termed “neu-
rogenic impotence”. It has been estimated that 10
to 19% of ED is of neurogenic origin [61,62]. If
Table 1: Peripheral ED
LOCAL ETIOLOGIES
SURGERY
PERIPHERAL NEUROPATHIES
TOXINS M ETABOLIC DISORDERS
? ?Organic compounds ? ?Diabetes mellitus
? ?Heavy metals ? ?Alcoholism
? ?Peptide neurotoxins ? ?Uremia
? ?Hypothyrodism
(References 18,61,63-66)
one includes iatrogenic causes and mixed ED, the
prevalence of neurogenic ED is probably much
higher. While the presence of a neurologic disor-
der or neuropathy does not exclude other causes,
confirming that ED is neurogenic in origin can be
challenging.
1. THE ETIOLOGIES OF NEuROGENIC ED CAN
BE CLASSIFIED AS:
• Peripheral (peripheral ED)
• Spinal (sacral-peripheral ED, suprasacral-central
ED)
• Supraspinal (central ED)
Peripheral ED can be secondary to the disruption
of sensory nerves that bring local information to
the brain and contribute the afferent arm of reflex
erection, or to the disruption of autonomic nerves
which mediate arterial dilation and trabecular
smooth muscle relaxation (See tables 1, 2, 3).
ED from central origin can occur from lack of
excitation or increased inhibition of central auto-
nomic pathways.
2. ERECTILE DYSFUNCTION IN SPINAL CORD
INJURY
Men with spinal cord injury have several associa-
ted sexual dysfunctions including alterations in
ejaculation, orgasm and erectile function. Patients
are frequently young and face a life long perspec-
tive of difficulties in their sexual and reproductive
capacities. The degree of completeness and the
level of the lesion determines the erectile function
of the patient [74]. In general patients with lesions
above the sacral parasympathetic center maintain
reflexogenic erection. In these patients minimal
TRAUMA PELVIC PATHOLOGY
INFECTIOUS DISEASES OTHERS
? ?Leprosy ? ?Systemic lupus
? ?HIV erythematosus
? ?Viral infections ? ?Hematochromatosis
80
Table 2 : Spinal ED Recovery of erectile function after radical pelvic
? Multiple sclerosis surgery can be slow over the course of 12 to 18
? Spinal cord injury months. Early treatment (with self intracavernosal
? Tumor administration of vasoactive agents) of these
? Syringomyelia patients has been shown to improve the probabili-
? Transverse myelitis ty of recovering erectile function. It is believed
? Arachnoiditis that the pharmacologically-induced erections pre-
? Disk disease vent the structural tissue changes associated with
? Myelodysplasia the prolonged ischemia associated in turn with
infrequent or no erections during the nerve reco-
(References 67-74) very process.

Table 3 : Brain ED
? Tumor
? Stroke
? Encephalitis
? Parkinson's disease
? Various dementias
? Olivopontocerebellar degeneration
(Shy-Drager syndrome)
? Epilepsy (temporal lobe)
(References 61,75,76)
tactile stimulation can trigger erection, albeit of
short duration requiring continuous stimulation to
maintain erection [74]. If the lesion is incomplete
patients can receive input from psychogenic erec-
tion and maintain erectile function. Patients with
significant lesions affecting the sacral parasympa-
thetic center do not have reflex erections and have
severe erectile dysfunction [74].
3. ERECTILE DYSFUNCTION AFTER RADICAL
PELVIC SURGERY
The mechanism of erectile dysfunction after radi-
cal prostatectomy or cystoprostatectomy is usual-
ly neurologic but can also be vascular (due to dis-
ruption of anomalous pudendal arteries that cour-
se the anterior aspect of the prostate) [77]. The
neurologic lesion occurs in the pelvic plexus or in
the cavernosal nerves located in the postero-lateral
aspect of the prostate. The incidence of erectile
dysfunction after radical bladder or prostate surge-
ry was, in the past in the vicinity of 100 %, but has
improved with the introduction of nerve-sparing
procedures. Maintenance of erectile capacity with
these techniques varies between 35% and 68%
depending on the surgical technique, the clinical
and pathological staging of the tumor and the age
of the patient [78,79].
II. VASCULAR ED
Alterations in the flow of blood to and from the
penis are thought to be the most frequent causes of
ED. Penile arterial vasodilation and relaxation of
the trabecular smooth muscle initiate erection.
This allows filling of the sinusoids and entrapment
of pressurized blood in the corpora cavernosa.
These are the primary hemodynamic events that
initiate and maintain penile erection.
An increase in intracavernous pressure of 50-90
mm Hg, depending on the geometry and penile tis-
sue factors, is required for erection with sufficient
rigidity for vaginal intromission.
Proximal arterial stenosis and an increase in peni-
le vascular arterial resistance can lead to organic
ED. A higher prevalence of ED is observed in
patients with cardiovascular risk factors, such as
hyperlipidemia, hypertension, smoking and dia-
betes. The prevalence of ED is increased with the
accumulation of cardiovascular risk factors, as
occurs in cardiovascular disease. Indeed, ED can
be a symptom of vascular disease.
The association of impotence with vascular disea-
se is well-documented in the literature. Prolonged
illness has been thought to account for a great por-
tion of the decline in sexual function with aging.
Alterations in corpus cavernosal arterial inflow
(CAI) and corporal veno-occlusive dysfunction
(CVOD) are thought to be the two most frequent
causes of organic erectile dysfunction. Both CAI
and CVOD have been reported in patients with
hypertension, myocardial infarction, cerebrovas-
cular accidents, peripheral vascular disease and
following coronary arterial bypass surgery.
Wabrek reported ED in 64% of the 131 males aged
31-86 years hospitalized for acute myocardial
infarction [80].

81
Several studies have correlated a prevalence of ED
with an increasing number of vascular risk factors
[81]. Shabsigh et al. reported that smoking, dia-
betes, and hypertension are risk factors for vascu-
logenic ED, and abnormal penile vascular findings
increased significantly as the number of risk fac-
tors increased with ED. Virag et al. investigated
distribution of four main arterial risk factors of
diabetes, cigarette smoking, hypertension, and
hyperlipidemia. A physiologic cause was reported
in 80%, with 53% reported to be in the arterial
atherosclerotic group and 34% secondary to
hypercholesterolemia. The study concluded that
hypertension, smoking, diabetes, and hyperlipide-
mia were all significantly more common in this
cohort than in the general population. In summary,
the major factors for vasculogenic ED are diabetes
mellitus, hypertension, hypercholesterolemia, per-
ipheral vascular disease, smoking, and coronary
arterial disease.
Cavernosal arterial insufficiency (CAI) and
CVOD are the main factors resulting in vasculo-
genic ED in diabetic patients. The incidence of
impotence is noted at earlier ages in diabetics than
in the general population. The prevalence of impo-
tence in diabetes has been estimated at 35%-50%,
and in some reports the percentage was as high as
75%. Deterioration of sexual function was the first
symptom in 12% of diabetics. The incidence of
impotence in diabetes has been found to be age-
dependent: 15% at 30 years and 55% at 34-
60 years. Other investigators have reported that at
ages 20-29, 9% of diabetics complained of ED,
and up to 50% of patients with diabetes were
impotent within 10 years of their diagnosis. While
there was no statistical correlation between the
duration of diabetes and ED, Rubin also reported
that 45% of men with diabetes of more than five
years developed impotence and diabetes in
conjunction with hypertension increasing the inci-
dence to 80% [82].
1. ED IN ATHEROSCLEROSIS AND HYPERCHO-
LESTEROLEMIA
Originally arterial disease and impotence were lin-
ked by the French surgeon Leriche, who in 1940
noted that a majority of patients with occlusive
arterial disorders at the bifurcation of the aorta into
the two major arterial trunks of the common iliac
arteries suffered from failure in erectile capacity
82
[83]. The cause for erectile dysfunction in these
patients can probably be ascribed to the presence
of a flow limiting stenosis caused by atherosclero-
tic lesions in the penile large arteries. The atheros-
clerotic lesions extend to the cavernous arteries in
men with erectile dysfunction [84, 85,86]. Athe-
rosclerotic disease is associated with a reduced
blood flow to the corpora cavernosa during erec-
tion.
In a rabbit model where proximal atherosclerotic
lesions were induced by ballon-deendothelizatioin
of the iliac arteries and by feeding a cholesterol-
rich diet, this was followed by vasculogenic erec-
tile dysfunction [87]. The erectile dysfunction in
these animals can probably be ascribed to both a
limited iliac blood flow and corporal venoocclusi-
ve dysfunction due to a decreased expandability of
the trabecular smooth muscle [88,89]. The authors
have later in the same animal model demonstrated
that the chronic ischaemia provoked by the proxi-
mal iliac stenosis is also associated with functional
changes in the distal part of the penile vasculature
such as decreased NOS activity, reduced endothe-
lium-dependent and neurogenic NO-mediated
relaxation in cavernosal tissue [90,91] (figure 11).
The changes were not altered by L-arginine sup-
plementation. NO inhibits endothelial eicosanoid
and superoxide production [92]. This observation
may explain that in the rabbit model the impaired
NO formation is also associated with increased
production of contractile thromboxane and prosta-
glandin formation and potentiation of neurogenic
contractions of the cavernosal smooth muscle
[90,91]. Indomethacin partially restored the func-
tional changes of the NO/cGMP-pathway. In the
latter studies the reduced NOS activity in these
rabbits can probably be explained either by
decreased NOS expression or reduced enzyme
activity. The above-mentioned studies, although
extensive, are concerned with the combined effect
of hypercholesterolemia and ischaemia and do not
allow for distinction of the influence of chronic
ischaemia alone on the erectile tissue. Moreover in
the cholesterol-fed rabbit model the plasma cho-
lesterol is extremely high (925 mg/dl or 20-25
mmol/l), [90] and it also increases liver weight
[93,94] probably leading to an altered metaboliza-
tion of the steroid hormones and hence expression
of NOS in erectile tissue.
In summary, atherosclerotic lesions in the penile
Figure 11 : Pathophysiology of erectile dysfunction in vascular disease.

large arteries are flow limiting and the disease can
extend to the cavernosal arteries. The chronic
ischaemia is associated with alterations of both
endothelial and neuronal NO/cGMP-pathways and
structural changes of the corpus cavernosum.
Besides the changes induced in the penile vascular
bed by atherosclerotic lesions in the large or
conductive arteries, hypercholesterolemia appears
to have an effect "per se" on the vasculature. Oxi-
dized low density lipoproteins (ox-LDL) inhibit
the endothelium-dependent NO-mediated relaxa-
tions in rabbit large arteries [95], but this does not
appear to be the case in small systemic arteries
[93,94] or the trabecular smooth muscle [96]. In
the latter study the lipoproteins did not interfere
with the NO/cGMP-pathway, but ox-LDL induced
contractions [96], and these contractions are pro-
bably mediated through increases in intracellular
inositol phosphate and calcium [97]. In contrast,
chronic hypercholesterolemia reduces endothe-
lium-dependent relaxations in the corpus caverno-
sum [98,99]. It has earlier been found that endo-
thelium-dependent relaxation was impaired only
in systemic arteries with atherosclerotic lesions
[100,101]. The cholesterol-fed rabbit ultrastructu-
ral studies of corpus cavernosum have also revea-
led an early atherosclerotic process in the caverno-
sal sinusoids [102]. In contrast to the endothelial
NO/cGMP-pathway, the neuronal vasodilation
does not appear to be affected in hypercholestero-
lemic rabbits [90]. The selective affection of the
endothelial NO/cGMP-pathway in hypercholeste-
rolemia could be ascribed to an increased super-
oxide production of NOS inhibitors such as L-
NMMA and ADMA. L-arginine supplementation
reverses the impairment of the endothelium-
dependent relaxations [90], and this observation
supports the suggestion that endothelial dysfunc-
tion is due to an increased endogenous production
of NOS inhibitors. Further studies are needed to
clarify whether hypercholesterolemia has induced
structural and functional changes in the distal part
of the penile vascular bed in patients with erectile
dysfunction.
Lipid-lowering therapy in hypercholesterolemic
patients improves endothelium-dependent vasodi-
latation measured in the forearm of hypercholeste-
rolemic patients probably due to an increased bio-

83
availability of NO [103]. This underlines the fact
that the dysfunction of the endothelial NO/cGMP-
pathway in hypercholesterolemia is reversible.
However, it remains to be elucidated whether this
is also the case for penile vasculature.
2. ED IN HYPERTENSION
Hypertension is a major risk factor associated with
atherosclerotic disease, stroke and myocardial
infarction, and antipypertensive treatment reduces
both morbidity and mortality [104]. The genesis of
hypertension is unknown in the majority (95%) of
hypertensive subjects. The disease is characterized
by an increased peripheral vascular resistance
[105]. Several studies have reported an increased
vasoconstrictor and decreased endothelium-
dependent vasodilation in spontaneously hyper-
tensive rats [106]. It remains controversial whe-
ther essential hypertension is characterized by
impaired endothelium-dependent vasodilation to
specific agonists in vivo [107]. Several mecha-
nisms have been suggested for this impairment:
1) a reduced endothelial synthesis of NO due to
either a disturbed signal-transduction pathway and
/or a reduced activity of NO synthase,
2) an accelerated NO degradation within the ves-
sel wall [107], or
3) alterations in the vessel architecture resulting in
an overall reduced dilatory capacity of the small
arteries [108]. However, in studies on isolated
human small arteries, the endothelium-dependent
relaxation induced by acetylcholine appears to be
conserved [109,110]. Therefore, the increased per-
ipheral vascular resistance in hypertensive patients
can probably be ascribed either to plasma factors
inhibiting the NO/cGMP-pathway or to structural
changes in the small arteries reflected as an increa-
sed wall/lumen ratio [105] (figure 11).
In addition to structural changes in the small arte-
ries, hypertension is a risk factor for atherosclero-
sis and such lesions in large arteries may explain
the increased incidence of sexual dysfunction in
untreated hypertension. However, there is an
obvious lack of studies addressing these questions
in the erectile tissue from animal models of hyper-
tension and in hypertensive patients.
3. PELVIC/PERINEAL TRAUMA
Blunt trauma to the pelvic or perineal region of the
corpora cavernosa has been considered a risk fac-
84
tor for the subsequent development of persistent
ED. The pathophysiology of traumatic erectile
impairment is multifactorial. Both psychogenic
and hemodynamic factors have been reported with
incidence of 4% and up to 80%, respectively. A
retrospective nine-year review revealed CVOD
prevalence in 62% and cavernosal arterial insuffi-
ciency in 70% of patients. Another study reported
52% incidence of ED in patients who self-reported
potency prior to the trauma. It has been proposed
that the traumatic CVOD occurs as a consequence
of focal trauma-induced changes in corporeal tis-
sue compliance [11].
4. DIABETES
Diabetes mellitus (DM) is a common chronic
disease throughout the world with a prevalence of
0.5-2%. It is characterized by hyperglycaemia
secondary to lack of insulin (Type I, insulin depen-
dent DM), or insulin insensitivity (Type II, non-
insulin dependent DM) which leads to pathological
changes in a number of cellular and organ systems.
There is good epidemiological evidence of a causal
link between diabetes and erectile dysfunction
(ED) [111]. The prevalence of ED is three times
higher in diabetic men (28% versus 9.6%) [112],
occurs at an earlier age and increases with disease
duration, being approximately 15% at age 30 rising
to 55% at 60 years [113,114]. Erectile dysfunction
amongst men with diabetes is more frequent in
those with co-existing neuropathy but the relation-
ship with vascular disease is less clear. The preva-
lence of coronary arterial disease (20%) and per-
ipheral vascular disease (5%) amongst men with
diabetes is far higher than in the general popula-
tion; both common associated physical health risk
factors for ED. Impotence however appears to be
equally common amongst diabetics with and
without evidence of atheromatous vascular disease.
Diabetes mellitus may cause ED through a number
of pathophysiological changes affecting psycholo-
gical function, CNS function, androgen secretion,
peripheral nerve activity, endothelial cell function
and smooth muscle contractility [115]. In a parti-
cular individual the problem may be due to one or
a combination of these possible factors. This sec-
tion will examine the evidence for a relationship
between diabetes and penile haemodynamic,
endothelial and smooth muscle dysfunction.
a) Experimental materials
Due to the multifactorial aetiology of ED in DM it
is difficult to isolate haemodynamic factors from
other changes, particularly peripheral neuropathy.
Data have been obtained from results of vascular
investigation of penile blood flow in impotent men
with diabetes, responses of isolated human caver-
nosal tissue and histological studies. Indirect evi-
dence is provided from isolated forearm blood
flow studies and experiments using other endothe-
lial tissue or cellular preparations.
The use of animal models such as streptozotocin-
induced diabetic rats and alloxan-induced diabetic
rabbits help the design of experiments focused on
particular aspects of the problem, but extrapolation
to the human condition is problematic. In addition
these animal models tend not to develop long term
atheromatous damage, commonly seen in the
human disease, because of their limited life span.
A substantial body of work looking at the cause of
vascular disease in diabetics is focused on changes
in endothelial cell function, in particular the nitric
oxide (NO)-cyclic GMP (cGMP) signal transduc-
tion pathway. Although not primarily concerned
with penile erection, it seems reasonable to assu-
me that results obtained from other vascular smoo-
th muscle preparations will be applicable to endo-
thelial cell - smooth muscle interaction within the
corpora cavernosa.
b) Haemodynamic changes
Penile erection depends upon a greatly increased
blood flow into the corpora cavernosa, which is in
turn dependent upon perfusion pressure, relaxa-
tion of the supplying arterial tree and relaxation of
cavernosal smooth muscle. Disturbances of these
mechanisms can be clinically detected by anato-
mical studies such as angiography or functional
studies such as duplex ultrasonography.
•Anatomical imaging: Large vessel atheromatous
disease is 40 times more prevalent amongst men
with diabetes compared to non-diabetics and is
more commonly associated with ED. The only
angiographic study primarily concerned with dia-
betic patients found that stenoses of the internal
pudendal and, to a lesser extent, internal iliac ves-
sels were more severe in men with ED in both dia-
betics and non-diabetics [116]. Other less well
characterized studies suggest a greater degree of
atheroma occurring at a younger age in men with
diabetes.
85
• Functional studies: Men with diabetes show a
reduction in the number and rigidity of nocturnal
erections experienced during sleep [117].
Although this suggests an organic aetiology the
test has many pitfalls; it has low predictive value
and will not discriminate between vascular and
neurological causes. Early diagnostic studies prior
to the use of vasoactive agents relied upon the
ratio of penile (measured by Doppler probe) over
brachial blood pressure as an index of penile arte-
rial insufficiency. Significantly lower values were
found in diabetics compared with both potent and
impotent men without diabetes suggesting penile
arterial insufficiency [118]. However results sho-
wed considerable overlap as the method measured
dorsal penile arterial pressure only and were
conducted in the flaccid state, making the results
of limited value. Reported use of artificial phar-
macological erection as a test of intact penile vas-
culature is limited to several uncontrolled case
series. In one study 40% of diabetic men with ED
achieved full rigidity following intracavernosal
papaverine (25 mg) compared to 70% in an unse-
lected group of non-diabetic men with ED [119].
Studies using duplex ultrasonography following
intracavernosal injection of vasoactive agents
have found a high prevalence of penile arterial
insufficiency amongst diabetics with ED ranging
from 75 - 100%[120]. None of these studies found
any differences between men with Type I or Type
II DM. In general it can be said that atheromatous
disease is more common in diabetic men and such
disease within the penile arterial tree is associated
with ED.
c) The effect of diabetes on cavernosal tissue
• Structural changes: One study using electron
microscopy has shown ultrastructural changes in
cavernosal tissue from diabetic men compared
with controls [121](figure 11). These include
reduction in smooth muscle content, increased col-
lagen deposition, thickening of the basal lamina
and loss of endothelial cells. Although these
changes were most marked in tissue from men
with diabetes they were also seen in those with
other non-diabetic causes.
• Functional changes: A number of studies tes-
ting the response of isolated preparations of
human cavernosal tissue to contractile and
relaxant agents have found differences in tissue
responses from diabetic and non-diabetic men
[122-125]. These experiments generally measure
relaxant responses in tissue strips pre-contracted
with ? -adrenergic agonists. The studies have
consistently found a reduction in the response fol-
lowing stimulation of the relaxant innervation
which is predominately mediated by the NO -
cGMP pathway. In addition relaxant responses
evoked by acetyl choline which are dependent
upon release of NO from the endothelium were
impaired [122-124] (figure 11). In comparison to
control tissue from potent men, specimens from
diabetic men showed a similar impairment in
relaxant responses to those from non-diabetics
with severe arterial disease or veno-occlusive dys-
function, suggesting a common aetiology [123].
Relaxation evoked by nitrovasodilators such as
sodium nitroprusside were similar in tissue from
diabetic men with impotence, to those with non-
diabetic impotence and controls, suggesting that
the cellular events following NO release are not
impaired [122,123]. Relaxation following PGE1,
which is mediated through cAMP was significant-
ly impaired compared to control tissue in one
reported study [125]. One study has looked direct-
ly at NO formation following relaxant nerve sti-
mulation in tissue from impotent men with and
without diabetes compared to controls [126]. Neu-
rogenic NO formation was significantly impaired
amongst men with diabetes and vascular impoten-
ce compared to those with non-vascular impoten-
ce and controls. This was mirrored by reduced
magnitude of the relaxant response. Subsequent
cGMP formation was also reduced, although diffe-
rences were less clear. These studies suggest a spe-
cific impairment in NO synthesis or release which
appears common to diabetic and non-diabetic men
with clinical evidence of vasculogenic impotence.
Direct smooth muscle relaxation with various
pharmacological agonists appears unimpaired. A
possible aetiology to explain these findings is the
presence of elevated levels of advanced glycosyla-
tion end products (AGEs) in diabetics which act as
oxidative free radicals and quench NO as it is
released, thus preventing its relaxant action on
smooth muscle. One study has found increased
levels of AGEs in the cavernosal tissue of impo-
tent men with diabetes compared to a non-diabetic
impotent control group [127]. The researchers
went on to speculate that AGEs may increase the
expression of inducible type II NOS (iNOS) which
in turn down-regulates eNOS.
86
The contractile responses to ? -adrenergic agonist
were similar in tissue from diabetic and non-dia-
betic men with impotence [123]. Recording of res-
ponses to endothelin-1, an endogenous contractile
agent, revealed no change in smooth muscle res-
ponsiveness between potent men and those with
ED irrespective of whether diabetes was present,
suggesting that endothelin is unlikely to have a
role in diabetic impotence [29]. A closer examina-
tion of the kinetics of cavernosal smooth muscle
contraction suggested that tissue responsiveness to
? -adrenergic agonist was higher in men with Type
I diabetes, but unchanged in Type II, this however
remains to be confirmed by other studies [128].
Overall there is limited evidence suggesting that
smooth muscle contractility to adrenergic stimula-
tion may be impaired in cavernosal tissue from
men with diabetes.
All such studies using human tissue report a hete-
rogeneous group of impotent men, generally with
severe erectile dysfunction. In addition sample
size, particularly in potent control groups, is small,
hampering firm conclusions on the data presented.
It does appear that physiological pathways of
relaxation of corpus cavernosum are impaired in
impotent men with diabetes and that the main area
of dysfunction appears to be at the level of NO
synthesis and release rather than the transduction
pathway within the smooth muscle cell.
•Animal models: In the streptozocin-induced dia-
betic rat incubation of cavernosal tissue with low
concentrations of sodium nitroprusside (a NO
donor) resulted in higher levels of cGMP than
healthy controls [129]. Similarly, incubation with
PGE1 produced higher levels of cAMP in the dia-
betic group suggesting an intact or upregulated
distal signalling mechanism. Other studies have
described reduced response to receptor-mediated
stimulation of endothelial nitric oxide synthase
(eNOS), suggesting down-regulation of the NO-
generating mechanism. An alternative pathway of
relaxation involving the release of the prostanoid,
prostacyclin was also found to be impaired
amongst aged diabetic rats1[130]. Increased
eNOS binding found in one study suggested
increased NOS production in diabetic rats [131].
This was confirmed by another study which found
higher NOS levels in diabetic rat penises and not
in pelvic ganglia, suggesting a tissue-specific
effect [132]. The cavernosal tissue appeared intact
in these studies with no demonstrable histological
or ultrastructural abnormality. Further studies sho-
wed that the increase in neuronal NOS (nNOS)
levels in diabetic rats can return to normal follo-
wing insulin therapy or treatment with free radical
scavengers [133]. In addition such therapy increa-
sed expression of eNOS. Against these findings, a
recent study found a significant decrease in nNOS
in similar streptozocin-induced diabetic rats and
could also find no induction of growth factor
expression [134].
In the alloxan-induced diabetic rabbit cGMP pro-
duction in response to direct stimulation by
sodium nitroprusside was unaffected [135]. Howe-
ver other findings in this study suggested a defect
in the receptor-activated formation of prostacy-
clin, perhaps as a result of reduced phosphokinase
C activity that has also been found in other endo-
thelial cell preparations in laboratory animals ren-
dered diabetic. In addition the formation of cAMP
by PGE1 which would normally result in smooth
muscle relaxation was impaired in the diabetic
rabbit model. Increased smooth muscle tone may
result from the increase in endothelin-B receptors
found in one study of diabetic rabbits [136]. In the
presence of high bathing sugar solutions, mimic-
king the hyperglycaemic state, responses of rabbit
corpus cavernosus to acetyl choline were impai-
red. This effect was reversed by both indometho-
cin and superoxide dismutase suggesting the
involvement of prostaglandins and free oxygen
radicals [137]. There was no change to the respon-
se evoked by nitrovasodilators in this study, sug-
gesting a mechanism through reduced activity of
eNOS. In another study using alloxan-induced dia-
betic rabbits the relaxant response to SNP was
again unaffected but neurogenic and relaxation
was impaired and remained so despite insulin
treatment [138]. In contrast the impairment in ace-
tyl choline-induced relaxation via eNOS was
reversed by treatment with either insulin or L-argi-
nine.
Data from animal studies is far from complete, but
despite conflicting results, some tentative conclu-
sions can be drawn which can then be fitted into
the prevailing view of the aetiology of generalized
diabetic vascular pathophysiology. There appears
to be a consistent finding of impaired endogenous
NO-evoked relaxation from both neural and endo-
thelial sources. The contractility of cavernosal
87
smooth muscle itself appears unaffected. This is in
agreement with the findings in human tissue des-
cribed above and suggests a defect in the forma-
tion or release of NO rather than in the signal
transduction pathway within the smooth muscle
cell. A possible pathological mechanism for these
events is the NO-quenching action of elevated
levels of AGEs.
d) Generalized endothelial dysfunction in
diabetes
•Introduction: Endothelial cells form a permissi-
ve layer that regulates the flow of nutrients and the
action of bioactive molecules circulating in the
blood upon the underlying tissue, particularly vas-
cular smooth muscle. This is achieved by a wide
range of membrane-bound receptors and junctio-
nal proteins. The endothelium also secretes
vasoactive molecules that regulate blood flow in a
paracrine fashion through induction of changes in
vascular smooth muscle tone. Knowledge of endo-
thelial physiology and pathophysiology in dia-
betes is chiefly derived from experimental data
from in vivo measurements of blood flow in
human subjects and laboratory animals together
with cell biological studies using endothelial cell
cultures from a variety of animal and human tis-
sues. The main clinical marker for endothelial dys-
function in diabetics is the presence of microalbu-
minuria indicating the presence of renal microan-
giopathy. This occurs in approximately 50% of
diabetics, the reason why the remainder are pro-
tected is unknown.
•Vasoregulation: Nitric oxide is released from
endothelial cells through the action of type III NO
synthase (eNOS) located within the cellular mem-
brane. The enzyme is activated by the binding of
various agonists such as thrombin, adenosine 5’-
diphosphate, bradykinin, substance P and acetyl
choline to specific membrane receptors and also
by gene amplification stimulated by sheer stress.
The released NO relaxes underlying vascular
smooth muscle and may also be involved in
enhancing endothelial repair following injury. The
endothelium also secretes endothelium-derived
hyperpolarising factor (EDHF) which enhances
muscarinic receptor-mediated smooth muscle
relaxation. The other major vasoactive molecule
expressed by the endothelium is the potent vaso-
constrictive agent, endothelin-1. This is formed by
gene transcription stimulated by hypoxia, sheer
stress and ischaemia. Endothelin acts through G-
protein coupled ET-A receptor activation which
elevates plasma calcium and hence causes
contraction. The eicosanoid, prostacyclin (PGI2)
is also produced by the endothelium and acts as a
paracrine signalling molecule, inducing vascular
smooth muscle relaxation through the IP receptor.
It is mainly implicated in the regulation of vascu-
lar tone in areas of injury or disease.
The following section describing our present
knowledge of the effects of diabetes on endothelial
cell physiology uses a number of recent specialist
reviews to which the reader is referred for more
information and references of original experimen-
tal work [139-144].
• Effect of diabetes on endothelial cell turnover:
Exposure to hyperglycaemia induces increased
expression of collagen, decreased proliferation
and increased programmed cell death (apoptosis).
This has an adverse effect on repair mechanisms,
enhancing the progressive damage associated with
atherosclerotic injury. Expression of the cytokine
TNF-? is also increased resulting in further endo-
thelial cell destruction.
• Effect of diabetes on nitric oxide synthase:
Insulin is thought to enhance NOS activity by
increasing transport of L-arginine into the cell and
furnishing greater quantities of the essential co-
factor NADPH. These effects are reversed in the
insulin lack or insulin resistance of diabetes. This
enhancement of NOS activity also occurs follo-
wing exposure to adenosine, a potent circulating
vasodilator. Some work has suggested a decreased
responsiveness of endothelial cells to adenosine in
gestational diabetes. The ratio of reductase co-fac-
tors NADH/NAD+ is increased in diabetes. This
reduces the levels of NADPH, an essential co-fac-
tor for NOS and increases the levels of calcium-
elevating second messengers such as diacylglyce-
rol (DAG) and protein kinase C (PKC) thus
increasing smooth muscle contractility.
• Effect of diabetes on nitric oxide-mediated
endothelium-dependent vasodilatation:
A number of human studies using arm vein ple-
thysmography have demonstrated fairly consistent
findings. Basal levels of NO-mediated endothe-
lium-dependent vasodilation appear similar to nor-
mal controls. The response to exogenous nitrova-
88
sodilators and some physiological agonists is
blunted, whilst infusion of muscarinic agonists
produces similar degrees of increased blood flow
to control. One study has suggested that in well
controlled diabetics vasoactivity appears normal.
In experimental animals blood flow responses
appear to be enhanced in the early stages of the
disease with decreased responses becoming preva-
lent with increasing disease duration. Isolated
reports also suggest increased endothelin levels in
patients with NIDDM which may act to indirectly
reduce dilator response.
• Enhancement of oxygen free radical produc-
tion in diabetes:
A body of evidence exists detailing various
mechanisms by which levels of oxygen free radi-
cals may be elevated in diabetes which quench
released NO thereby reducing the vasodilator res-
ponse. The most important appears to be the for-
mation of advanced glycosylated end products
(AGEs). These molecules formed from crosslin-
ked products of glucose and lysine or arginine
residues on various proteins and are produced in
approximately four-fold greater quantities in
hyperglycaemic states. They may also have a fur-
ther role in endothelial cell dysfunction by increa-
sing inflammatory cell activity. Elevated PKC
levels may also induce the formation of excess
free oxidative radicals. Increased sorbitol produc-
tion in the diabetic state encourages hydrogen per-
oxide formation which again enhances quenching
of NO causing oxidative stress injury.
• Summary: Diabetes causes generalised endothe-
lial cell dysfunction which results in increased
prevalence of vascular disease in both type I and
type II diabetics. Particular important effects are
reduced activity of eNOS, diminished effect of
released NO and the presence of oxidative free
radicals including AGEs.
III. ED IN END-STAGE RENAL
DISEASE (ESRD)
Thirty-eight to 80% of patients with ESRD have
decreased sexual activity with complete impoten-
ce in 20-60% of patients [145].
The pathophysiology of ED in these patients can
be multifactorial, including: endocrinologic, neu-
ropathic, vascular and iatrogenic.
Vascular disease and ESRD are commonly asso-
ciated. It is recognized that some patients with
ESRD can develop accelerated atherosclerosis
and, usually, have associated vascular risk factors
also identified as risk factors for the development
of erectile dysfunction, i.e. diabetes mellitus,
hypertension and hyperlipidemia [86].
In addition to arterial disease impotent men with
ESRD have a high prevalence of corporo-veno-
occlusive disease [86].
Further mechanisms proposed that can alter the
vascular response of the penis would be the accu-
mulation of naturally occurring analogs of L-argi-
nine (eg. L-NMMA) that inhibit NOS and per-
ipheral hypoxia associated with anemia.
As mentioned before, oxygen is a substrate for NO
synthesis and its reduced concentration can limit the
activity of NOS and thus the production of NO.
The association of neuropathy and ESRD also
exists. Peripheral neuropathies in ESRD can be
secondary to uremia, associated to diabetes melli-
tus or may be secondary to hyperparathiroidism
[146].
Endocrinologic alterations are common in men
with ESRD. Elevations of FSH, LH and prolactin
are well recognized in these patients. In addition it
is common to observe low levels of total and free
testosteronee [146,147].
Finally, men with ESRD frequently need medica-
tion for the disease or associated diseases that can
interfere with erectile function (see section on
drug induced erectile dysfunction). Some of these
medications include anti-hypertensives, digoxin,
clofibrate and antidepressants [144-146].
IV. PRIMARY ERECTILE
DYSFUNCTION
Primary erectile dysfunction (ED) is defined as
“absence of full sustained erections since early
childhood or puberty” [148]. In a study of 67
patients, it was found that there were organic
causes of ED in 85 percent (57/67) [148]. Of these
patients, there were overlapping etiologies of
disease with 18 percent with neurologic disease,
52 percent with arteriogenic disease and 52 per-
89
cent with veno-occlusive dysfunction [148]. Pri-
mary ED can be subdivided up into three basic
categories
1) malformations of the erectile apparatus inclu-
ding the corpora cavernosa,
2) endocrinologic disorders which result in ED
and
3) trauma to the crus and/or penis sustained in
early childhood or puberty.
Case reports of congenital malformations of the
corpus cavernosum penis resulting in primary ED
are rare [149-151]. In the first report, two cases
seen as adults were described where the congeni-
tal defect was identified as a problem in complian-
ce secondary to corporal fibrosis [149]. Diagnosis
was initiated by Doppler ultrasonography, and
both patients were treated by penile prosthesis
insertion [149]. In the second report, a 33-year-old
man was described with a similar congenital
defect characterized by isolated cavernous bodies,
veno-occlusive dysfunction, and hypoplastic
cavernous arteries [150]. The most recent report of
two young men also describes a patient similar to
the previous reports with separation of the corpo-
ral bodies and complaining of veno-occlusive dys-
function [151]. Interestingly, the other patient had
a partial aplasia of the distal corpora cavernosa
which was corrected surgically [151]. While there
remain to be reported genetic links to ED in
humans, a single gene mutation in mice has been
described which is linked to ED [152]. Regardless
of the fact that the bulk of patients reporting ED
suffer primarily from nongenetic causes (e.g., vas-
cular risk factors, depression, trauma), [112,153-
155] further research is required to identify gene-
tic causes of human ED.
The importance of testosterone for penile develop-
ment prepubertally as well as during puberty is well
recognized [156,157]. However, the role of andro-
gens in penile erection is currently unclear [158]. It
should be noted that one class of primary ED
patients is those with secondary endocrinologic
complaints [159-162]. For these patients, the reader
is referred to the section on “Endocrinologic ED.”
The final group of patients which may complain of
primary ED are those patients who have sustained
penile or crural trauma early in life, resulting in
subsequent dysfunction. Management of similar
patients has been described [11]. If the patient is
young and healthy and the defect appears to be
arterial in origin, penile revascularization collate-
rals of the internal pudendal artery may be a valid
surgical option. Otherwise, treatment entails the
insertion of a penile prosthesis.
V. DRUG INDUCED IMPOTENCE
Many classes of drugs can induce ED. In some
cases the association of a specific drug with ED is
well established through appropriately controlled
studies, but in many others the evidence is anec-
dotal and based on case reports.
THEORETICAL BASIS FOR DRUG-INDUCED
ERECTILE DYSFUNCTION
a) Drugs
1. change the hormonal milieu
2. specifically antagonize any of the key pathways
3. induce hemodynamic instability
b) Timing
1. the proposed drug effect must occur within the
known time of action of the drug
2. the off-setting of drug effect may be critical in
inducing an erectolytic effect (for example
twice-a-day antihypertensives used once a day)
3. the effect of a drug on erectile function (EF) has
to take into account the usual domestic schedu-
le (sex at night) in comparison to the time of
administration. Most trials for instance adminis-
ter drugs in the morning. It is therefore possible
to take a highly erectolytic drug with a T1/2 of
2 hours in the morning and not report any
adverse sexual effects where the same drug
administered 2 hours before sex would have
profound effects.
c) Dose
1. Drugs may have different receptor binding
capacities at different concentrations.
2. Small doses of a drug (e.g., clonidine) may have
profoundly different effects when compared
with large doses.
d) Idiosyncratic effects
1. In treating patients, any occurrence of an adver-
se event with a reasonable basis for a temporal
90
link should be treated seriously even if a causal
basis is not immediately apparent.
e) Impact
1. Drug effects offer one of the few windows of
opportunity for prevention in treating men with
erectile dysfunction (ED).
2. A careful assessment of the medical program of
a patient is a prerequisite to further treatment of
ED.
3. All drugs with possible or definite negative
impacts on EF should be changed if possible to
less noxious drugs.
PUBLISHED EVIDENCE OF EFFECTS
1. ANTIHYPERTENSIVES
a) Diuretics
The negative impact of diuretics on EF, particular-
ly thiazide diuretics, has been suggested and
reported for years. In truth, men taking antihyper-
tensive medications have hypertension, which is a
form of vascular disease. In addition, penile erec-
tions are dependent on normal functioning vascu-
lature. There are no studies in normal men where
the primary outcome variable was erectile status
and the drug on trial was hydrochlorthiazide. The-
refore in practice, the reports for all antihyperten-
sives have to be taken in the context of at least the
revealed hypertension, if not the unrevealed vas-
cular and supposed cardiac disease. Some studies
have shown no discernable effect beyond that of
treated hypertension [163]. In others, thiazides
have contributed to a great extent to the high rate
of non-compliance with antihypertensive regimes
– and ED has been a major complaint causing
drop-outs [164]. More recently an excellent study
of mildly hypertensive men found a significant
association between men with ED and hydrochlor-
thiazide therapy [165].
b) Beta adrenoceptor blockers
There is much real and anecdotal evidence to sug-
gest a profound effect of beta-adrenoceptor bloc-
kers on EF [166,167]. There are reports that chal-
lenge this assertion [163]. However, what seems
clear is that there may be variation in the adverse
event profile among the available agents
[168,169,170]. Also, in binding studies on human
erectile tissue, it was demonstrated, that the alpha
adrenoceptors dominate over the beta adrenocep-
tors in a 10:1 relation [51]. These experimental
results indicate a low functional role of the beta
adrenoceptors in the penile erectile process. The
mechanism underlying beta-blockers induced ED
is presently unknown.
c) Alpha adrenoceptor agents
Alpha antagonists are known to provide no pro-
blem [164] or to have a positive impact on EF
[171]. Prazosin has been reported to induce pria-
pism [172]. Alpha adrenoceptor agonists are used
therapeutically to treat priapism (epinephrine, etc)
and are intrinsically vasoconstrictive and erectoly-
tic [173]. Other alpha adrenoceptor agonists, such
as neo-synephrine, ephedrine etc, are commonly
found in decongestants and even the moderate
potency of most of the current agents is enough to
impose a degree of penile vasoconstriction [174].
Clonidine, an alpha 2 adrenoceptor agonist,
deserves special mention because of its predomi-
nently central action [175]. Hydralazine, alphame-
thyldopa and reserpine have also been associated
with ED.
d) Calcium channel blockers
The general consensus is that calcium channel
blockers have little impact on EF, but may intefe-
re with the ejaculation mechanism [176].
e) Angiotensin-converting enzyme-inhibitors
The report on erectile impact for the Treatment of
Mild Hypertension Study (TOMHS) is a key piece
of evidence in the evaluation of antihypertensive
therapy and ED, where five antihypertensive
agents of different drug families were compared
on their effects on sexual function. In brief, the
incidence of erectile problems was “lowest in the
doxazosin group but was not significantly diffe-
rent from the placebo group“. Incidence for ace-
butolol, amlodipine, and enalapril groups was
similar to that in the placebo group“ [177] while
thiazide diuretics did have a negative impact on
erectile function. In most cases, ED did not requi-
re withdrawal of medication. The study was not
designed to assess true pharmacological impact
because the design was for equipressor doses not
for sex at fully stable equipressor moments.
f) Potassium channel openers
Use of these drugs has not been associated with
ED. Intracavernosal administration of potassium
channel openers has been reported to have erecto-
genic effects [178,179].
91
2. PSYCHOTROPICS
a) Antipsychotics
Sexual side-effects during antipsychotic treatment
have been estimated in a high number of psychia-
tric patients [180]. Erectile dysfunction, altera-
tions of ejaculation and reduced libido are known
sexual difficulties related to these compounds,
conspicuously so during thioridazine therapy
[180]. Theoretically, the induced sexual dysfunc-
tion (SD) in patients on antipsychotics is the result
of anticholinergic effects and alpha-adrenergic
antagonism. Several antipsychotic drugs cause
increased release of prolactin following blocking
of the dopamine release [181]. Thioridazine has
associated effects on serum testosterone, which is
reduced, but haloperidol has not.
b) Antidepressants
There are two main groups of antidepressants, the
tricyclic antidepressants and the monoamine oxi-
dase (MAO) inhibitors, both of which interfere
with sexual function. The tricyclics are sedative
and have anticholinergic and antihistaminic
actions. However, the clinical documentation of
side-effects during antidepressant therapy is based
on small series of controlled studies [182]. Ejacu-
lation and orgasmic dysfunction are reported to be
of main concern for these compounds. Different
chemical configuration of the tricyclics explains
modified and differentiated effects between the
compounds, which inhibit the reuptake of the cen-
trally working neurotransmitters, noradrenaline
and serotonin [183].
The MAO inhibitors are more frequently linked to
sexual dysfunction (SD) but are rarely used today.
Delayed ejaculation and abscence of or reduced
orgasm are the most commonly reported side-
effects of the selective serotonin reuptake inhibi-
tors (SSRI) [184,185]. Fluoxamine was described
to have a low incidence of ED.
c) Anxiolytics
The benzodiazepines do not normally interfere
with the penile erectile mechanism. Improved
sexual performance has been described at lower
doses but at higher doses, these anxiolytics will
have a sedative effect with impaired sexual func-
tion [186].
The main conclusion on the effects on sexual func-
tion of psychotropics is that in general these agents
cause sedation and central nervous depression
[187]. The mental condition of the individual
patient is also a factor of main concern. Interpreta-
tion of data on sexual dysfunction must always be
related to methodological considerations [188].
3. MISCELLANEOUS COMPOUNDS
a) Hormonal agents
The normal penile erectile process depends on an
intact hypothalamic-pituitary-gonadal system
[189]. Any agent suppressing pathways of this sys-
tem will have the risk of inducing ED. Generally,
it is accepted to treat impotent hypogonadic men
with androgen administration [189,190,191].
Androgen substitution to impotent male subjects
with mild hypogonadism showed improved sexual
function in men with low levels of serum free tes-
tosterone but not in men with normal levels [192,
193]. Recently, in a placebo-controlled study
Schiavi et al (1997) [194] reported, that ejaculato-
ry frequency was higher and sexual desire impro-
ved in healthy men with ED following testostero-
ne substitution. Interestingly, even if the sexual
capacity increased in these eugonadal men during
testosterone administration compared to placebo,
there was no effect on the penile erectile function.
In men with endocrine therapy for prostatic mali-
gnancy, all antiandrogen therapy dramatically
decreased sexual activity [195]. By using pure
anti-androgens or 5 alpha-reductase inhibitors in
patients with prostatic malignancy, sexual function
may be preserved to a greater extent [195,196,
197]. In treatment of benign prostatic obstruction
with finasteride, the erectile capacity has been
reported as being intact in most patients [198].
b) Antineoplastics
From clinical experience in practice, it is known
that during anti cancer therapy patients are repor-
ted to have reduced sexual function. Also, it is
confirmed in extended series of cancer treatment
with specific antineoplastics that libido is reduced
with impaired erectile function [199]. However,
there is limited documentation in the literature on
objective effects on EF by different antineoplastic
compounds.
Hansen (1992) [200] reports on the long-term
effects after treatment with cisplatinum, vinblasti-
92
ne and bleomycin (CVB) in patients with metasta-
tic germ-cell cancer. He found that most patients
had a peripheral sensory neuropathy with a central
conductive defect. In approximately 30% of the
patients,cholinergic nerve dysfunction was obser-
ved. Azoospermia was documented in one third of
the patients but only a few reported ED.
Naturally, in the total perspective of SD in patients
during therapy of diagnosed malignancy, it may be
difficult to separate, if the selected treatment or the
disease is the main cause of the erectile failure. In
most cases, a combined effect of the two is a more
rational explanation.
c) Digoxin
Neri et al (1987) [201] investigated sexual function
after long-term administration of digoxin. They
found a correlation between SD and a reduced plas-
ma level of testosterone. Correspondingly, the plas-
ma level of estrogens were raised. The interference
by digoxin on EF may be explained by the similari-
ty in chemical structure to sex steroids. Another
possible mechanism has been suggested by Gupta
et al (1998) [55,202]. In an experimental study on
isolated human corpus cavernosum, they found that
digoxin concentration-dependently inhibited
sodium pump activity and counteracted the relaxant
effect induced by acetylcholine and by electrical
field stimulation. In this study, they also reported
that therapeutic concentrations of digoxin dimini-
shed penile rigidity compared to placebo during
visual sexual stimulation. In conclusion, the authors
suggested that digoxin promoted contraction of cor-
pus cavernosum tissue by inhibition of sodium /
potassium adenosine triphosphate causing impaired
nitric oxide relaxation.
d) Histamine-H2-receptor antagonists
The histamine-H2-receptor antagonist cimetidine
has been used world-wide by several million
people over the last 20 years [203,204]. The safe-
ty record of the drug is impressing but a small
number of different adverse events have been
reported including SD [172,203,205,206]. Raniti-
dine is another histamine-H2-receptor antagonist
with lesser incidence of adverse events than those
reported for cimetidine [172,205]. Cimetidine is
described to have potential for inhibiting acetyl-
cholinesterase activity and will cause ganglionic
blockade at high doses. The effect on sexual func-
tion by cimetidine may be two fold. The ganglio-
nic blocking effect at peripheral sites has only
been suggested at supratherapeutic doses [205].
Also, cimetidine has been found to have antian-
drogenic actions with incresed prolactin levels
[207]. Ranitidine has been reported to induce SD
but with lower incidence compared to cimetidine.
e) Hypolipidaemic agents
Clofibrate is a hypolipidaemic agent, which has
been reported to induce SD by interfering with the
androgen metabolism [172,207]. Recently, a high
incidence of SD was observed in a population of
men with primary hyperlipidaemia [208]. The
authors concluded that ED was a frequent disorder
in hyperlipidaemic patients but as the results
revealed a higher number of impotent men on acti-
ve hypolipidaemic treatment, SD was seen as a
possible side-effect of the drug. In a controlled
study, a slow releasing nicotinate, pentaerythriol
tetranicotinate, was given to hyperlipaemic impo-
tent patients [209]. The results indicated that
patients on active treatment had improved sexual
function compared to the pretreatment period and
to the control group.
4. OTHER DRUGS
It has been reported that carbonic anhydrase inhi-
bitors used in glaucoma therapy decreased libido
with SD [210,211,212]. Sexual function was res-
tored after discontinuation or by giving supplental
sodium bicarbonate [207]. The exact mechanism
of this side-effect may be explained as a result of
the malaise and depression found in some patients
on carbonic anhydrase inhibition [211,212].
The antimycotic drug ketoconazole has been
found to cause SD by inhibition of testosterone
biosynthesis [186,213]. In a placebo-controled
study, the effects by ketoconazole were compared
to another antimycotic agent, terbinafine [213].
Terbinafine showed no influence on the pituitary-
gonadal axis in normal young men compared to
ketoconazole and placebo.
5. SUBSTANCE OF ABUSE
a) Nicotine (cigarette smoking)
Cigarette smoking was reported by Rosen el al
(1991) [214] to be an independent risk factor for
artheriosclerosis in men with arteriogenic impo-
93
tence. Smoking was described to induce early
atherosclerotic lesions in the internal pudendal
artery. In 1987, Juenemann et al [215] showed in
an acute dog model that smoking caused vaso-
constriction, decreased penile arterial inflow and
venous leakage with a reduced intracavernosal
pressure during pelvic nerve electrical stimulation.
Similar observations have been reported in
humans [216].
b) Alcohol
In chronic alcoholism SD appears to be a common
problem [217]. Acute alcohol intake will in mode-
rate and high doses have a central sedative effect
but in small doses libido may be raised [218].
Impaired sexual function in chronic alcoholics
may be related to insufficient liver capacity, testi-
cular damage and polynephropathy [219]. Several
studies have focused attention on SD in chronic
alcoholics with normal liver function compared to
subjects with liver damage [220,221,222,223]. It
was emphasized, that in men with liver damage an
increased prevalence for SD was observed. Howe-
ver, cirrhotic alcoholics reported a higher inciden-
ce of SD than age-matched men with non-alcoho-
lic liver disease [221].
c) Narcotics
Cocaine is regarded as an aphrodisiac and its use
is often combined with alcohol abuse. The com-
pound is suggested to have potent dopamine ago-
nist properties as described for opioids [186].
However, chronic use of cocaine, heroine and
metadone increase the incidence of ED [211,
224,225]. Interestingly, Hanbury et al (1977) [226]
found that street heroin addicts with altered sexual
function had a higher risk of developing persistent
SD on metadone therapy.
6. IN WOMEN
In women, SD has not been rated of the same prio-
rity as in men. Until now, drug-induced SD is
women has not been of specific clinical interest.
Consequently, SD in women is not fully explored
and relevant clinical documentation is missing.
However, encouragingly there are studies in which
female SD has been studied and related to treat-
ment with antihypertensives [163,177,181] and
antipsychotics [180,181,184].
The results available indicate that drug-induced
SD in women is of lesser magnitude than in men.
Nevertheless, most studies point out that reduced
vaginal lubrication and delayed or impaired
orgasm are the manifestations of drug-induced
sexual disfunction in women [163,181,227].
7. IN THE ELDERLY
Drug-induced geriatric SD if of main concern for
different reasons. Firstly, the normal aging process
is counteract the sexual physiology. Secondly, the
risk of adverse events in ageing men and women
on treatment with antihypertensives, cardiovascu-
lar agents and antipsychotics are heavily increased
compared to their younger counterparts [228].
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102
 Committee 4

Symptom Score and Quality of Life

Chairman
G. WAGNER

Members
A. BÉJIN,
A. R. F UGL-MEYER,
S. GLINA,
Y. KIMOTO,
C.S.B LUKACS,
J. M ULCAHY,
M. O’L EARY,

103
 CONTENTS

I. SYMPTOM SCORE III. CONCLUSION

II. QUALITY OF LIFE REFERENCES

104
 Symptom Score and Quality of Life
G WAGNER,
A. BÉJIN, A. R. F UGL-MEYER, S. G LINA, Y. KIMOTO, C.S.B L UKACS, J. M ULCAHY,
M. O’LEARY,
Sexual health is the integration of the somatic,
emotional, intellectual, and social aspects of
sexual being, in ways that are positively enri -
ching, and that enhance personality, communi -
cation and love (WHO, 1974).
This chapter falls in two closely connected, but
separate parts. These are symptom evaluation of
the severity of erectile dysfunction (ED) using
questionnaires or checklists and evaluation of
the quality of (sexual) life. The main topics
addressed are:
What information can be adequately obtained by
checklists/questionnaires?
Why use questionnaires or checklists in the eva-
luation of ED and quality of life?
Which instrument(s) can be recommended for the
use in clinical practice, particularly by those who
are not specially trained urologists or sexologists?
I. SYMPTOM SCORE
Some conceptual considerations: A sexually well-
being man has adequate function (at the anatomi-
cal and physiological organ-levels, cf WHO,[1])
that allow him to act in order to fulfil his sexual
aspirations. Through reaching these aspirations, or
believing that he can reach them, he can reach
satisfaction with his sexual life if he has no or litt -
le sexual impairments such as decreased desire
(we shall here avoid to use the psycho-analytical
term libido as it denotes something over and above
desire), ED, ejaculatory disabilities (premature or
retarded ejaculation and orgasmic disability). And
105
if his partner(s) to his knowledge has little or no
sexual disabilities.
In the case of ED; anatomical, endocrinological,
neurological or vascular disorders may constitute
bodily sexual impairments that may cause loss of
erectile function. A loss which per se may result in
sexual disability. Hence, and following the recent
suggestions of the WHO[1] ED may refer both to
an impairment and to a disability.
This is shown in figure 1 (right half of diagram).
Both erectile impairment and psychosexual mala-
daptation may cause ED which, in turn may cause
erectile problems. In this context it must be
emphasised that ED is not synonymous with
having erectile problems. In a recent epidemiolo-
gical investigation it has, thus, been demonstrated
that among sexually active men who at least quite
often during the preceding year had experienced
ED, 69% stated that the ED was a problem for
them [2]. Among those who stated that the ED was
a problem 75 % reported low level of overall satis-
faction with sexual life. However, erectile dys-
function has become a widely accepted term in
English language and will be used in this chapter.
The distinctions between erectile impairment,
erectile disability (dysfunction) and erectile pro-
blems are necessary for reaching an adequate-
based differential diagnosis as a starting point for
therapeutic interventions. In other words, in order
to obtain valid guidelines for treatment, ED must
be seen within the framework of each individual’s
somatic, psychological and social adaptation and
ED will often, but far from obligatorily, lead to
experienced erectile problems that for the majori-
ty will result in low level of sexual satisfaction.
Figure 1: A model for case-analysis
What information on ED can or should be obtai -
ned by questionnaires or checklists, whether or
not in the form of aggregated sum-scores? Given
the conceptual model outlined above, it appears
that neither somatic sexual impairment per se nor,
at reasonable depths, psychological and social fac-
tors (including partner’s sexual disabilities that
may or may not cause or contribute to ED) can be
sufficiently analysed by reasonably brief and
simple questionnaires or checklists. A good case
history, preferably taken from both partners,
together with, if indicated, an adequate physical
examination including proper laboratory investi -
gations are the necessary ingredients for the
choice of treatment strategy in ED. On the other
hand it appears that questionnaires can be impor-
tant, both for initial focusing of ED as an intro-
duction to the case history and also as a simple
means for following up treatment effects. Other
advantages are that subject self-administered
indexes are “private,” and when properly psycho-
metrically validated, are both reliable and repro-
ducible.
When choosing what to include in a battery of sta-
tements/questions whether or not using aggregated
scores, it is of paramount importance to observe
106
that conceptual lucidity must prevail. Thus, the
following “domains” of overall sexual function,
while highly intercorrelated, need to be considered
individually and separately, particularly in scoring
scenarios.
• Physical impairments and psychological mala-
daptation
• Erectile dysfunction
• Erectile problems
• Sexual satisfaction
• Overall life satisfaction/quality of life
should rigidly be kept apart.
Another constructional main issue that influences
the choice of what to measure is the width of the
measuring instrument. The construct may in its
simpliest form solely focus on ED per se. It may
include diseases/injuries, abuse, etcetera, that
directly - or in most cases, indirectly – have an
impact on the individual’s capacity to achieve an
erection. The instrument may further, address
other sexual disabilities such as decreased or low
desire and interest, occurrence of premature and
retarded ejaculation, inability to reach orgasm and
also dyspareunia.
Moreover it may be considered relevant to incor-
porate items addressing erectile capacity during
masturbation and also to include one or more
items on the occurrence of nocturnal penile tumes-
cence. Other aspects that can be encompassed by
the instrument could be whether the ED is life-
long (primary or secondary, situational only with
present partner) and also to which extent present
partner (if the patient has a partner) is sexually
attractive for him (hence addressing the question
of partner related vs general level of desire). The
patient’s sexual identity, orientation and occurren-
ce of paraphilias could also be included. Besides
the sheer complexity of such a checklist/question-
naire, cultural (including patient’s own attitudes
and taboos) and legal factors seem to prohibit the
inclusion of several or all of these items.
Even partner’s (if any) sexual impairments,
Komma disabilities/problems, as experienced by
the patient might be included. The rationale for
including this kind of items would be that female
sexual disabilities have a profound influence on
their male partner (and vice versa). For instance,
female excitatory and orgasmic impairments (dys-
functions)/disabilities often (in about 35-50%) are
experienced as problems for their male partners
and among these men only about 20% feel that
their sexual life is satisfactory [3].
In summary much can be measured. We, howe-
ver, prefer to recommend that ED symptom
score should include only items that focus the
ED per se. The committee feels that additional
domains from various instruments may be
helpful in describing the overall condition of
sexual function, but for the purposes of descri-
bing erection, the symptom score should focus
on that alone.
The duration of an individual’s dysfunction has
been handled differently in different indexes. A
general principle is to use a time frame that allows
a sufficient “window” to adequately ascertain the
subject’s true state, but not so long as to be affec-
ted by his ability to recall. A duration of 3 months
(or more) seems adequate.
Why use ED symptom scores?:
Firstly, well validated, reliable, repeatable and
standardised symptom scores may provide a
simple means for the medical and sexological
practioner to quantitatively and semi-qualitatively
gain an impression of the patient’s perception of
107
the magnitude of his ED. Thus, the committee’s
basic consideration is that a narrow and brief (few
items) checklist should be recommended for gene-
ral use in clinical practice. This does not preclude
a modular system by which increasing complexity
can be introduced. Increasing levels of complexity
are probably inevitable when dealing with clinical
trials, in depth epidemiological investigations and
when it comes to more specialised treatment of
complicated cases of ED.
Which set of questions/statements should then
be recommended?
There are several batteries to be found that address
sexual disabilities, emotions and problems. Most
of them appear to mix different components such
as ED per se, its possible somatic and psychologi-
cal etiologies – the component that in the concep-
tual model given above is characterised as impair -
ment/maladaptation, the extent to which the ED
causes problems – the statement component in the
case analysis model, which indicates to which
extent the ED causes what by Michalos [4] has
been labelled an aspirations/achievement gap and
the perceived quality of sexual life. Some such
instruments are those described Derogatis and
Melisarotis [5] and more recently by O’Leary et al
[6] and Rosen et al [7].
Turner et al [8] used a sexologically oriented non-
specific checklist to measure sexual desire, arou-
sal, orgasm and satisfaction when assessing treat-
ment effects with the use of vacuum devices and
intracavernous injections. Recently Althof et al [9]
described yet another instrument that wholly
addressed ED in a prospective treatment related
way. These authors devised a questionnaire that
included 11 items on how treatment itself and its
effects are perceived by the patient and his partner.
This inventory is as such truly outcome-oriented.
In an epidemiological investigation Feldman et al
[10] stated that: ”Impotence is best defined by the
individual’s assessment of his own situation in
simple terms of minimal, moderate or complete
impotence as presented to a physician for treat-
ment”. These authors used a 4-graded ordinal
scale: no/minimal/moderate/complete impotence
to characterise degree of ED. In some contrast
Spector and Carey [11] emphasised that meticu-
lous descriptions are necessary in order to make
possible reasonably (epidemiological) comparati-
ve analyses. In an epidemiological investigation
performed in Scandinavia [2]another simple (sta-
tement) scale was used: «it happens that the man’s
penis does not become rigid or gets flaccid during
intercourse». Has this happened in your sexual life
during the last 12 months? Answering alternatives
were: never/hardly ever/quite rarely/quite often/
nearly all the time/ all the time. In a recent inves-
tigation of sexual dysfunction in the USA Lau-
mann et al [12]formulated their one item on male
arousal using a “mixed” question that encompas-
sed both ED as such and trouble caused by ED.
Whereas these three types of - nearly nominal -
ordinal scales may be adequate in broad surveys
and may be useful for analyses that aim to investi-
gate their relationship with other components such
as etiology or problems, they are most definitely
much too simple for use in clinical practice.
Which items are, at the moment, conceptually
clear enough for use as denominators of ED?
To our knowledge there is at present no globally
accepted item (or series of items) for such use.
During the 1990:ies two symptom score assess-
ment batteries have been proposed. Both are based
upon the widely acknowledged contention (see for
instance [10, 13] that sexual abilities are best
assessed by ”subjective” self reports. One of these
two instruments called the BMSFI was described
by O’Leary et al [6] the other the IIEF-15 introdu-
ced by Rosen et al [7]. The validity and test- retest
reliability are good for both instruments. This, in
particular, pertains to that part of the IIEF-15 that
focuses ED. The IIEF-15 has, in subsequent publi-
cations by Cappelleri et al [14, 15]been shown to
possess excellent properties concerning conver-
gent, divergent, and discriminant validity and also
clearly acceptable sensitivity and specificity.
There are, though some major mutual drawbacks
for these two instruments. Thus, both of them mix
ED per se with other conceptual categories such as
confidence (in maintaining erection) and sexual
satisfaction. They, moreover, provide information
on a wider aspect of sexual performance than ED.
It should also be observed that both instruments
have largely been developed on the basis of self-
reports of men who have more or less pronounced
impotence. Hence, so far, they have not been epi-
demiologically validated. On the other hand, the
IIEF-15 questionnaire was statistically validated
in more than 1000 men with ED (and about 100
without ED!) in a cross-cultural study [7], transla-
108
ted into ten (now 30) different languages. A factor
analysis of the 15 IIEF-items has been found to 5
questions that focus on erectile ability but this fac-
tor also to a considerable degree is influenced by a
confidence and by a general intercourse satisfac-
tion item. Lately an abbreviation of the IEEF-15,
termed IEEF-5, has been described [16] and wide-
ly distributed. This inventory includes items 2, 3,
5, 7 and 15 from factor 1 in the IEEF-15. It does
not solely focus ED per se as one of the 5 items
addresses confidence and another satisfaction. The
abbreviated inventory has been validated.
One major advantage of the BMFSI and the IIEF-
15 inventories is that they do not exclusively
concentrate on erection during penetrative inter-
course. Thus none of the 3 ED-related items of the
BMFSI do so. Furthermore, item 1 in the IEEF-15
is phrased: How often were you (during the last 6
months) able to get an erection during sexual acti-
vity? Item 2 does not, either, necessarily focus
intercourse as it is phrased: When you had erection
(during the last 6 months) with sexual stimulation,
how often were your erections hard enough for
penetration?
It may be concluded that there to our knowled-
ge is no available conceptually lucid ED symp-
tom score. There are, however, widely used and
partially validated items. Upon this back-
ground and as a preliminary step the five items
given in table I are recommended for scoring
quantity and quality of achievement and main-
tenance of erection following the definition of
the NIH [17]. All these items are taken nearly
verbatim from the IEEF 15 and none of them
transgress the rigid conceptual framework for
acceptance established by us above. (Table 1)
An important issue to address is whether or not
these five items can be cumulated into one score.
Evidently a sum-score may be easy to apply; in
particular if different cut-offs into for example
severe, moderate, mild and no erectile dysfunc-
tion: However, the 5 items each having 5 answe-
ring alternatives offer no less than about 3000 dif-
ferent combinations or ”profiles” and it would,
just knowing the total score, be impossible to
deduct which type(s) of erectile dysfunction a par-
ticular man has (i.e. lack of capacity to achieve
and/or maintain an erection) as well as the severi-
ty of the ED. In this context it should be emphasi-
sed that although sexual erection achievement and
Table 1: ED intensity scale

ED INTENSITY SCALE
Each question has several responses. Put in the empty box the number of the response that best describes your own
situation. Please be sure that you select one and only one response for each question.
PATIENT NAME : DOB : ID : DATE OFASSESSEMENT :
Almost never A few times Sometimes Most times Almost always
or never (much less than (about half (much more than or always
half the time) the time) half the time)
1. H OW OFTEN WERE
YOU ABLE TO GET AN
ERECTION DURING 1 2 3 4 5
SEXUAL ACTIVITY?

2. WHEN YOU HAD

ERECTIONS WITH
SEXUAL STIMULATION,
HOW OFTEN WERE 1 2 3 4 5
YOUR ERECTIONS HARD
ENOUGH FOR PENETRA-
TION (ENTERING YOUR
PARTNER )?

3. WHEN YOU ATTEMPTED

INTERCOURSE, HOW OFTEN
WERE YOUABLE TO PENE- 1 2 3 4 5
TRATE (ENTER) YOUR
PARTNER?

4. DURING SEXUAL INTER

COURSE, HOW OFTEN WERE
YOU ABLE TO MAINTAIN 1 2 3 4 5
YOUR ERECTION AFTER
YOU HAD PENETRATED
(ENTERED) YOUR PARTNER?
Extremely Very Difficult Slightly Not
difficult difficult difficult difficult
5. DURING SEXUAL INTER
COURSE, HOW DIFFICULT
WAS IT TO MAINTAIN YOUR 1 2 3 4 5
ERECTION TO COMPLETION
OF INTERCOURSE ?

ED Intensity Score :

• Instructions for Possible Scoring: Add the scores for each item 1-5 (total possible score =25). ED Severity Classification:
Total score 5-10 (severe); 11-15 (moderate); 16-20 (mild); 21-25 (normal).

Note: The above questions should only be completed by individuals who have been sexually active and have attempted sexual
intercourse in the past 3 months. For sexually inactive individuals, the questionnaire may be answered for the last period of time
(3 months or longer) during which the individual was sexually active.

109
maintenance may be closely associated they are
basically two different categories of ED and it is
arguable whether nominal data can be added to
each other. Moreover, in many cases ED is accom-
panied or precipitated by premature ejaculation
[18]; a combination which may be overlooked by
the clinician if only using a sum-score.
If the main application of the suggested 5-items is
to initiate and facilitate for the clinician a dialogue
with the patient in order to focus on a precise dif-
ferential diagnosis an aggregated score appears to
be somewhat insufficient.
On the other hand, many clinicians may want to
have overall score at hand in order primarily to
obtain a general impression of the effect of one or
more treatment modalities. For this purpose a
cumulated score may be well worth using and
post-hoc analyses may evidence whether such a
score is not only statistically valid, but in fact is an
adequately useable clinical indicator.
It is, thus, at the moment not unambiguously clear
whether the five ED-items can be aggregated. The
committee, though, recommends that at least those
clinicians that are well acquainted with the diffe-
rent aspects of ED use the set of items both as
separate entities and in aggregation.
II. QUALITY OF LIFE
Some conceptual considerations. All assessment
questions and inventories must be ontologically
well-anchored. The dimensionality of each item
and scores must be well defined. When dealing
with measurements of Quality of Life (QoL) it is
highly relevant to clearly define if the assessment
has it’s background in generally or medically
accepted normality (ie: is based upon a Gaussian
distribution) or if the single individual’s experien-
ced QoL is the central issue. From the methodolo-
gical point of view validity, reliability and repea-
tability is as important for assessment of QoL as
for symptom scores. It is also highly relevant to
ascertain whether items or instruments are mono-
or pluriculturally oriented.
During later years QoL and life satisfaction have
been increasingly emphasized as indicators of the
impact of pathological conditions and of the effect
of therapeutic endeavours. Quality of life is,
however, an ambiguous concept. More than 20
years ago Campbell et al [19] stated that QoL is
110
“something many people talk about but nobody
very clearly knows what is and what to do about”
and Bowling [20] has seconded that opinion by
stating that QoL is a vague, multidimensional
concept, which theoretically incorporates all
aspects of an individual’s life. This is further
underlined by the definition offered by the WHO
[21]: “QoLis defined as an individual’s perception
of their position in life in the context of the cultu-
re and value systems in which they live in relation
to their goals, expectations, standards and
concerns. It is a broad ranging concept affected in
a complex way by the person’s physical health,
psychological state, level of independence, social
relationships and their relationships to salient fea-
tures of their environment”. The concept has as a
caricature been characterised thusly: “QoL is like
love. Everybody knows what it is, but who would
trust anybody else’s definition?”
What information on QoL/life satisfaction can
be obtained?
From a philosophical perspective Musshenga [22]
identified three different, but interrelated,
concepts. QoLcan be seen as the dcgree of normal
functioning as a member of the biological species
homo sapiens. QoL can also denote degree of
satisfaction derived from an individual’s life.
Thirdly, QoL can be seen as the level of human
development. In medical research the two first of
these concepts are increasingly used.
The degree of normal biological function may
from the medical but even the psychological point
of view erroneously be interpreted as the level of
quality of life. This type of medicalized objecti-
vism (a professional on-looker judges somebody
else) does not take into account the individual’s
experienced goal-achievements. We shall, therefo-
re, disregard such judgements as irrelevant to the
conceptual model given above. The second defini-
tion above, characterising QoL as degree of life
satisfaction appears relevant. Here we deal with
two different categories; namely health related
satisfaction and general satisfaction. While health
related QoL/life satisfaction might be adequate to
measure within a certain specified area, this type
of assessments has drawbacks as it is biased in two
ways. First of all comparisons with health (in a
narrow, pathology-specific sense as well as in a
broad general health-related context) does not
allow for comparisons with people who assess
themselves as being at good health. Secondly,
people who are not at good health appear to assess
their QoL as relatively lower when they answer a
health-related QoL-question than they do if the
questionnaire is not so. On the other hand, clinical
practitioners often feel a need for specialized heal-
th-related “subjective” assessment of health rela-
ted QoL. Within this area a series of instruments
exist. The pro tempore most used general instru-
ments are the SF-36 [23, 24] the Nottingham Heal-
th Profile [25, 26] and the Sickness Impact Profi-
le [27]. These are broad ranging questionnaires or
checklists that only to a very limited extent, if at
all, address sexual life. They may therefore not be
sensitive enough to detect subtle differences in
ED-subjects.
Concerning health-related QoL the most simple
item is that employed in the IPSS [28] namely: “If
you were to spend the rest of your life with your
urinary condition the way it is now, how would
you feel about that?” The 5-graded scale now
being: very satisfied/rather satisfied/mixed equal -
ly satisfied and dissatisfied/rather dissatisfied
/very dissatisfied.. A considerably more elaborate
ED-related instrument is the 19 items inventory
described by Wagner et al [29]. Each item has a
four-graded response scale and taken together the
items are suggested to characterize masculinity,
emotional reactions to ED and overall life satis-
faction (but none of the items addresses QoL
explicitly). This scoring system has been applied
in two, rather small samples of men with ED. It
has excellent internal consistency and test-retest
reliability.
About a decade ago Fugl-Meyer et al [30] introdu-
ced a life satisfaction inventory, which has later
been expanded slightly. It has now been validated
in a nationally representative Swedish population
sample aged 18-74 (1475 men and 1335 women).
Table 2: ED impact scale
ED IMPACT SCALE
VERY RATHER
DISSATISFIED DISSATISFIED
IF YOU WERE TO SPEND
THE REST OF YOUR LIFE
WITH YOUR ERECTILE
CONDITION THE WAY 1 2
IT IS NOW, HOW WOULD
YOU FEEL ABOUT THAT?
111
It contains one overall item (satisfaction with life
as a whole) and 10 domain specific items. The lat-
ter are included (factor analysis) in a very robust
factor pattern among which sexual life, partner
relationship and family life form one. Besides the
instrument having very good internal consistency,
all items (6-graded scale) have good test-retest
reliability and a high degree of specificity and sen-
sitivity. For instance, in a sample of ED-men
(n:413) satisfaction with sexual life was particu-
larly low, but men with psychogenic ED were also
significantly less satisfied with partner relation-
ship and family life than were a reference group
[32]. Successful treatment that restored the erecti-
le ability resulted in “normalization” of level of
sexual satisfaction. This instrument is now widely
used and has been translated into more than 10 dif-
ferent languages. In a recent statistical analysis (to
be published) it has been shown that in the general
population sample (cf above) an aggregated score
incorporating the four items: Satisfaction with life
as a whole, with sexual life, with partner relation-
ship and with family life is valid. Even this aggre-
gation is, however, from the differential diagnostic
point of view, unspecific.
Which items should be included to provide ade -
quate information, primarily for general practitio -
ners, on the impact of ED?
Bearing in mind that the instrument should be brief
and easy to administer and, furthermore that the ins-
trument should provide information as to the impact
of ED on quality of life, so that a decision could be
made whether and to which extent therapeutic inter-
ventions are indicated, the following items appear
adequate indicators of quality of life in relation to
ED:
1. The ED impact (bother) item given in table 2: A
5-graded scale is believed adequate, for charac-
terizing the degree of distress or bother caused
MIXED, ABOUT RATHER VERY
EQUALLY SATISFIED SATISFIED SATISFIED
AND DISSATISFIED
3 4 5
2. Four life satisfaction items (table 3): Satisfac-
tion with sexual life, partner relationship (if the
patient has a partner), family life and with life
as a whole, using the test-re-test reliable 6-gra-
ded scale.
III. CONCLUSION
The committee has reached the conclusion that a
brief, by and large validated, robust, sensitive, spe-
cific and test-retest reliable set of totally 10 items
can be recommended. Among these, 5 items cha-
racterise ED per se, one characterises prospective-
ly judged, quality of sexual life (“bother”), one
characterises overall quality of sexual life, two
items concern quality of other intimate aspects of
life (partnership and family) and, finally, one item
addresses overall quality of life.
Table 3: Life satisfaction score
112
Whereas clinicians may prefer to use aggregated
scores the committee recommends cautiousness in
such use. Aggregated scores may be statistically
valid, but they may provide in sufficiently detailed
information as they mix different categories of ED
or of quality of life. On the other hand, the 10
items can be used as an “ED-profile”.
The committee emphasizes that both the ED inten-
sity score inventory and the two QoL-inventories
aim to provide the general practitioner with guide-
lines that can not only save time but primarily can
be an aid or a prelude to taking an adequate case
history. The committee, again, wishes to stress that
a good case history, if indicated leading to further
biological and psychological investigations, is a
sine qua non for adequate treatment of ED.
Finally, the committee believes that this instru-
ment is applicable for establishing evidence based
follow-up.

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bilities, Problems and Satisfaction in 18-24-Year-Old
Swedes. Scand J Sexol 2:79-105, 1999.
3. FUGL-MEYER KS. Erectile Problems – The Perspecti-
ve of the Female. Scand J Urol and Nephrol 32:12,
1998.
4. MICHALOS AC.Satisfaction and Happiness. Soc Indic
Res 8:385-422, 1980.
5. DEROGATIS LR, MELISARATOS N. The DSFI: A
Multidimensional Measure of Sexual Functioning. J Sex
Marital Ther, 1979.
6. O’LEARY MP, Et al. A Brief Male Sexual Function
Inventory for Urology. Urology. 46:697-706, 1995.
7. ROSEN RC, et al. The International Index of Erectile
Function (IIEF): A Multidimensional Scale for Assess-
ment of Erectile Dysfunction. Urology 49:822-830,
1997.
8. TURNER LA et al. Twelve-month Comparison of Two
Treatments for Erectile Dysfunction: Self-injection ver-
sus External Vaccuum Devices. Urology 39:822-830,
1992.
9. ALTHOF SE et al. EDITS: Development of Question-
naires for Evaluating Satisfaction with Treatments for
Erectile Dysfunction. Urology 53:793-799, 1999.
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chosocial Correlates: Results of the Massachusetts Male
Aging Study. J Urol 151:54-61, 1994.
11. SPECTOR IP , CAREYMP. Incidence and Prevalence
of the Sexual Dysfunctions: A Critical Review of the
Empirical Literature Arch Sex Behav 19:389-408, 1990.
12. LAUMAN EO et al. Sexual Dysfunction in the United
States: Prevalence and Predictors. JAMA 281:537-544,
1999.
13. ANDERSON BL, BROFFIT B. Is there a Reliable and
Valid Self-report Measure of Sexual Function? Arch Sex
Behav 17:509-525, 1988.
14. CAPPELLERI JC et al..???Some Developments on the
(incomplete!).
15. CAPPELLERI JC et al. Diagnostic Evaluation of the
Erectile Function Domain of the International Index of
Erectile Function. Urology 54:346-351, 1999
16. ROSEN RC et al. Development and Evaluation of the
IIEF 5 as a Diagnostic Tool for Erectile Dysfunction. Int
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17. NIH Consensus Development Panel on Impotence.
Impotence. JAMA. 270:83-90, 1993.
18. BEJIN, A.Epidémiologie de l’éjaculation prématurée et
de son cumul avec la dysfonction érectile. Andrologie
9:211-225, 1999.
19. CAMPBELL et al. The Quality of American Life: Per-
ceptions, Evaluations and Satisfactions. Russel Sage
Foundation, New York, 1976.
20. BOWLING A. Measuring Disease. Open University
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21. WHO QoL Group. Measuring Quality of Life. The
Development of the World Health Quality of Life Ins-
trument (WHO QoL), Geneva, 1995.
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Quality-of-Life, Health and Happiness. J Med and Phi-
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23. WARE J et al. The MOS 36-item Short-Form Health
Survey (SF-36):I. Conceptual Framework and Item
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24. MCHORNEY CA et al. The MOS 36-item Short-Form
Health Survey (SF-36):II. Psychometric and Clincal
tests of Validity in Measuring Physical and Mental
Health Constructs. Medical Care 31:247-263, 1993.
25. MCEWEN J, MCKENNASP. Nottingham Health Pro-
file. In: Spilker B (ed) Quality of Life and Pharmacoe-
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Raven Publishers. Philadelphia, 1996.
26. LUKKARINEN H AND HENTINEN M.Assessment of
Quality of Life with the Nottingham Health Profile
Among Patients with Coronary Heart Disease. J Advan-
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Medical Care. 19:787-806, 1981.
28. BARRY, MJ et al. The American Urological Association
Symptom Index for Benign Prostatic Hyperplasia. J
Urol 148:1549, 1992.
29. WAGNER TH et al. Cross-cultural Development of a
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___________________
114
 Committee 5

Clinical Evaluation and the

Doctor-Patient Dialogue

Chairman
E. MEULEMAN

Members
G.BRODERICK,
H.MENG TAN,
F. MONTORSI,
I.SHARLIP,
Y.VARDI

115
 CONTENTS

2. PENILE PHARMACO DUPLEX ULTRASOUND

INTRODUCTION (PPDU) [68]
3. PPDU EXAMINING PROTOCOL
A. INITIAL ASSESSMENT OF 4. PPDU ASSESSMENT OF THE PENILE
A PATIENT WITH ED INFLOW TRACT
5. PPDU ASSESSMENT OF THE
I. HISTORY VENOOCCLUSIVE MECHANISM
1. M EDICAL HISTORY 6. PPDU IN STAGING OF PEYRONIE'S
DISEASE
2. SEXUAL HISTORY [4]
3. P SYCHOSOCIAL HISTORY 7. DYNAMIC INFUSION PHARMACO-CAVERNO-
SOMETRY AND CAVERNOSOGRAPHY (DICC)
II. PHYSICAL EXAMINATION 8. DICC UNDER CONTROLLED COMPLETE
SMOOTH MUSCLE RELAXATION
III. DIAGNOSTIC TESTS 9. PENILE ARTERIOGRAPHY [87, 88,89]
10. CT- AND MR IMAGING
1. RECOMMENDED DIAGNOSTIC TESTS
11. NUCLEAR IMAGING
2. O PTIONAL DIAGNOSTIC TESTS
3. S PECIALIZED DIAGNOSTIC TESTS III. PSYCHOPHYSIOLOGICAL
TESTS
IV. PATIENT EDUCATION
1. NOCTURNAL PENILE TUMESCENCE /
RIGIDITY TESTING (NPT)
V. TREATMENT
2. VISUAL EROTIC STIMULATION (VES)
VI. SPECIALIST CONSULTATION IV. NEUROLOGICAL TESTING
AND REFERRAL [105, 106]

B. SPECIALIZED 1. BASIC PRECEPTS IN NEUROPHYSIOLOGICAL

EVALUATION TESTING
2. TESTING OF THE EFFERENT (MOTOR)
I. ENDOCRINE EVALUATION PATHWAYS
3. TESTING OF THE AFFERENT (SENSORY)
1. TOTAL TESTOSTERONE
PATHWAYS
2. Free TESTOSTERONE [23]
4. AUTONOMIC TESTS
3. LUTEINIZING HORMONE (LH) AND
FOLLICLE STIMULATING HORMONE (FSH)
V. PSYCHOLOGICAL OR
4. PROLACTIN (PRL) PSYCHIATRIC EVALUATION
5. THYROXINE
6. THYROID STIMULATING HORMONE (TSH)
VI. SUMMARY STATEMENT
II. VASCULAR DIAGNOSTICS

1. IN OFFICE PENILE INJECTION PHARMACO- REFERENCES

TESTING

116
 Clinical Evaluation and the
Doctor-Patient Dialogue
E. MEULEMAN,
G.BRODERICK, H.MENG TAN,, F. MONTORSI, I.SHARLIP, Y.VARDI
INTRODUCTION
The recent proliferation of laboratory and clinical
research concerning erectile function and erectile
dysfunction (ED) and the resulting emergence of
effective oral treatment has greatly increased the
number of patients seeking medical help for ED.
ED-care has shifted from the specialist to the pri-
mary care physician. Consequently, the basic
approach to the management of ED has become
multidisciplinary and goal-directed [1].
The aim of the committee was to serve three pur-
poses. The first is to help the primary care physi-
cian who does not have much experience in mana-
geing patients with ED (Initial assessment). The
second is to define the indications for referral to a
specialist. The third is to outline the optional com-
ponents of a specialised evaluation.
A. INITIAL ASSESSMENT OF
A PATIENT WITH ED
The cornerstone of clinical assessment for all men
with ED is the initial evaluation. This work-up
should be performed by a physician knowledgeable
in male sexual function and dysfunction, and with
sensitivity toward cultural, ethnic and religious fac-
tors. Although a patient with ED may be referred to
a non-physician for psychosexual therapy, the
medical (pharmacological) and surgical therapies
for ED require the involvement of a physician (a).
Basic knowledge of anatomy and physiology of
male sexuality is essential. In special situations, a
multidisciplinary approach may be required. The
initial evaluation of the patient with ED should
consist of a comprehensive medical, sexual and
117
psychosocial history, a physical examination and
diagnostic testing. Additionally, diagnostic tests are
recommended with a proven value in specific
patient profiles. Their utility is left to the clinical
judgement of the treating physician.
The rationale for testing and the potential impact
of a positive test should be explained to the
patient. Upon completion, the physician should be
able to characterize the problem, to propose the
treatment-options and to assess the need for addi-
tional testing and specialist consultation. Patient
and (partner’s) need, expectations and priorities
are important elements in this assessment.
I. HISTORY
It is very important for the physician to create a
therapeutic alliance with the patient. Although not
always possible on the first visit, every effort
should be made to involve the patient’s partner in
the process. Cultural and social preferences as
well as individual patient needs and preferences
may influence the partner ’s availability.
FLOW CHART FOR THE INITIAL EVALUATION
History
• Medical
• Sexual
• Psychosocial
Physical Examination
Diagnostic Tests
Patient Education
Treatment ↔ Specialist consultation
(a) It was the opinion of some of the delegates at the meeting of
the first consultation on Erectile Dysfunction in Paris, July first
1999, that the initial work-up may be done by a specialized
nurse under the supervision and responsibility of a physician.
1. M EDICAL HISTORY RISK-FACTORS FOR ORGANIC ED
The goal of the medical history is to differentiate • Ageing
between psychogenic and organic ED and to iden-
tify risk factors for organic ED. For the first pur- • Hypertension
pose the Leiden Impotence screening Test (LIST) • Atherosclerosis
may be helpful [2]. • Diabetes mellitus
• Smoking
THE KEY-ELEMENTS OF THE LEIDEN • Depression
IMPOTENCE SCREENING TEST • Pelvic/perineal/penile trauma or surgery
Characteristic Organic Psychogenic • Neurological illness
• Onset Gradual Acute • Endocrinopathy
• Circumstances Global Situational • Prescription and recreational drugs
• Course Constant Varying
2. SEXUAL HISTORY [4]
• Non-coital
erection Poor Rigid BASIC-ELEMENTS IN THE SEXUAL HISTORY
• Psychosexual
problem Secondary Long history • Nature of the problem
• Partner problemSecondary At onset • Psychosocial context
• Anxiety and fear Secondary Primary • Chronology of the problem
• Severity of the problem
For the latter purpose the medical history should • Definition of patient’s needs and
focus on risk factors for organic ED. In this context, expectations
it is appropriate to make inquiries into the patient’s
lifestyle. Does the patient have any high-risk habits The goal of the sexual history is to define the
such as smoking, excessive alcohol consumption or nature, chronology, psychosexual context and
drug-abuse? Referral to a specialist may be appro- severity of the problem. To obtain an accurate
priate at this point to assist the patient in controlling sexual history it is necessary for the doctor and
his abusive habits. Often ED is a first symptom of patient to discuss matters privately. Many men
cardiovascular disease or chronic illness. An and women find it difficult to talk about their
example is that 16% of patients presenting with ED sexual problems. The physician should put the
have previously undiagnosed coronary artery disea- patient at ease by listening carefully and by crea-
se [3]. Or, over 35% of all male patients with dia- ting an atmosphere of privacy, security and confi-
betes mellitus suffer from some degree of ED [125]. dentiality. It is also of importance for the physi-
The patient’s prescription drugs must be carefully cian to be «open» to the patient’s problems and to
identified, because they may be an important causal speak in terms which the patient uses and unders-
factor. The most important of these are antihyper- tands. In the initial consultation, the physician
tensives, antidepressants and tranquillisers [126]. should let the patient do most of the talking in
The use of certain drugs can be a contraindication to order to acquire a clear idea of what the problem
some forms of ED-treatment (e.g. nitrates in the is and what the patient wants. Any questions that
case of sildenafil). the physician asks during this phase should have
Depression is often associated with ED. Depressed an open-ended character.
mood is a common reaction to marital or sexual Validated sexual-function questionnaires may be
difficulties and primary depression is often asso- used to assist in obtaining the sexual history. Sex
ciated with ED. Treatment of depression may questionnaires are a valuable option to the sexual
result in improved sexual function and mood history; they may help the physician to initiate or
[127]. structure the interview but are not a substitute for

118
the patient - physician dialogue. In clinical practi-
ce, the substitution of a questionnaire for ‘the
patient - physician dialogue’ may result in a failu-
re to diagnose the etiology of ED (organic versus
psychological), and may not address the specific
religious, cultural, educational and economic fac-
tors of the individual patient.
Primarily, sex questionnaires are research tools,
which provide efficacy endpoints in drug studies.
To date, the ‘international index of erectile func-
tion (IIEF)’ [5], the ‘erectile dysfunction invento-
ry of treatment satisfaction (EDITS)’ [6], and the
‘brief male sexual function inventory for urology’
[7] are frequently used for this purpose.
To acquire a clear understanding of the various
aspects of the patient’s sexual activity, the sexologi-
cal mini-anamnesis may be used. [8] This history,
which is based on the sexual response cycle defined
by Masters & Johnson [9], enables the physician to
obtain in a simple manner a global picture of the
nature and extent of the problem. To acquire a dee-
per understanding of ED this list can be supple-
mented by a few specific questions. Physicians
manageing patients with sexual dysfunction should
be thoroughly familiar with the sexual response
cycle. Many patients who ask for help with a sexual
problem have little difficulty answering the ques-
tions on the sexological minianamnesis.
SEXUAL RESPONSE CYCLE ACCORDING TO
MASTERS & JOHNSON
1. Desire
2. Excitement
3. Plateau
4. Orgasm
5. Resolution
Problems with erection arise, in particular, in
phases 2 and 3, where interaction with the envi -
ronment and the partner plays an important role
a) Desire
The assessment of sexual desire is somewhat easier
in men than in women, because desire is manifested
in men as the urge to initiate lovemaking. However,
the patient may misinterpret a reduced level of desi-
re (libido) as ED. Sexual response for many men is
synonymous with obtaining an erection, but also, of
course, sexual response has an experiential compo-
119
nent. The main difficulties are 1) to decide whether
loss of sexual desire preceded or is a result of ED,
and 2) to distinguish between loss of desire and
concern about sexual performance, which can
become a preoccupation. Loss of desire following
ED is an understandable response to the genital fai-
lure. But loss of sexual desire, which clearly prece-
ded other dysfunction, may have organic causes,
such as hormonal deficiency, which need to be
identified. The pathogenesis of decreased sexual
desire is often complex and heterogeneous. Its elu-
cidation may require much more careful history
taking than is necessary with other types of sexual
problems. A man’s attitude to his general health
may be important because concern about sexual
function is sometimes part of a general hypochon-
driacal pattern. Concerns about body image are
sometimes important.
b) Excitement
In assessing the excitement phase, it is important
to establish whether full erection can occur in any
situation or at any stage during lovemaking.
c) Orgasm and ejaculation
Orgasmic disturbances, such as premature ejacula-
tion, are common and must be clearly distinguished
from erectile disturbances. Premature ejaculation is
sometimes mistaken for an erectile problem becau-
se of the rapid loss of erection that follows it.
Adult-onset premature ejaculation is often associa-
ted with erectile failure, as a result of the perfor-
mance anxiety caused by the erectile problem.
Also, with erectile impairment, the time taken to
elicit an erection may be prolonged, whereas that
required to produce ejaculation is not. This can
give the impression of premature ejaculation.
Absent or delayed ejaculation also requires careful
description. Does the problem occur only in the
presence of the partner; e.g. is the patient able to
ejaculate normally when masturbating on his own?
Or is it only a problem intravaginally, i.e. can he
ejaculate outside the vagina during love play with
his partner?
d) Pain
Pain experienced by one of the partners during
lovemaking (e.g. as a result of balanitis or post-
menopausal changes in the female) can also have
an inhibiting effect on sexuality. The degree of
satisfaction can be reduced even though there are
no serious problems with erectile function.
 SEXOLOGICAL MINI-ANAMNESIS
• I understand that, at present, things are not going
quite right sexually. I want to ask you a few
questions so I can get a clear idea of your pro -
blem. Can you tell me again what is not going
quite right in your sexual relationship?
• Have you noticed any changes in the level of
your sexual desire?
• Have you noticed any changes recently in the
pleasure you get from sex?
• Do you get turned on sexually as easily as you
used to?
• Have you noticed any changes in the way your
penis gets hard?
• What are your nighttime/early morning erections
like?
• Is intercourse still satisfying? Do you occasio -
nally come too soon?
• Do you experience any pain when inserting your
penis into the vagina or during sexual inter -
course?
• Do you usually have a satisfying orgasm?
• How long have you had these problems? Are they
always present under all circumstances when
you want to have sex, or are you occasionally
free from them?
• Does your partner also have a sexual problem,
as a result of illness or old age perhaps, which
she doesn’t want to talk about?
• Do you or does your partner suffer from any ill -
nesses which you think your sexual problems
are responsible for?
• How are you coping with these problems? Are
you, or your partner or both of you weighed
down by them?
• Finally, can you tell me something about the
things which, in your opinion, are going well in
your sex life?
• Is there anything else you would like to ask me
about your sexuality?
120
THE COMMITTEE’S SAMPLE SEXUAL HISTORY
QUESTIONS
CHRONOLOGY
- Could you describe your sexual problem?
- When was the last time you had a satisfactory
erection?
- How was your sexual function prior to this time?
- Was the onset of your dysfunction gradual or sud -
den?
- When was the last time you had satisfactory pene -
tration?
- What portion of sexual attempts is satisfactory to
you?
- Is your partner satisfied with your sexual func -
tion?
- If we can restore your erections what would be
your average frequency of sex each month?
SEVERITY / QUANTIFY
- Do you have morning or night time erections?
- How strong are the erections you get with mastur -
bation?
- On a scale of 1 to 10 how would you rate the stiff -
ness of those erections, ten being normal?
- With sexual stimulation can you initiate an erec -
tion?
- With sexual stimulation can you maintain an erec -
tion?
- Do you lose erection before penetration, or before
climax?
- Do you have to concentrate to maintain an erec -
tion?
- Do you lose the erection if you don’t have conti -
nuous direct stimulation to the penis?
- Is there a significant bend in your penis?
- Do you have pain with erection?
SEVERITY / QUALIFY THE IMPACT ON
THE PATIENT / PARTNER
- How strong is your desire for sex, now and in the
past?
- Is your erectile problem partner or situational
specific?
- Is your partner able to become aroused when you
have sex together?
- What has been your partner’s reaction to your
sexual difficulties?
- Do you have difficulty reaching orgasm?
- Do you have problems with ejaculating too
soon or not at all?
3. PSYCHOSOCIAL HISTORY
A psychosocial assessment is valuable in every
patient. Given the interpersonal context of sexual
problems, the physician should carefully assess
past and present partner relationships. Sexual dys-
function may affect the patient’s self-esteem and
coping ability, as well as his social and occupatio-
nal performance. The physician should not assume
that every patient is involved in a monogamous
heterosexual relationship. For that reason, it is
advisable to begin with the «Are you sexually acti-
ve at the moment» or «do you have a regular sex
partner?» and then ask «Is that a hetero- or homo-
sexual relationship?» The early stages in the deve-
lopment of a problem are often of crucial signifi-
cance to treatment. Were there particular times of
change in the sexual relationship? If so, what was
going on in the patient’s life at those times? In
addition, questions should be asked about other
important elements of the patient’s life, including
other relationships, work, financial security and
family life. Does overload or stress play a part,
either at work or in his private life?
ELEMENTS OF THE PSYCHOSOCIAL HISTORY
• ageing
• lifestyle factors
• current psychological state
• symptoms of depression
• altered self esteem
• coping skills
• past and present partner relationships
• sexual practices
• job and social position satisfaction
• history of sexual trauma / abuse
• educational attainment
II. PHYSICAL EXAMINATION
Although in general, a physical examination does
not identify the cause of ED, a focused physical
examination should be performed on every patient
with ED. The physical examination should include
a general screening for medical risk factors that
are associated with ED (co-morbidity) such as,
121
body habitus (secondary sexual characteristics), an
assessment of the cardiovascular, neurological and
genital system focusing on penile, testicular and
rectal exam. The physical examination may cor-
roborate aspects of the medical history and may
occasionally reveal unsuspected physical findings
(e.g. decreased peripheral pulses, penile plaques,
atrophic testes, and suspicion of prostate cancer.
PHYSICAL EXAMINATION
• Complete genital exam (digital rectal)
• Gynaecomastia
• Body hair, fat distribution
• BP, heart rate, peripheral pulses, edema
• Vibratory sensation, BCR
• Lower extremity strength and coordination
III. DIAGNOSTIC TESTS
The physician must tailor the laboratory work-up
based on patient complaints and risk factors outli-
ned by the history and take into consideration the
cost and availability of testing resources.
The diagnostic tests used in the assessment of the
patient with ED may be stratified as:
1. RECOMMENDED DIAGNOSTIC TESTS
A test of proven value in the evaluation of patients
with ED, use of which is recommended during ini-
tial evaluation. These tests include the following:
a) A fasting glucose or glycosylated hemoglobin
(HbA1C) and lipid profile - if not available within
the previous 12 months - to rule out diabetes mel-
litus and hyperlipidemia both of which are signifi-
cant risk factors for ED.
b) A morning testosterone assay to assess the
hypothalamic-pituitary-gonadal axis. Although
controversy exists as to the relative value of the
various testosterone assays (total, free or bioavai-
lable), consensus exists that at least one of these
assays should be performed. It may be argued that
testosterone testing is statistically associated with
a low positive yield. In a group of men with hypo-
gonadism, testosterone replacement represents a
potentially reversible form of ED.
2. OPTIONAL DIAGNOSTIC TESTS
A test of proven value in the evaluation of specific
patient profiles, with use left to the clinical judge-
ment of the treating physician.
OPTIONAL DIAGNOSTIC TESTS
- Prolactin, free and total testosterone, LH
- Thyroid stimulating hormone (TSH)
- CBC
- Urinalysis (dip or microscopic)
- PSA
3. SPECIALIZED DIAGNOSTIC TESTS
A test of value in selected patients. Should be
considered only in a specialized setting (see sec-
tion B).
IV. PATIENT EDUCATION
The rational selection of therapy by patients is
only possible following appropriate education.
Patient education is also important in fostering a
therapeutic relationship, facilitating patient-physi-
cian communication and enhancing patient com-
pliance.
When all the information from the history, physi-
cal examination and the supplementary diagnostic
tests have been collected, it is time to actually for-
mulate the complaint. Generally, the information
obtained from the initial evaluation is sufficient to
direct the majority of patients toward therapy.
Not everyone who presents with an erection pro-
blem is a candidate for treatment. With older
patients, it is advisable to explain that the rigidity
of erection decreases with age, as also does the
extent to which the penis stands upright. The fre-
quency of sexual activity also decreases. The
refractory period after orgasm, in which the penis
can not become rigid, increases from several
minutes in a young man to hours or even days in
older men. Many men find that the pleasure of the
orgasm becomes less intense as they get older.
Finally, the patient’s female partner may also
experience changes in sexuality, complicating the
couple’s sexual dysfunction
122
V. TREATMENT
Following the completion of the diagnostic eva-
luation, all treatment options should be discussed
with the patient (and his partner) and treatment
choices should be made.
VI. SPECIALIST CONSULTATION
AND REFERRAL
With the advent of effective oral treatment and the
subsequent popularization of ED, new categories
of physicians are involved in the initial evaluation
and treatment of ED. Only in a minority of
patients, referral to a specialist is necessary. Tradi-
tionally, the urologist is the specialist in the eva-
luation and treatment of men with ED.
A wide range of diagnostic tests is available.
These can be used to separate somatically deter-
mined from purely psychogenic ED or to tailor
specific vascular surgery in patients with arterial
disease or venoocclusive dysfunction. In the majo-
rity of ED patients, the diagnostic evaluation has
little impact on the therapeutic options. Diagnostic
categorization is particularly worthwhile for those
patients in whom a reversible form of ED is sus-
pected.
INDICATIONS FOR SPECIALIST REFERRAL
• Patient’s request
• Treatment failure
• Peyronie’s disease
• Primary ED
• History of pelvic/perineal trauma
• Cases requiring vascular or neurosurgical
intervention
• Complicated endocrinopathy
• Complicated psychiatric or psychosexual
disorder
• Complex relationship problems

B. SPECIALIZED
EVALUATION
Some of these tests are illustrated in the Atlas
section p. 679
OPTIONS FOR TESTING IN A SPECIALIZED
EVALUATION
• Endocrine evaluation
• Vascular evaluation
In office penile injection pharmacotest
Penile pharmaco Doppler Ultrasound (PPDU)
Dynamic infusion pharmaco-cavernosometry and
cavernosography (DICC)
Penile arteriography
CT - and MR-Imageing
Nuclear imageing
• Psychophysiological tests
• Nocturnal Penile Tumescence/rigidity Testing
• Visual Erotic Stimulation (VES)
• Neurophysiological evaluation
I. ENDOCRINE EVALUATION
Although endocrinopathy is a rare cause of male
erectile dysfunction, ED can be the presenting
symptom of several endocrine disorders. Hypogo -
nadism and hyperprolactinemia account for the
majority of these cases [10]. In the literature the
prevalence of hypogonadism in men with ED
ranges from 4.3 to 19.3% [11]. The rate of hyper-
prolactinemia ranges from 1% to 5% [12,13,14].
The prevalence of thyroid disorders is less than
1% [15]. Despite the low diagnostic and therapeu-
tic [16] yield and the persisting controversy as to
the relative value of the various testosterone
assays (total, free or bioavailable) it is considered
important to include a routine total testosterone in
the evaluation to detect subtle hormonal changes
in men with ED so as not to miss hypogonadism or
a partial androgen deficiency syndrome in the
ageing male [17] (PADAM) (c) or associated
serious medical conditions, such as pituitary
tumours, which are treatable [18, 19, 20,21].
(b) Only 55 percent of men with ED and primary hypogonadism and 17 percent of men with ED and secondary hypogonadism respond to andro-
gen replacement therapy [129]. (c) The clinical manifestations of androgen deficiency in the ageing male are :Depression, diminished libido, ED,
fatigue, infertility, muscle weakness and osteoporosis. (d) When SHBG is increased, the non-SHBG bound testosterone fraction, which constitutes
the bioavailable testosterone may be decreased, despite normal level of total testosterone.
123
QUESTIONS AND ANSWERS IN DIAGNOSIS OF
ENDOCRINE CAUSES OF ED
• Which test should be used for screening
of androgen deficiency, total or free testostero -
ne?
Ideally, free if cost is not a factor.
• Should any test at all be done for the initial eva -
luation of the standard patient with ED? Yes, at
least total Testosterone. If cost is a factor, only in
men > 50 years. Otherwise you may miss 40%
of patients with androgen deficiency [128].
Because steroid hormone binding globulin
(SHBG) is known to be decreased in hypothyroi-
dism, obesity and acromegaly, and increased in
hyperthyroidism and oestrogen therapy, it is
necessary to measure the free biologically active
testosterone in these conditions, when total tes-
tosterone can be misleading (d). If testosterone is
low, a repeat test is advised. If the second test
reveals again a low serum testosterone, a full hor-
monal evaluation consisting of LH, Prolactin,
FSH, and TSH is recommended.
If the patient has a history of decreased libido
and/or the physical examination reveals gynaeco-
mastia or testicular atrophy, a full endocrinologi-
cal evaluation is advised. The blood samples
should be taken between 8 and 10 am because of a
diurnal peak in the morning.
If the prolactin level is raised, a repeat test should
be done with the patient completely rested and
blood sample taken in the morning after awake-
ning. Secondary causes of hyperprolactinemia
should be looked for. Persistent, unexplained
hyperprolactinemia should warrant a CT- or a
gadolinium enhanced MRI-scan of the head to
exclude a pituitary tumour.
ED and inhibition of sexual drive also may be
associated with thyroid disorder, both hypothy-
roidism and hyperthyroidism. However, the
mechanism of how thyroid disorders affect male
sexual function is still uncertain. It is not known
whether dysthyroidism causes ED or whether
dysthyroidism and ED are associated by occur-
rence in similar populations. Therefore evalua-
tion of thyroid should be considered only in a
specialised setting.
 SECONDARY CAUSES FOR HYPERPROLACTINE-
MIA IN THE MALE
• Coitus
• Hypothyroidism
• Stress
• Chronic renal failure
• Exercise
• Severe liver disease
• Sleep
• Drugs [22]
Protirelin, fenfluramine, thyrotropin-releasing
hormone, estrogens, antipsychotic agents,
methyldopa, opiates, opioids, metoclopramide,
reserpine and amoxapine
DESCRIPTION OF THE AVAILABLE HORMONAL TESTS
1. TOTAL TESTOSTERONE
• Secreted episodically from testicular Leydig
cells in response to luteinizing hormone (LH)
pulses.
• Diurnal pattern with a peak level in the early
morning and a nadir in the evening.
• 98% of testosterone is bound to plasma proteins;
majority of the binding is to albumin 40% and
globulin 57%. Only 2% of total testosterone are
free. Bioavailable testosterone consists of both
free and albumin-bound testosterone.
• Total testosterone level decreases with age.
2. Free TESTOSTERONE [23]
• Consists of only 2% of total. Biologically active.
• Exert effects in target cell where it is converted
to more potent dehydrotestosterone by 5 alpha-
reductase.
• Level affected by estrogens [24], thyroid hormone
and cirrhosis (decrease free testosterone) and
androgen, growth hormone, glucocorticoids and
obesity (increase free testosterone level).
• Very much more expensive to measure free tes-
tosterone than total testosterone.
• Testosterone replacement improved sexual func-
tions only in men with low free fraction but NOT
in subjects with a normal free fraction [25].
• Free testosterone level lowers significantly with
ageing.
• Prevalence of partial androgen deficiency in
ageing males (PADAM) may be as high as 50%
if free testosterone level is used.
124
3. LUTEINIZING HORMONE (LH) AND FOL-
LICLE STIMULATING HORMONE (FSH)
• LH and FSH are gonadotrophins, synthesised
in the pituitary gland.
• LH and FSH increase testicular testosterone
and spermatogenesis respectively.
• Metabolic clearance rate of LH is considerably
greater than that of FSH.
• FSH is a more sensitive reflection of the serum
gonadotropin level than LH, because FSH is rai-
sed before LH and LH is rapidly metabolised.
• Asingle measurement of circulating LH may be
as much as 50% above or below the mean level.
• Circulating levels of both LH and FSH are
increased in ageing.
4. PROLACTIN (PRL)
• Synthesised and secreted by the anterior pitui-
tary gland.
• Serum prolactin increases during sleep, peak
in the early morning and decline immediately
after awakening. Basal concentration varies
considerably.
• The hypothalamic peptides, thyrotropin -
releasing hormone (TRH) and vasoactive
intestinal peptide (VIP) stimulate release of
PRL from the pituitary.
• The hypothalamus exerts tonic inhibitory
control over prolactin release, mainly through
the prolactin - inhibiting factor dopamine.
• Prolactin levels in human blood are elevated
with oestrogen, antipsychotic, antidepressant,
some tranquillising drugs and stress and
decreased by L-dopa and ergot derivatives.
5. THYROXINE
• The L-isomer is the active iodine compound
existing normally in the thyroid gland.
• May need to measure T3 for certain cases of
thyroid disorders.
6. THYROID STIMULATING HORMONE (TSH)
• Produced by the anterior lobe of the pituitary
gland.
• Stimulates the growth and function of the thyroid
gland.
• Used in diagnostic test to differentiate primary
and secondary hypothyroidism.

II. VASCULAR DIAGNOSTICS
Organic factors in ED may be classified as neuro-
genic, myogenic, endocrine arteriogenic and
venoocclusive [26]. The latter two are the causes
of the clinical entity known as vascular ED. Risk
factor assessments suggest that ED is most often
of a vascular etiology [27]. However, because
combinations of etiologies are common, the term
vascular ED does not rule out the presence of
contributing psychological or neurological factors.
The two principal causes of arteriogenic ED are
atherosclerotic vascular disease [28, 29] and trau-
matic arterial occlusion, following blunt pelvic or
perineal trauma. The most common comorbidities
for ED due to atherosclerotic vascular disease are
cigarette smoking, diabetes, hypertension and
hypercholesterolemia.
Venoocclusion is a hydraulic process related to
volume and pressure changes mediated by varia-
tions of the tone of the cavernous smooth muscle
cells. Venooclusive dysfunction of the cavernous
body may have several causes [30], such as
1) neurogenic changes;
2) altered intercellular communication [31,32];
3a) heightened contractility of corporeal smooth
muscle, secondary to increased reactivity to alpha1-
adrenoceptor activation with age and disease [33];
3b) impaired relaxation of corporeal smooth
muscle [34]; and
4) parenchymal changes at the level of extracellu-
lar matrix or of the corporeal smooth muscle cells
[35, 36, 37].
Several tests are available for evaluating the peni-
le vascular inflow and venooclusion. These inclu-
de pharmacotesting, enhanced pharmacotesting
such as in pharmaco penile duplex ultrasonogra-
phy (PPDU) [38], cavernosometry and selective
penile angiography.
INDICATIONS FOR VASCULAR TESTING
• To select patients for penile vascular surgery
• To establishing the proper dose of drug for intra -
cavernous injection therapy
• To allow the patient to experience the degree of
rigidity he still may get after a maximal pharma -
cological stimulus
125
• For scientific and clinical reasons to define the
cause of ED in groups of patients with a chronic
disease, such as diabetes mellitus or renal failure
[39, 40, 41].
• For medicolegal reasons.
The basic indications for vascular testing are
either to select patients for penile vascular surgery
or to test for the proper dose of drug for intraca-
vernous injection therapy. An adequate test for the
latter is the pharmacotest in the office, or even-
tually a trial of auto-injection therapy at home.
One should realise, however, that an adequate
erectile response does not rule out obstruction of
the penile inflow tract and that an inadequate erec-
tile response may be due to anxiety [42 , 43, 44].
To select patients for specific surgical treatments
such as penile revascularization or veno-restrictive
surgery, PPDU may be used as the first-line test to
discriminate between hemodynamic abnormalities
in the penile inflow tract and venoocclusive sys-
tem. If abnormal, more invasive tests such as
dynamic cavernosometry or penile angiography
may be required [45]. Today, it is recognised that
the best candidates for revascularization are youn-
ger men with isolated lesions in the pudendal arte-
ry, the common penile artery, or both, due to pel-
vic or perineal trauma [46]. The best candidates
for venorestrictive surgery are men with anatomic
abnormalities such as ectopic veins exiting the
cavernous corpora or abnormal communications
between the cavernosum and glans/spongiosum.
These men may have a history of primary ED,
congenital penile abnormalities, urethral surgery,
or blunt trauma to the erect penis [47].
In the era of effective oral medication, a reason for
a pharmacotest in the office is to allow the patient
to experience the maximal degree of rigidity he
still may get after maximal pharmacological sti-
mulation. This is clinically important because it
will allow the patient to compare the responses to
the oral agent and the intracavernous injection.
Thus, men failing on oral medication who have
experienced an effective response to an injection
may recall this a more advantageous therapy and
wish to try it at home when oral medication fails.
There are several methods to enhance the erectile
response to an intracavernous pharmacological
challenge: genital self-stimulation [48], vibratory
stimulation [49, 50] visual erotic stimulation
[51,52] and the application of a penoscrotal tour-
niquet [53].
Furthermore, it may be important for scientific and
clinical reasons to define the cause of ED in
groups of patients with a chronic disease, such as
diabetes mellitus or renal failure [54, 55, 56].
1. IN OFFICE PENILE INJECTION PHARMACO-
TESTING
The demonstration that vasoactive injections can
produce penile erection revolutionised the diagno-
sis and treatment of ED [57]. Intracavernous
vasoactive injectables provide a direct test of end
organ vascular integrity, and the first aetiology
specific pharmacotherapy (vasoactive medicine
for a penile vascular problem). Pharmacotesting is
the intracavernous injection of a vasoactive medi-
cation and rating of the subsequent erection quali-
ty by visual inspection and palpation [58]. Several
numeric scales have been proposed for rating erec-
tile rigidity; the simplest scale assesses the erec-
tion with three qualifiers:
1) inadequate for penetration;
2) adequate for penetration; and
3) unbending rigidity of at least 20 minutes dura-
tion.
The office pharmacotest is the most commonly
used diagnostic procedure for erectile dysfunction.
It is, despite its lack of specificity, cost-effective,
simple, minimally invasive, and performed
without special monitoring [59]. A positive res-
ponse (normal erectile rigidity of sustained dura-
tion of at least 20 minutes) implies the patient does
not have significant venooclussive or arterial
pathology. Recent correlation with PPDU
confirms that a positive pharmacological erection
test is indicative of normal venoocclusion but may
occur with borderline arterial function [60].
PHARMACOTESTING
• Pharmacotesting consists of an intracavernous
injection of a vasoactive agent and rating of the
subsequent erection quality by visual inspection
and palpation
• A positive response rules out significant vascular
pathology.
126
The most feared complication of pharmacotesting is
prolonged erection. The group most prone to pro-
longed erection are younger patients with nonvas-
cular ED and a better baseline erectile function [61].
There is no consensus as to the best intracavernous
agent or dosage for pharmacotesting. The ideal
agent offers a maximal erectogenic effect and a
minimal chance of prolonged erection [62,63]. A
variety of agents and dosage regimens have been
studied: papaverine 60 mg, papaverine 60 mg /
phentolamine 1 mg, papaverine 30 mg / phentola-
mine 1 mg, papaverine 45 /phentolamine 2.5,
PGEI 10 µg, 20 µg and 30 µg [64].
To date, a challenge of 10 µg of PGEI, combined
with genital stimulation and/or visual erotic stimu-
lation [65] (VES), is considered to be the best pos-
sible initial challenge [66]. It is noteworthy that
Montorsi et al advocate that «visual erotic stimula-
tion (VES) and manual self-stimulation of the geni-
talia should always be associated with a pharmaco-
test in order to maximise the relaxation of corporeal
smooth muscle and subsequently to obtain the grea-
test erectile response [67]. In case the best quality
erection is not obtained 20 minutes after this chal-
lenge, a second and eventually third injection at the
same dosage (re-dosing) is advised.
2. PENILE PHARMACO DUPLEX ULTRASOUND
(PPDU) [68]
All too often the response to pharmacotesting is
suboptimal. This situation leaves the physician
questioning: «does my patient have venous leakage,
arterial insufficiency, high anxiety or was the phar-
macological challenge too low?» PPDU provides a
more objective, minimally invasive evaluation of
penile hemodynamics following a pharmacotest
[69]. The accuracy of PPDU has been tested
through comparison to visual rating of erection fol-
lowing penile injection, cavernosometry-ography
and pharmaco-penile angiography [70].
Since its introduction by Lue (1985) [71] duplex
Doppler penile sonography has proven to be an
accurate and reproducible technique for evaluating
erectile dysfunction. With the initial grey scale
imaging of duplex sonography, study quality was
highly dependent on the skill of the examiner. Ves-
sel localisation within the corporal tissue was diffi-
cult and dorsal vessel imaging all but impossible.
The addition of colour has facilitated consistent
detection of dorsal, cavernous and urethral vessels.
PPDU permits the rapid acquisition and measure-
ment of small vessels in low flow states. High fre-
quency linear array transducers (5 to 10 MHz) pro-
vide the best images of the penis. The most recent
development in non-invasive penile diagnostics, 3-
dimensional power Doppler ultrasonography, facili-
tates the study of morphology and functionality of
the cavernous microcirculation in full detail [72 ,73,
74].
PPDU uses the imageing principles of pulsed Dop-
pler: a pulse of ultrasound is emitted from the trans-
ducer, reflected back and received. When the retur-
ning echo has a different frequency than the emitted
frequency a Doppler shift has occurred; ultrasound
reflecting back off a moving object (penile blood)
causes a Doppler Shift. Doppler frequency shift
depends on several factors: frequency of the trans-
ducer, velocity of the moving object (penile blood),
speed of sound through the medium (penile tissue)
and angle between the Doppler beam and direction
of blood flow. The blood flowing in a vessel, which
is approaching the transducer, will produce echoes
with a higher frequency than was emitted; blood
flowing away produces a lower frequency. As blood
flow velocities increase Doppler shift increases.
The Doppler shift is displayed on grey scale as
spectrum (waveform) or in PPDU as two dimensio-
nal colour image. In PPDU the colour display has
an angle dependence just like the grey scale spec-
trum of the Doppler shift. If the vessel runs paral-
lel to the skin surface, ultrasound scanning lines are
perpendicular (90’ Doppler angle). This will yield
no Doppler shift and no colour within the vessel.
To correct this problem of physics, linear array
transducers use phasing to steer the scan lines at a
more appropriate angle or an angled stand-off
wedge on the end of the transducer to provide a
non-perpendicular Doppler angle.
It should be noted that PPDU merely allows for a
qualitative and not for a quantitative assessment of
penile blood flow, because blood flow velocities
and not blood flow are measured.
3. PPDU E XAMINING PROTOCOL
The examination should be performed in a warm
darkened room. A warm secure setting is essential
to reduce anxiety and thus sympathetic cavernous
smooth muscle tone. The patient should be assu-
red that the examination setting is private and
secure. The patient should be supine; he need only
disrobe from the waist down. His attention should
be directed at the video monitor with periodic
explanation of images displayed: ‘you are going to
127
see ultrasound views of your penile vessels; some
of these run on the surface of the penis and two are
central arteries providing the pressure to your
erection. When the Doppler is activated the sound
you hear will be blood flowing into your penis
with each heartbeat.’
The corporal bodies should be scanned in the
transverse plane from base to tip to demonstrate
normal anatomy (paired cavernous and dorsal
arteries). The echo texture should be homoge-
neous, fibrotic processes are relatively hyper-
echoic in comparison. The penile vessels and flow
velocities are assessed in the sagittal plane (paral-
lel to the long axis of the penis). Vessels may be
scanned from a dorsal, ventral or lateral aspect of
the penile shaft. Lateral scanning will demonstra-
te both cavernous vessels in the same image, with
the hyper echoic septum in between both arteries.
Cavernous to cavernous collaterals are best ima-
ged in the sagittal projection.
4. PPDU ASSESSMENT OF THE PENILE
INFLOW TRACT
The parameters used to infer the integrity of the
penile inflow tract are cavernous peak systolic
velocity (PSV), acceleration time (time from the
start of systolic velocity to the maximum value),
and acceleration [75] (peak flow velocity over
acceleration time) [76]. Because penile erection is
a dynamic event, with a maximal challenge of the
cavernous inflow tract in the early phase of erec-
tion (tumescence), multiple blood flow velocities
should be measured between 1 to 10 minutes after
injection [77, 78]. Delayed responses are typical in
smokers and both the hypertensive and the
anxious patient.
PPDU ASSESSMENT OF PENILE INFLOW TRACT
• Parameters: Peak Systolic blood flow Velocity
(PSV) and Acceleration Time.
• A PSV < 25cm/s and/or an acceleration time
>122ms are indicative for severe penile arterial
insufficiency.
• PSV > 25 cm/sec but < 30 cm/s suggests mild
arterial insufficiency
• To assess the penile inflow tract, the blood flow
velocities should be measured between 1 and 10
minutes following pharmacostimulation
• Cavernous blood flow velocities decrease with
age. A functional venoocclusive mechanism may
compensate for decreased inflow across a wide
range of velocities
In the series from the University of California
San Francisco, normal subjects had a mean PSV
of 34.8 cm/sec [130, 131]. In the Baylor Univer-
sity study normal volunteers had mean PSV of 40
cm/s [132]. Normal volunteers in the Harvard
Medical School study [133] had mean PSV of 47
cm/s. Each of these groups concurs that a peak
systolic velocity < 25 cm/sec suggests severe peni-
le arterial insufficiency. In the Mayo Clinic series
PSV < 25 cm/sec had a sensitivity of 100% and
specificity of 95% in selection of patients with
abnormal penile angiography.A PSV of 35 cm/sec
or more is consistently associated normal penile
arteriograms. The Mayo Clinic group recom-
mends that in patients with bilateral peak systolic
velocities > 30 cm/s, arteriography should not be
performed [134].
Penile blood flow velocities decrease with age[79].
This does not necessarily imply that erectile func-
tion decreases proportionally, because, a functional
venoocclusive mechanism may compensate for
decreased inflow across a wide range of velocities.
Thus, the dynamics of venoocclusion is the more
critical factor in the ageing erectile response.
5. PPDU ASSESSMENT OF THE VENOOCCLUSI-
VE MECHANISM
Parameters to assess the venooclussive function are
end diastolic flow velocity (EDV) and resistance
index (RI) [80 , 81]. Clinically, EDV and RI corre-
late with erectile response, since both are descrip-
tions of penile rigidity/intracavernous pressure.
The formula for RI = PSV - EDV / PSV. The
value of RI depends on the resistance to arterial
inflow, and in the context of corporeal physiolo-
gy this is a function of changing intracorporeal
pressure during the various phases of erection. As
penile pressure equals or exceeds diastolic syste-
mic pressure, diastolic flow in the corpora will
approach zero and the value for RI approaches
1.0. In full rigidity diastolic flow in the caver-
nous arteries may reverse (momentarily be retro-
grade) in which case the calculated RI will be >
1.0. During tumescence or with a partial erection
diastolic antegrade flow persists and the value for
RI remains < 1.0.
128
PPDU ASSESSMENT OF THE VENOOCCLUSIVE
MECHANISM
The diagnosis 'venoocclusive dysfunction' should
be considered when PSV > 30 cm/s, and EDV > 3
- 5 cm/sec or RI < 0.9. , associated with erectile
rigidity rated as inadequate.
In a Mayo Clinic study an EDV of > 3cm/s mea-
sured 15-20 minutes after intracavernous pharma-
cological stimulation yielded a specificity of 94%
and sensitivity of 69% for detection of venoocclu-
sive dysfunction when compared with pharmaco-
cavernosometry. In an Australian series, investi-
gators found RI calculations 15 minutes after
intracavernous pharmacological stimulation corre-
lated well with cavernosometry [135]. In Japan,
investigators found RI > 0.9 was associated with
normal dynamic infusion cavernosometry in 90%
and RI < 0.75 was associated with venous leakage
in 95% of patients [136]. Based on these data, the
diagnosis 'venoocclusive dysfunction' should be
considered when PSV > 30 cm/s, and EDV > 3 - 5
cm/sec or RI < 0.9, associated with erectile rigidi-
ty rated as inadequate.
It is important to note that the deep dorsal vessels
are not subjected to changing intracorporeal pres-
sure during erection. Therefore, a well-sustained
rigidity is associated with persistent antegrade
diastolic flow in the dorsal arteries. Moreover,
deep dorsal vein flow is not reduced or shut off
during erection and therefore blood flow in the
deep dorsal vein should not be interpreted as evi-
dence of venoocclusive dysfunction
6. PPDU IN STAGING OF PEYRONIE'S
DISEASE
Indications for performing PPDU in Peyronie's
disease include patients with a severe angulation
in whom corrective surgery is considered or men
who claim complete loss of erection and request
placement of a penile prosthesis.
Potentially the most useful preoperative staging
information, is the demonstration of collaterals
from the dorsal vascular bundle. Dorsal artery
collaterals piercing down through the tunica to
anastomose with the ipsilateral cavernous artery
may be in proximity to plaques. Operative mobi-
lisation of the neurovascular bundle for plaque
excision in these cases would of necessity sacrifi-
ce the dorsal contribution to cavernous inflow. The
tunica albuginea is normally hyper- echoic compa-
red to the corpora proper. As the corporal bodies
distend with blood the cavernous sinusoids beco-
me more hypo-echoic increasing the contrast bet-
ween the tunica and corpora. Penile plaques are
hyper-echoic thickenings of the tunica albuginea.
The typical dorsal plaque underlies the dorsal
vasculature. Denser plaques cast an acoustical
shadow and are well visualised in either the
transverse or sagittal plains. If the plaque casts
an acoustic shadow like a renal stone, then calci-
fication should be suspected and plain radio-
graphs taken. Although most plaques localise to
the proximal and middle third of the pendulous
shaft, distal plaques even at the level of the coro-
na may cause curvature. Circumferential narro-
wing of the corporal bodies by plaque sonogra-
phically results in an hour glass shape to the erec-
tion; the patient complains of 'hinging' with erec-
tion.
For medicolegal reasons it also may be important
to measure penile length and diameter during
PPDU, as every operation on the penile shaft is
associated with some risk of shortening. Often
the patient's perception of postoperative shorte-
ning of his penis exceeds the reality and it is use-
ful to document the pre- and postoperative peni-
le measurements.
7. D YNAMIC INFUSION PHARMACO-CAVERNO-
SOMETRY AND CAVERNOSOGRAPHY (DICC)
Insufficient corporal venoocclusion is implicated
in up to 50% of patients complaining of ED who
have vascular testing. DICC is invasive requiring
two needles to remain in the penis one for hepari-
nized saline / radiographic contrast infusion and
one for pressure recording. DICC is reserved for
the rare patient who might have a site-specific
venous leak, e.g. Peyronie's disease with poor rigi-
dity, history of penile fracture, perineal / pelvic
trauma history.
129
INDICATIONS FOR DICC
In patients who are suspected to have a site-speci -
fic leak and in whom vascular surgery is conside -
red a treatment option
• Congenital
• Peyronie's disease with poor rigidity
• History of penile fracture
• Perineal / pelvic trauma history
DICC is only performed when vascular surgery is
considered a treatment option [82]. A correct dia-
gnosis and the demonstration of venous leakage
require complete smooth muscle relaxation. Failu-
re to achieve complete pharmacological corporal
smooth muscle relaxation is an inherent source of
error in DICC testing. A method that enables
DICC under conditions of known corporeal smoo-
th muscle relaxation increased its reliability for
clinical practice [83,84,85].
8. DICC UNDER CONTROLLED COMPLETE
SMOOTH MUSCLE RELAXATION
Two 21-gauge needles are inserted into the mid-
pendulous shaft (dorsolateral); injection of
vasoactive agent is made and equilibrium pressure
measured at ten minutes. An intracavernous pres-
sure of 80-90 mm Hg associated with rigidity is a
normal response with no significant venoocclusive
dysfunction. Infusion of heparinized saline is the
next step; the flows to maintain the intracaverno-
sal pressures at respectively 30, 60, 90,120,and
150 mm Hg are measured. Complete smooth
muscle relaxation is characterised by a linear rela-
tionship between the flows to maintain and intra-
cavernosal pressures. If this linear relationship is
not obtained, the patient is re-dosed with a vasoac-
tive agent. At 150 mm Hg, flow of saline is stop-
ped and intracavernosal pressure fall over 30
second is recorded. Maintenance flow rate (MFR)
is considered [86] as the most important criterion
of venoocclusive function. It is the flow to main-
tain the intracavernous pressure at 150 mm Hg. In
a state of complete smooth muscle relaxation, nor-
mal flow rates to maintain intracavernous pressu-
re at a pressure of 150 mm Hg is 3 ml/min or less.
The Pressure Decay, fall of intracavernous pressu-
re over 30 seconds from 150 mm Hg should be
less than 45 mm Hg.
 DICC RECOMMENDATIONS
• A correct diagnosis of venoocclusive dysfunction
requires complete cavernous smooth muscle
relaxation.
• Failure to achieve complete smooth muscle
relaxation is an inherent source of error in DICC
testing.
If cavernosometry performed in a proven state of
complete smooth muscle relaxation, suggests that
significant venoocclusive dysfunction is present,
the anatomic site of leakage can be demonstrated
by intracavernous infusion of contrast (cavernoso-
graphy) at an intracavernosal pressure of 90 mm
Hg.
Please note that establishing a diagnosis of isola -
ted venous insufficiency requires demonstration of
intact normal arterial inflow.
A method of functional evaluation of the caver-
nous artery at the time of cavernosometry is by
measuring its occlusion pressure. Cavernous arte-
ry systolic occlusion pressure (CASOP) is obtai-
ned during the third phase of DICC, following
complete smooth muscle relaxation after one or
several intracavernous vasoactive injections. The
CASOP is demonstrated by saline infusion and
monitoring cavernous arterial pulsatile flow with
Doppler. The intracavernous pressure at which
arterial pulsations reappear after suppression by
saline infusion (suppression by high intracaver-
nous pressure) is the CASOP. Normal CASOP
varies by < 35 mm Hg with the brachial artery sys-
tolic pressure.
9. PENILE ARTERIOGRAPHY [87, 88,89]
Penile arteriography is the radiographic imaging
of the internal pudendal arteries and their outflow
tracts. It set the initial standards for diagnosis of
vascular ED. Accurate penile arteriography
requires pharmacologically stimulated erection
since the vessels of the flaccid shaft are contracted
and tortuous and consequently hard to visualize.
Arteriography provides the best anatomic infor-
mation about the origin of the common penile arte-
ries, but as a screening test it is too invasive and
nonspecific for the assessment cavernosal hemo-
dynamics. It is generally reserved for young men
with a history of pelvic / perineal trauma who may
be candidates for operative revascularization [90].
130
10. CT- AND MR IMAGING
Computer Tomography and Magnetic Resonance
Imageing are sophisticated imageing techniques,
which visualize pelvic and genital anatomy. They
may be used in specialized settings of pelvic, per-
ineal or penile trauma or Peyronie's disease. These
imageing techniques provide no insights into
cavernosal hemo-dynamics.
11. NUCLEAR IMAGEING
Radioisotopic penography assesses the rate of
washout of a radioisotope from the penis follo-
wing pharmacotesting or visual erotic stimulation
[91, 92, 93, 94,95]. This test remains experimental
without standardization of isotopes or parameters
of penile blood flow. It provides dynamic but not
anatomic information.
III. PSYCHOPHYSIOLOGICAL
TESTS
1. NOCTURNAL PENILE TUMESCENCE /
RIGIDITY TESTING (NPT)
NPT or sleep related erection is a recurring cycle
of erections associated with rapid eye movement
during sleep [96]. Sleep erections are androgen-
dependent and thus usually impaired in hypogona-
dal men. Registration of nocturnal penile tumes-
cence (NPT) is useful for separating psychological
and organic cases [97]. Its main advantage is that
it is relatively free from psychologically mediated
effects. The documented presence of a full erec-
tion indicates that the neurovascular axis is func-
tionally intact and that the cause of the ED is most
likely psychogenic. Although this assumption
seems overall plausible, doubts have been raised
about it. Anxiety and depression can at times
influence the content of the dream state, negative-
ly affecting spontaneous nocturnal erections. In
addition, sleep disturbances such as apnoea or
motor agitation can also induce erroneous recor-
dings. Dysfunction at the level of the cortex and
spine may still permit nocturnal tumescence while
causing an ED in the awake state. Moreover, nor-
mal NPT may also occur in patients with a mild
vascular problem who often loose an erection
during pelvic thrusts. Finally, NPT evaluation has
proved to be age-dependent [98] and quite costly,
as it is ideally done in a specially equipped sleep
center [99,100].
NPT is tested over at least 2 nights, to eliminate
the 'first night effect'. To be accurate, it must inclu-
de measurements not only of penile circumference
but also of penile rigidity. The Rigiscan® device,
providing real-time recordings of tumescence and
rigidity, used in the sleep laboratory is regarded as
the optimal standard of NPT recording [101].
However, because the Rigiscan® measures radial
rigidity (compressibility) in stead of axial rigidity
(buckling force) the validity of the rigidity measu-
rements have been questioned. Allen et al reports
that, when Rigiscan® base and tip radial rigidity
exceeds 60% of maximum, correlation with axial
rigidity is poor. In this range, the Rigiscan® fails
to discriminate axial rigidities between 450 and
900 g of buckling force. As an axial rigidity of
more than 550 g is necessary for vaginal penetra-
tion, the Rigiscan® may not be able to detect subt-
le abnormalities in erectile function [102].
Hatzichristou et al demonstrated in a study in heal-
thy volunteers that NPT with at least 1 erectile epi-
sode of tip penile rigidity greater than 60% and 10
minutes in duration might be associated with
potency [103].
2. VISUAL EROTIC STIMULATION (VES)
A full erectile response to VES makes a psychoge-
nic cause of ED likely. Although this theory seems
reasonable, the clinical value of VES is questio-
nable. Unlike NPT, response to VES, although
possibly closest to normal sexual response, is
strongly susceptible to psychological factors, such
as erotic excitement inhibition, and maybe normal
in states of endocrine abnormality. Degree and
latency of erectile responses to VES in eugonadal,
sexually non-dysfunctional men correlates with
endogenous testosterone levels. Moreover, the res-
ponse to VES is negatively correlated with age,
limiting its value in older man. To date, the most
important application of VES is to investigate the
erectogenic or antierectogenic effect of drugs, in
clinical pharmacological studies [104].
IV. NEUROLOGICAL TESTING
[105, 106]
Penile erection is elicited by two different neuro-
physiolocal mechanisms and mediated by somatic
and autonomic pathways. Psychogenic erections,
initiated in supraspinal centres in response to audi-
131
tory, visual, olfactory, and imaginative stimuli, are
mediated by sympathetic pathways. Reflexogenic
erections, elicited by tactile stimulation at the
genital level, are mediated by a spinal reflex arc
consisting of afferent somatic and efferent para-
sympathetic nerve fibres. Therefore, the neurolo-
gical factor in ED may include central and per-
ipheral neural structures [107 ,108].
The ideal neurophysiological assessment will
objectively and quantitatively evaluate the func-
tional status of all parts of this neurological net-
work. In the last two decades, a series of tests has
been developed, each of which reflects a specific
part of the network. The medical history and phy-
sical examination provide the basis for these tests.
Test can be classified as those detecting somatic
efferent (motor) pathways, afferent (sensory) path-
ways, reflexes and autonomic responses. Wise use
of these tests, should consider the relations bet-
ween each specific test and the neural function it
detects.
NEUROLOGICAL TESTING
Motor
• Bulbocavernosus EMG
• Magnetic stimulation
• Reflex latency testing
Sensory
• Nerve conduction velocity
• Evoked potentials
• Biothesiometry
• Thermal threshold testing
• Reflex latency testing
Autonomic
• Cardiovascular reflex tests
• CcEMG
• Sympathetic skin response
In general however, a goal-directed approach to
ED does not tend to neurophysiological testing
because history and a physical examination alone
are likely to reveal clinical signs of neuropathy.
Neurophysiological testing is recommended in
research protocols or liability procedures after
trauma or surgical interventions and it should be
specifically tailored for the individual patient - No
routine work-up should be used. Patients suspec-
ted of having CNS lesions should be studied by
magnetic stimulation and somatosensory evoked
potentials. In patients with a history of neuropathy
tests of the peripheral system such as nerve
conduction, EMG and thermal testing in the lower
limbs are relevant. Patients with a history sugges-
tive of low spine or pelvic disorder should be stu-
died by EMG of the sphincter muscles, bulboca-
vernosus reflex, dorsal nerve conduction and
magnetic stimulation of the genitalia.
1. B ASIC PRECEPTS IN NEUROPHYSIOLOGICAL
TESTING
In clinical practice, the somatic nerves are eva-
luated by testing nerve conduction velocities and
evoked potentials. These tests have well-known
reproducibility, validity and range of confoun-
ding factors. Autonomic function tests are less
reliable, because they simultaneously measure a
chain of events or reactions involving receptors,
small fibers, and target organs. Confounding fac-
tors such as medication, caffeine, temperature,
hypo- and hypervolemia, mental mood, and
receptor or target organ dysfunction may influen-
ce each individual component. Additionally, the
complex interaction between central and periphe-
ral sympathetic and parasympathetic nerve sys-
tems, as in the pelvic plexus, makes autonomic
testing difficult. Moreover, efferent autonomic
function tests involve the evaluation of vasomo-
tor and sudomotor fibres and target organs, which
may not be equally affected by neuropathy. Toxic
metabolic events, especially cause length- depen-
dent neuropathy, because long fibres are more
prone to metabolic damage than short fibres
[109]. Finally, current autonomic tests are not
well standardised. therefore reproducibility, vali-
dity and comparability of test results between
laboratories are difficult. Thus, autonomic testing
is difficult and must be tailored to the specific
small fibres or target organ to be tested, with eli-
mination or standardisation of confounding fac-
tors. If these conditions are fulfilled, a normal
test result rules out neuropathy, while an abnor-
mal test result does not necessarily imply neuro-
pathy. In ED, tests must be focused on vasomotor
parasympathetic and sympathetic fibres with vas-
cular and trabecular smooth muscles as target
organs.
132
2. TESTING OF THE EFFERENT (MOTOR)
PATHWAYS
a) Electromyography of the musculus bulboca -
vernosus (bulbocavernosus EMG)
This test can identify damage to the sacral 2-4
motor roots and the pudendal efferents .It samples
large myelinated fibres. The test is well known and
extensively used. It is clinically relevant in ED
associated with lesions to the low backbone, with
nerve root damage. Indications: conditions that
affect the continuity of the pudendal nerve such as
lumbar disc disorders, pelvic anatomical lesions,
pelvic surgery etc.
Reference values: No activity at rest. Units have
less than 10ms of duration, and normally, full
recruitment can be obtained.
b) Magnetic stimulation
With this test the conduction velocity in the central
and peripheral efferent pathways of the bulboca-
vernosus muscle can be measured. The test is limi-
ted to large myelinated fibres and their central
connections. The clinical value of the test is not
clear, since it is not yet validated. More data are
needed in order to evaluate the role of this test in
neurogenic ED.
Reference values: In 18 normal males, cortex to
bulbocavernosus muscle latencies of 28.8 ms
during rest and of 22.5 ms during contraction have
been found.
c) Bulbocavernosus reflex (BCR)
Traditionally, the measurement of the BCR laten-
cy time has been used as first line test in the neu-
rophysiological evaluation of erectile and lower
urinary tract dysfunction [110]. BCR attempts to
determine the integrity of the neural reflex arc S2-
S4. The afferent and efferent arm of the reflex
consists of the pudendal nerve and its distal senso-
ry branch, the dorsal penile nerve. A prolonged
BCR latency or the absence of the BCR is a sign
of neurological dysfunction. The test is relevant
for patients with lesions in the lower spinal cord
(cauda) and pelvis. Pathology of the roots or
pudendal nerves is likely to result in prolonged or
absent response. The use of BCR in patients with
suspected neuropathy, and in patients with no evi-
dence of neurological disease is discouraged,
because of its low sensitivity.
Reference values: In a study in 39 potent males a
mean BCR of 34.6 ms was found. Bemelmans et
al found a normal range of 20 - 40 ms [111].
3. TESTING OF THE AFFERENT (SENSORY)
PATHWAYS
a) Dorsal nerve conduction velocity
This is a test for the large myelinated dorsal peni-
le sensory fibres, which can be valuable in the eva-
luation of neuropathy, for example in patients with
diabetes mellitus. Sensitivity and specificity of
this test have not been established yet.
Reference values: Mean normal velocity of 27.4
ms, and mean amplitude 12 µV was found. When
the penile shaft was stretched with a weight of 1
pound, velocity decreased to 33 ms.
b) Somatosensory evoked potentials (SEPs)
Latencies of SEPs are a measure for the conduc-
tion velocity along the sensory pathways from the
genital region to the sensory cerebral cortex.
Reference values [111]: (mean + 2sd) (50 healthy
males, mean age 54 years, range 29-62): Tibial
evoked potential (TEP): 35-46ms, Pudendal Evo-
ked Potential (PEP).
c) Biothesiometry [112]
Biothesiometry and thermal threshold testing may
be used to measure the integrity of sensory path-
ways quantitatively [113]. Biothesiometry is desi-
gned to measure the perception threshold of large
sensory fibres to various amplitudes of vibratory
stimulation [114]. Although extensively used,
solid data regarding its sensitivity and specificity
is lacking.
d) Thermal threshold testing
In this test a temperature surge is offered as a sti-
mulus to the patient [115]. The afferent pathway
consists of small nerve fibres - warmth conduction
by unmyelinated C-fibres with conduction veloci-
ties of 0.5 - 2.0 m/s, cold conduction by A8 fibres
with conduction velocities of 6 - 30 m/s. The test
thus yields objective data on the conductance of
small sensory nerve fibres and therefore may
133
reflect indirectly the function of the penile efferent
(motoric) nerve fibres. Thus, the rationale of per-
forming this test is that evidence of impaired ther-
mal sensation might suggest similar impairment of
the autonomic motoric innervation of the caver-
nous body. However, more data are needed regar-
ding its clinical application.
e) Bulbocavernosus reflex (BCR)
4. AUTONOMIC TESTS
a) Cardiovascular reflex tests
In 1982, Campese first related abnormal cardio-
vascular reflexes with ED. Cardiovascular reflex
tests assess variations in heart rate and blood pres-
sure in response to various stimuli such as forced
breathing, standing up or tilting, Valsalva's
manoeuvre, sustained isometric handgrip, mental
arrhythmic task, or cold pressure [116]. Heart rate
variations reflect parasympathetic function, while
blood pressure variations reflect sympathetic func-
tion. Loss of variation is indicative for autonomic
neuropathy, presuming absence of confounding
factors such as cardiac arrhythmia, nicotine, or
caffeine use before testing, medication (especially
antihypertensives), hypo, or hypervolemia, and
dysfunction of baroreceptors or target organs
[117].
b) Corpus cavernosum EMG (ccEMG)
This is a relatively new technique, in which need-
le or surface electrodes record the electrical activi-
ty of the corpora cavernosa [118 , 119, 120, 121,
122]. Basic questions regarding the signal recor-
ded, and how to interpret it, are still unresolved.
Thus, despite some clinical use this test must be
regarded as experimental.
c) Sympathetic skin response:
Measures a sudomotor related potential, which is
evoked in response to sympathetic activation
[123,124]. The potential can be recorded from the
penis, assessing the sympathetic innervation of
this organ. However, basic questions regarding
the technique are still unresolved, and its clinical
usefulness is limited.

V. PSYCHOLOGICAL OR
PSYCHIATRIC EVALUATION
See chapter 11
VI. SUMMARY STATEMENT
The number of patients seeking medical help for
ED has greatly increased and the care for these
patients has shifted from the urologist to the pri-
mary care physician and other specialists in the
field of sexual medicine. Consequently, the basic
approach to the management of ED has become
multidisciplinary and goal-directed. Key-ele-
ments in the initial evaluation are the medical and
sexual history and the identification of indications
for referral to a specialist.
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___________________

138
 Committee 6

Current Research and Future Therapies

Chairman
K-E ANDERSSON

Members
A.L. B URNETT,
K.K. CHEN,
G.J. CHRIST,
O. RAMPIN,
C. STIEF

139
 CONTENTS
I. INTRODUCTION
II. MODELS OF ERECTION.
BEHAVIORALAND PHYSIOLOGI-
CAL MEASURES IN CONSCIOUS
ANIMALS
1. CONTEXTS
2. P ERIPHERAL MECHANISMS UNDERLYING
PENILE ERECTION RECORDED IN
CONSCIOUS ANIMALS
3. CORRELATIONS WITH CHANGES IN BRAIN
NEUROTRANSMISSION
4. C ONSEQUENCES OF THE LESION OF SELEC-
TIVE BRAIN NUCLEI:
5. EXPLORATION OF PERIPHERAL AND CEN-
TRAL NEURAL PATHWAYS IN ANESTHETI-
ZED ANIMALS
6. IN VITRO PREPARATIONS AND THE STUDY OF
MEDIATORS, RECEPTORS, ION CHANNELS
AND SECOND MESSENGERS.
7. N EURAL CONTROL
III. TRANSMITTERS AND
RECEPTORS
1. CENTRAL NEUROMEDIATION
2. PERIPHERAL NEUROMEDIATION
IV. SIGNAL TRANSDUCTION
1. THE SYNCYTIAL TISSUE TRIAD : THE
MECHANISTIC BASIS FOR THE LOCAL
COORDINATION OF PENILE ERECTION.
2. THE FLOW OF INFORMATION AND THE
DIVERSITY OF SIGNAL TRANSDUCTION
3. I ONIC DISTRIBUTION ACROSS THE CORPO-
RAL SMOOTH MUSCLE CELL MEMBRANE
4. K+ CHANNELS IDENTIFIED IN HUMAN COR-
PORAL SMOOTH MUSCLE
V. SMOOTH MUSCLE FUNCTION
1. ELECTROMECHANICAL COUPLING
2. PHARMACOMECHANICAL COUPLING
3. RELAXATION
140
VI. THERAPEUTIC ASPECTS :
GENE THERAPY & MOLECULAR
BIOLOGY: THE PROMISE OF
MOLECULAR SURGERY
1. WHAT IS MOLECULAR BIOLOGY?
2. GENETIC PREDISPOSITION TO ERECTILE
FAILURE
3. GENETIC/MOLECULAR ALTERATIONS AT-
TRIBUTABLE TO, OR wHICH ACCOMPANY,
ERECTILE FAILURE
4. DIFFERENTIALLY EXPRESSED TRANSCRIPT
IN CULTURED CORPORAL SMOOTH MUS-
CLE CELLS FROM DIABETIC PATIENTS
5. AGE-RELATED DECLINE IN CONNEXIN43
(CX43) MRNA EXPRESSION IN HUMAN
CORPORAL TISSUE STRIPS
6. MOLECULAR MECHANISMS OF CORPORAL
FIBROSIS
7. I DENTIFICATION OF SMOOTH MUSCLE SPE-
CIFIC GENES
8. SOMATIC GENE THERAPY FOR THE TREAT-
MENT OF ERECTILE DYSFUNCTION
9. THE EVOLUTION OF CARDIOVASCULAR
GENE THERAPY
10. RATIONALE FOR GENE THERAPY AS A
TREATMENT OF ERECTILE DYSFUNCTION
11. BRIEF REVIEW OF CURRENT GENE THE-
RAPY APPROACHES
VII. THERAPEUTIC ASPECTS :
PHARMACOLOGICAL BASIS FOR
CURRENT AND FUTURE
THERAPIES
1. DRUGS FOR INTRACAVERNOUS ADMINIS-
TRATION
2. DRUGS FOR NON-INTRACAVERNOUS ADMI-
NISTRATION
VIII. RECOMMENDATIONS
REFERENCES
 Current Research and Future Therapies
K-E ANDERSSON,
A.L. BURNETT, K.K. C HEN, G.J. C HRIST, O. R AMPIN, C. S TIEF
I. INTRODUCTION
The introduction of intracavernous injection of
papaverine as a treatment of erectile dysfunction [1]
has stimulated a wide research interest in the
mechanisms of penile erection. Recent progress
concerning both the central [2, 3, 4, 5, 6] and per-
ipheral [4, 7, 8] control mechanisms of penile erec-
tion has made it possible to define several new tar-
gets for pharmacological treatment of the disorder.
In this review, models of erection as well as the
physiological basis for erectile function and dys-
function are discussed, as are current and future
therapeutic aspects on erectile dysfunction.
II. MODELS OF ERECTION.
BEHAVIORALAND PHYSIOLOGI-
CAL MEASURES IN CONSCIOUS
ANIMALS
In mammals, penile erection occurs in several dif-
ferent natural contexts, e.g., during copulation, as
a reflex response to stimulation of the genital area,
in the presence of an estrous female (contact with
the female is not required), and during sleep. In an
attempt to better understand the mechanisms
underlying such responses, pharmacological
manipulations of neural and endocrine pathways
have been used to elicit penile erection. Lesions or
electrical stimulation of central brain nuclei have
also been performed. Extensive analysis of the
variety of contexts that elicit penile erections led
to the concept that erections were governed by a
variety of neural and endocrine mechanisms,
depending upon the sources of information that
elicited them.
141
Perspective 1: Today’s challenge is to search for
central brain and spinal nuclei, neurotransmit -
ters, receptors and second messengers involved
in the control of penile erection. Another aim is to
find out whether one or several peripheral path-
ways exist between the brain and the penis. This
latter aspect gains importance when one considers
the impact of peripheral nerves lesions or spinal
cord injury on penile erection in patients.
1. CONTEXTS
a) Erections in copula
Erections in copula are difficult to number and
measure under direct behavioral observation. The-
refore data have been inferred either from models
in which penile erection was allowed in a copula-
tion-related context, but intromissions were pre-
vented so as to directly observe the penis, [9], or
has been inferred from the motor pattern that
accompany penile insertion [10]. Finally tech-
niques for recording the response of the erectile
tissue or the activity of the perineal striated
muscles have been used. A concern regarding the
measure of penile erection in copula has emerged
in several instances from the difficulty to separate
between mechanisms that regulate sexual beha-
vior, the latter including penile erection as one of
its several outputs, and those more directly related
to penile erection itself.
b) Reflexive erections
In conscious dogs and rats, manual stimulation or
tonic retraction of the penile sheath elicits epi-
sodes of penile erection that are easily observed
[11]. In rats, an appreciable characteristic of these
erections is that they are grouped into clusters, and
the number and frequency of clusters and of
reflexive erections are easily measured. Further-
more reflexive erections are independent from
social interaction with the female. Spinalization
releases reflexive erections from supraspinal
influences, making the model appropriate to study
the spinal control of penile erection.
c) Noncontact erections
A new model has been established in conscious
rats. Noncontact erections (NCE) occur in male
rats in response to the presence of estrous females
[12]. The model has been proposed as a tool to
understand the psychogenic erections displayed by
humans. Because volatile odors from the estrous
females have been shown to be the necessary and
sufficient stimulus for this response [13], noncon-
tact erections are very likely due to integration of
peripheral information by supraspinal structures.
d) Erections induced by pharmacological or elec -
trical stimulation in conscious animals
A variety of drugs that interact with brain neuro-
transmission have been delivered either periphe-
rally (sc, ip, im, iv) or into the cerebral ventricles,
or into some specific brain nuclei, and episodes of
penile erection reported in solitary male rats or
monkeys [14, 15]. The mixed D1 and D2 or D2
receptor agonists, apomorphine, amantadine, N-n-
propyl-norapomorphine, LY 171555, LY 163502,
bromocryptine, lisuride, the mixed dopaminergic
and 5-HT1A receptor agonist, RDS-127, the cho-
linergic receptor agonist, pilocarpine, the seroto-
nin uptake inhibitor, fenfluramine, and the 5-
HT2C receptor agonist, m-chlorophenylpiperazi-
ne (mCPP), were identified as proerectile drugs
[16, 17, 18, 19, 20, 21, 22, 23]. As well, apomor-
phine, LY 171555, glutamate, oxytocin (OT) and
NO donors elicited episodes of penile erection
when delivered in the hypothalamic paraventricu-
lar nucleus of conscious rats [14]. In contrast
opioid peptides had inhibitory effects. From these
experiments, two hypothalamic nuclei were put in
front: the medial preoptic area [15], and the para-
ventricular nucleus [14]. Dopamine and nitric
oxide seem to play a major regulatory role in these
two structures. Furthermore, oxytocin is a main
proerectile neurotransmitter in the paraventricular
nucleus.
In conscious animals, penile erection has been
reported in response to electrical stimulation of
brain nuclei, including the gyrus rectus, the septo-
142
preoptic-anterior hypothalamic region, the paraven-
tricular nucleus, the medial forebrain bundle, and
the mamillary bodies [24, 25, 26, 27] and during
cortical spreading depression in rats [28, 29].
2. P ERIPHERAL MECHANISMS UNDERLYING
PENILE ERECTION RECORDED IN
CONSCIOUS ANIMALS
The activity of the two peripheral tissues involved
either directly (the penile smooth muscles) or indi-
rectly (the perineal striated muscles) in penile
erection have been recorded in unanesthetized ani-
mals, in a variety of erectile contexts.
By recording intracavernous or intraspongiosus
pressure during copulation or reflexive erections
in goats, bulls, dogs, stallions and rats, experi-
ments demonstrated that erection was characteri-
zed mainly by a two-step increase in penile pres-
sure, the first leading to a plateau reaching systo-
lic levels, the second represented by suprasystolic
peaks. The plateau increase lasted several seconds
to minutes. By recording the electromyographic
activity of the perineal striated muscles, i.e. the
ischiocavernosus (IC) and bulbospongiosus (BS)
muscles, it was demonstrated that suprasystolic
peaks, whose duration was shorter than plateaus,
were paralleled by an intense activity of the IC and
BS muscles. Anesthesia of the IC or BS muscles
abolished the suprasystolic peaks respectively in
the corpus cavernosum and corpus spongiosum,
and in rats excision of the IC or BS respectively
abolished intense corpus cavernosum and glans
erections. Plateaus of pressure were not recorded
in rats during copulation, suggesting in this spe-
cies a particular mechanism supported by a coor-
dination of autonomic and somatic pathways to
the penis and perineal muscles [30, 31, 32, 33, 34,
35, 36].
3. CORRELATIONS WITH CHANGES IN BRAIN
NEUROTRANSMISSION
The limits of the pharmacological experiments
reported hereabove reside in the use of exogenous
compounds, either agonists or antagonists. A
means through which the biological support of
these studies may be better determined is to mea-
sure the natural release of endogenous neurome-
diators or their related metabolites in brain nuclei
during penile erection. Recently an increase in
nitric oxide production was demonstrated in the
hypothalamic paraventricular nucleus during non-
contact erections and copulation [37].
4. C ONSEQUENCES OF THE LESION OF SELEC-
TIVE BRAIN NUCLEI:
Evidence for supraspinal inhibitory pathways.
Penile erection occurred as one of the conse-
quences of large lesions of the limbic structures
(amygdala, insular cortex) in cats as well as lesion
of the locus coeruleus in rats [38]. In rats and dogs,
lesioning the spinal cord at the middle thoracic
level, or (in rats) pharmacological or electrolytic
lesions of serotoninergic systems projecting to the
spinal cord, facilitated reflexive erections [39, 40,
41, 42].
Contribution of other nuclei to penile erection. In
rats, noncontact erections were abolished by
medial amygdala lesions and were severely affec-
ted by lesion of the paraventricular nucleus,
nucleus accumbens and bed nucleus of the stria
terminalis [43, 44, 45, 46]. In contrast, medial
preoptic area (MPOA) lesions had no effect on
such responses [45].
5. EXPLORATION OF PERIPHERAL AND CEN-
TRAL NEURAL PATHWAYS IN ANESTHETI-
ZED ANIMALS
a) Measuring penile erection in anesthetized ani -
mals
A variety of methods have been used to qualify
and quantify erection, this variety reflecting the
historical evolution of the concepts of the basic
mechanisms of erection, and the techniques avai-
lable at the same time. As early as the end of the
nineteenth century, penile erection has been esti-
mated through the number of blood droplets lea-
king from the sectioned penis, thereby pointing
out the importance of blood flow changes through
the penile tissue during penile erection. More
recently, the changes in the volume of the penis
comprising corpus cavernosum and corpus spon-
giosum have been measured by using penile ple-
thysmography, bringing a reliable quantification to
the common observation of increased volume of
the organ. By the 1980-ies, recording of intraca-
vernous or intraspongiosus pressure rises in res-
ponse to peripheral nerve stimulation or drug
injections became a standard of penile erection
143
measure. Another outstanding basic mechanism of
penile erection, the increased blood flow in the
penile arteries, became measurable by using tech-
niques issued from cardiovascular explorations,
e.g., Doppler techniques. Finally, since the erecti-
le tissue represents a bulk of smooth muscle fibers,
the electromyographic activity of this tissue has
been recorded and proposed as a tool to measure
the response of smooth muscle to a variety of
manipulations.
b) Stimulation applied on peripheral efferent
pathways
Electrical stimulation applied on the sacral para-
sympathetic pathways (lumbosacral spinal cord,
sacral ventral roots, pelvic nerve and plexus,
cavernous nerve) elicited penile erection in either
dogs, cats, rabbits, rats, mice and humans. In some
of these species, because the additive stimulation
of the lumbosacral paravertebral sympathetic
chain elicited subsidence of erection, an effect
suppressed by sectioning the pudendal nerves, it
was inferred from these studies that the sympathe-
tic antierectile pathways ran in these nerves. To
date, the role of the hypogastric nerve in erection
remains controversial. Depending on the animal
species studied, and the model used (peripheral
nerves intact or lesioned, spinal cord intact or
lesioned), there has been demonstration of a proe-
rectile role of at least some fibers running in the
hypogastric nerve in some intact anesthetized ani-
mals, and a compensatory proerectile role follo-
wing interruption of the pelvic nerve in rats [47].
By stimulating the motor pudendal nerve, i.e., eli-
citing contraction of the IC and BS muscles, on an
erect penis, an additional rigidity and suprasysto-
lic penile pressure rises were recorded. It was the-
refore suggested that under physiological condi-
tions, both autonomic pathways to the smooth
muscle of the erectile tissue, and somatic path-
ways to the muscles and sphincters of the per-
ineum contributed to penile erection. The spinal
cord, at the origin of these pathways, represents
the coordinating center of these activities.
By injecting contrast medium in the internal
pudendal artery of anesthetized male goats, then
eliciting penile erection via electrical stimulation
of parasympathetic pathways, an interruption of
the flow of contrast medium in the penis was
recorded, suggesting that compression of the arte-
rial supply to the penis and its venous outflow
occurred [48]. In dogs and monkeys, a 10 fold
increase in arterial inflow to the penis was recorded
that was resistant to anticholinergic agents [49, 50].
In the same species, stimulation of the cavernous
nerve elicited a transient arterial blood flow increa-
se in the internal pudendal artery that preceded the
sustained increase in intracavernous pressure [51,
52]. Increased blood flow to the penis also elicited
a local increase in oxygen tension [53].
c) Stimulation applied on peripheral afferent
pathways
The dorsal nerve of the penis conveys sensory
information from the glans penis and the preputial
skin to the spinal cord. In rats, it joins more proxi-
mally the sensory branch of the pudendal nerve,
the latter also conveying sensory information from
the perigenital area. In anesthetized rats, stimula-
tion of the dorsal penile nerve or of the sensory
pudendal nerve elicited reflex responses of the
cavernous and motor pudendal nerves [54, 55]. It
also elicited rises in penile pessure, and activity of
the bulbospongiosus muscles, both responses
being more reliable in spinalized animals [54, 56,
57]. In the spinal cord, neurones of the dorsal
horn, dorsal grey commissure, and intermediolate-
ral cell column, mainly at the lumbosacral levels,
are activated by such stimulation [58, 59, 60]. Pri-
mary afferents from the dorsal penile nerve project
only in the dorsal horn and dorsal grey commissu-
re, suggesting intraspinal relayed pathways bet-
ween sensory afferents and autonomic and soma-
tic efferent pathways. In contrast, this central pro-
jection extends largely to very rostral levels of the
spinal cord, suggesting a possible regulatory role
of genital afferents on many autonomic and soma-
tic outflows [61]. Stimulation of penile sensory
fibers elicits responses in the medullary reticular
formation, and hypothalamic nuclei such as the
medial preoptic area and paraventricular nucleus
[62, 63, 64].
d) Stimulation applied to central brain nuclei
A limited number of data are available on the
exploration of brain nuclei in anesthetized ani-
mals. In rats, stimulation of the paraventricular
nucleus and the medial preoptic area of the hypo-
thalamus, and of the hippocampus, elicited epi-
sodes of penile pressure rises, either during or
after application of the stimulation [65, 66, 67,
144
68]. The pressure rises recorded shared the cha-
racteristics of pressure rises elicited by the activa-
tion of the sacral parasympathetic outflow, and in
some instances were eliminated by pelvic nerve
section. The contribution of the sympathetic out-
flow, recruited by the same central stimulation, has
also been coined out.
e) Pharmacological studies
The stimulation of neural pathways helped identi-
fying those nerves or brain nuclei that contributed
in some way to penile erection. Many of these
experiments combined a pharmacological approa-
ch. Drugs that could block or mimick the effects of
neural stimulation have been tested. It was soon
recognized that antierectile effects were due to
noradrenaline (NA) release by sympathetic nerve
endings in the corpus cavernosum. In contrast,
blocking postganglionic cholinergic transmission
with atropine had few or no effects on electrically
induced erections, suggesting that proerectile
pathways peripherally released a non-adrenergic,
non-cholinergic transmitter. Further experiments
tested the role of calcitonin gene-related peptide
(CGRP), substance P (SP), vasoactive intestinal
polypeptide (VIP), adenosine triphosphate (ATP)
and nitric oxide (NO) [7, 69]. In parallel, morpho-
logical studies demonstrated the presence of these
compounds or enzymes required for their synthe-
sis in nerve terminals running in the erectile tissue.
CGRP, SP, VIP, ACh and NO (synthase), all pre-
sent in nerve terminals, displayed proerectile
effects, i.e. were responsible for a change in peni-
le pressure when either injected intracavernously
or intra-arterially, or released upon nerve stimula-
tion. Transmitter release has no consequence per
se if the target cell does not bear the appropriate
receptor. Furthermore, binding of the transmitter
to its receptor activates a cascade of intracellular
events, in some instances leading to second mes-
senger synthesis. Modulation of the penile respon-
se to either intracavernous injection of proerectile
drugs or electrical stimulation of nerves by speci-
fically targeting receptors or affecting second mes-
sengers has been a tremendous growing field in a
recent past. The use of α-AR (adrenoceptor) anta-
gonists (phentolamine), activators of cAMP syn-
thesis (prostaglandin E1 ; PGE 1 and non specific
(papaverine) or selective (sildenafil) inhibitors of
phosphodiesterases illustrates the clinical develop-
ments of these pharmacological approaches.
f) Tracing peripheral and central neural path -
ways controlling penile erection
Some synthetic molecules or exogenous enzymes
can be captured by nerve terminals and transpor-
ted along the axons to the neural soma. By using
this qualitative technique, several studies have
identified the location of neurones that innervate
the corpus cavernosum, and the motoneurones that
innervate the IC and BS muscles. This technique
allows the use of immunohistochemistry to reveal
the neuromediators present in these neurones. In
rats, postganglionic neurones that innervate the
corpus cavernosum are present in the major pelvic
ganglion, the cavernous nerve and the paraverte-
bral sympathetic chain. In this species, the puden-
dal motoneurones that innervate the IC and BS
muscles are present in the dorsomedial and dorso-
lateral nuclei of the L5-L6 spinal cord [70, 71]. A
limit to conventional tracing techniques is that tra-
cers don’t cross synapses. Therefore only direct
links between a neurone and its target tissue are
evidenced. Hence the presence of preganglionic
sympathetic neurones in the intermediolateral cell
column and dorsal grey commissure of the T12-L2
spinal cord, as well as the location of parasympa-
thetic preganglionic neurones in the sacral para-
sympathetic nucleus of the L6-S1 spinal cord have
not been demonstrated from retrograde labelling
from the corpus cavernosum, but have been infer-
red from dye injection in the pelvic or hypogastric
nerves, the major pelvic ganglion or the lumbar
sympathetic chain. This obstacle was recently eli-
minated by the use of neurotropic viruses (mainly
herpes-like viruses, e.g. pseudorabies virus) in
neuronal tracing. Those viruses are selectively
captured by nerve terminals, replicate in the neural
soma of first order neurones, and cross the synap-
tic cleft to reach the soma of second order neu-
rones, where they again replicate [72, 73]. Pseu-
dorabies viruses were injected either in the corpus
cavernosum or the ischiocavernosus or bulbospon-
giosus muscles. Neurones transsynaptically label-
led by the virus were identified in the spinal cord
and supraspinal nuclei that send projections either
directly or through relayed pathways onto autono -
mic and somatic spinal neurones that control erec-
tion [74, 75]. Main characteristics of these studies
were:
1) the presence of many neurones in the dorsal
grey commissure in and between the thoraco-
145
lumbar sympathetic and the lumbosacral para-
sympathetic levels, those neurones likely
contributing to integration of peripheral and
supraspinal information,
2) constant labelling of neurones in the raphe
nuclei, the source of the serotoninergic innerva-
tion to the spinal cord;
3) labelling of neurones in hypothalamic nuclei,
mainly the medial preoptic area and paraventri-
cular nucleus.
6. IN VITRO PREPARATIONS AND THE STUDY OF
MEDIATORS, RECEPTORS, ION CHANNELS
AND SECOND MESSENGERS.
In vitro preparations of retractor penis, penile arte-
ries and veins, and corpus cavernosum have been
widely used as a tool to understand the local
effects of agents supposed to play a role in penile
erection. A basal tension is applied either mecha-
nically and/or pharmacologically to these prepara-
tions of penile tissue, the latter containing smooth
muscle cells, nerve terminals and endothelial cells.
Electrical field stimulation (that elicits release of
neurotransmitters by nerve terminals) or drugs
(that act on receptors present on either kind of
cells or nerve terminals) are then further applied to
the preparation. Changes in the tone of the prepa-
ration evidences contractant or relaxant properties
of endogenous or exogenous compounds.
Contractile effects of NA released by nerve
endings of the sympathetic nervous system
through α1- and α2- ARs have been shown,
whereas stimulation of β-ARs elicited relaxant
effects. Contractile effects of peptides on corpus
cavernosum smooth muscle fibers have been
demonstrated for e.g., endothelin-1, released by
endothelial cells and acting at endothelin recep-
tors. Acetylcholine, released by parasympathetic
nerves, had contracting effects on isolated smooth
muscle cells of the corpus cavernosum. Because
antagonists to cholinergic and adrenergic trans-
missions did not prevent relaxation induced by
electrical field stimulation, relaxation of the peni-
le tissue and artery was associated with the relea-
se of a non adrenergic non cholinergic agent [76,
77, 78]. The close similarity between the relaxant
effects of nerve stimulation and those elicited by
an endothelium derived relaxing factor was
demonstrated. Nitric oxide (NO) release and
cGMP formation were demonstrated upon electri-
cal stimulation of isolated strips of rabbit corpus
cavernosum [79]. NO could also be released spon-
taneously in this preparation, as well as in response
to acetylcholine. Both the endothelium and nerve
terminals can release NO [80, 81, 82, 83, 84, 85].
A reevaluation of neuromediators present in para-
sympathetic nerve endings (NO synthase, VIP, ace-
tylcholine) suggests that NO is the main mediator of
penile erection. Acetylcholine can inhibit NA relea-
se by sympathetic nerve endings and facilitate NO
release by endothelial cells. Finally, VIP, whose role
in the local mechanisms of penile erection has been
extensively investigated during the 1980-ies, may
play a role in proerectile mechanisms occurring at a
longer latency and displaying a longer effect (e.g.,
vascular tone and adaptation of penile arteries).
Recent experiments have used quantitative and
qualitative analysis to evaluate the presence and
physiological relevance of synthase (NOS), in the
corpus cavernosum. Demonstration of the presen-
ce of several NOS isoforms in the penis was obtai-
ned combining measurement of the enzyme speci-
fic activity, immunohistochemistry, protein analy-
sis with Western blot and mRNA analysis with
Northern blot. A variety of experiments converge
to evidence the presence of nNOS (neuronal NOS)
in the rat penis [86]. Today’s directions are the
search for other NOS isoforms in the penis of
other animal species. There are also studies using
animal models that mimic diseases known to elicit
erectile dysfunction in humans (diabetes, hyper-
cholesterolemia, hypertension, atherosclerosis) or
natural alteration of erection (ageing). In some of
these models, an alteration of the NOS functions
has been demonstrated [87, 88, 89].
Perspectives 2: The above cited experiments
point out the need of appropriate models for the
study of erectile dysfunction, the need to develop
animal models of erectile dysfunction [90] and
the need for correlating datas collected in studies
using animal models of erectile dysfunction with
clinical studies evaluating erectile dysfunction in
humans.
7. N EURAL CONTROL
Penile erection is a complex hemodynamic func-
tion that occurs principally under regulatory
control of the nervous system. Multiple levels of
the neuroaxis, from the brain to the nerves termi-
146
nating within the penis, originate or mediate the
neurophysiologic events required for an erectile
response. Intuitively, the brain originates erotic
thoughts whereas neuronal circuits from the spinal
cord to the genitalia process tactile sensations per-
ipherally. The neural control of penile erections
involves the integration of diverse neurochemical
mechanisms at both peripheral and central nervous
system levels (Figure. 1)
Figure 1: The neural control of penile erections involves
the integration of several mechanisms at both peripheral
and central nervous system levels.
a) Central regulation
The central nervous system (CNS) is involved at
least in the initiation of penile erection, either
through spinal mechanisms by local stimulation,
or through supraspinal stimulation in the brain.
However, due to the complexity in the CNS, the
loci in the brain, neuronal circuits and pathways,
and neurotransmitters (or neuromodulators) invol-
ved in the control of penile erection are relatively
little investigated, and, as compared with periphe-
ral neural mechanisms, knowledge is limited.
b) Loci in CNS involved in regulation of penile
erection
Current status. The medial preoptic area (MPOA)
[91, 92, 93, 94], paraventricular nucleus of hypo-
thalamus (PVN) [95, 96, 97, 98] and hippocampus
[95, 99] have been reported to be the brain loci,
which elicit penile erection when stimulated.
There is a linkage between hippocampus and PVN
[98, 100]. Removal of the temporal lobes bilate-
rally, including the amygdala, uncus and the most
part of the hippocampus, results in hypersexuality
in monkeys and humans [101, 102]. This suggests
that the temporal lobes may exert an inhibitory
effect on penile erection.
Nucleus paragigantocellularis (NPG) in the
medulla has also been considered to exert a des-
cending inhibition of penile erection. Lesions of
the NPG enhance male copulatory behavior and
alter ex copula penile reflexes [103, 104, 105].
Future research. An important aim of future
research is to investigate more brain loci, which
upon stimulation elicit or inhibit penile erection.
Amygdala, ventral tegmental field, and locus coe-
ruleus may be the potential targets for investiga-
tion. Electrical stimulation or lesioning, and che-
mical stimulation with L-glutamate to the neuro-
nal body (not to fibers passing by are suitable
methods for these future studies.
c) Neuronal circuits and neural pathways
Current status. The subnucleus parvocellularis of
PVN may through the descending oxytocinergic
pathways to the lumbosacral spinal cord mediate
apomorphine-induced penile erection [106, 100].
A direct descending projection from the PVN to
the spinal nucleus of the bulbocavernosus and the
dorsolateral intermediolateral nucleus in lumbosa-
cral region of the spinal cord has also been repor-
ted [107, 108]. Axons from motoneurons of both
the above mentioned two neural nuclei innervate
bulbospongiosus and ischiocavernosus muscles,
which are essential for penile erection [109, 110].
Besides a direct projection to the sympathetic pre-
ganglionic neurons in the spinal cord, PVN neu-
rons also project to the dorsolateral funiculus indi-
rectly through the reticular formation in the pons
and medulla [111, 112, 113, 114, 115]. Neurons in
PVN also send fibers to the parasympathetic pre-
ganglionic neurons in the lumbosacral cord [111,
112, 113]. The efferent fibers in MPOA project to
the midbrain through the medial forebrain bundle
[116]. As mentioned above, there exists a hippo-
campal-PVN pathway in the neuronal circuitry for
the regulation of penile erection [98].
Future research. To identify the neural pathways,
several methods mentioned above may be used:
1) retrograde injection of tracer, such as horse
radish peroxidase, wheat germ agglutinin [117]
into peripheral sites to find the innervating neu-
rons, or anterograde injection of tracer into the
surroundings of neuronal cell body to identify
the neurons,
147
2) neurotropic virus as a tracer, such as pseudora-
bies [118, 119] to investigate the network of
neurons, and
3) c-fos labelling by immunohistochemical study
[120, 121] to find the distribution of neurons
after sexual stimulation.
III. TRANSMITTERS AND
RECEPTORS
1. CENTRAL NEUROMEDIATION
The central mechanisms influencing the erectile
response involve spinal and supraspinal pathways.
While the central neurotransmission of penile
erections has remained complex, progress conti-
nues to be made to identify effectors involved in
this function. Much of the knowledge gained in
this area relates to morphological and pharmaco-
logical studies in experimental animal models
(e.g., rodents, primates) in which neurochemical
perturbations can be achieved and responses
monitored in a reasonably meaningful way.
However, it has been wisely stated that results of
these investigations must be carefully interpreted,
because these studies may encompass a range of
types and modes of elicitation of sexual function,
species differences, drug dependent effects, and
multiple central nervous system drug sites of
action [2]. Monoamines (e.g., 5-hydroxytryptami-
ne, dopamine, and norepinephrine), amino acids,
neuropeptides (e.g., oxytocin, ACTH and opioids),
acetylcholine and recently NO have been conside-
red to interact in the central mechanisms of penile
erection.
a) 5-Hydroxytryptamine
A large proportion of the studies investigating the
central regulation of sexual behavior have focused
on the serotonergic system. 5-hydroxytryptamine
(5-HT; serotonin) has been most strongly implica-
ted in the spinal pharmacology of erectile function
with participation in both sympathetic and para-
sympathetic outflow mechanisms. Experimental
paradigms in animals have indicated that 5-HT
pathways exert a general inhibitory effect on male
sexual behavior [122], although these pathways
may be inhibitory or facilitatory depending upon
the action of the chemical at different 5-HT recep-
tors located in the central nervous system [3].
5-HT-positive nerve terminals are present throu-
ghout the central nervous system and influence
multiple neurological levels of control of sexual
behavior. 5-HT-containing neurons exist in the
medullary raphe nuclei and ventral medulla reticu-
lar formation, including the rostral nucleus paragi-
gantocellularis, as well as the lumbosacral spinal
cord in association with mainly somatic and possi-
bly autonomic outflow projections to the pelvis
[105, 123, 124, 125, 126].
Sexual activity is enhanced with the decreased
amount of 5-HT in the brain, occurring experi-
mentally with the inhibition of serotonin synthesis
with parachlorophenylalanine administration, des-
truction of 5-HT-containing axons by intracranial
administration of 5,7-dihydroxytryptamine or
electrolytic destruction of the dorsal raphe nucleus
[127, 128]. Conversely, sexual activity is attenua-
ted following the intracerebroventricular or intra-
thecal administration of 5-HT and drugs that
increase central release or synthesis of 5-HT [22,
129, 130]. Despite this general understanding,
conflicting reports of 5-HT agonists either enhan-
cing or depressing sexual function were recogni-
zed and then attributed to the action of multiple 5-
HT receptors. In accordance with the selective use
of 5-HT receptor agonists and antagonists, compo-
nents of male copulatory behavior were found to
be displayed variably. The sum of multiple studies
suggests that 5-HT2 and 5-HT1A receptors media-
te inhibitory effects on penile erection whereas 5-
HT1C receptors mediate facilitatory effects on this
function.
The predominant role of 5-HT in the central neu-
romediation of erectile function appears to be
associated with inhibitory control of spinal sexual
reflexes involving the brain stem level [105].
Intrathecal injection of 5-HT in the spinalized
anesthetized male rat blocked the appearance of
the coitus reflex suggesting that endogenous 5-HT
may act in the descending input to the lumbar spi-
nal cord that inhibits sexual reflexes [105]. A simi-
lar procedure in other experiments also inhibited
ejaculation as well as penile intromission in rats,
suggesting an alternative role of 5-HT in the trans-
mission of sensory feedback information necessa-
ry for sexual responses [130].
A role for 5-HT in the supraspinal neurotransmis-
sion of penile erection has been suggested, since
148
NOS inhibitors given by intracerebrovascular
administration prevent 5-HT 1C-receptor mediated
erectile responses [131]. Thus, 5-HT appears to
serve various functions in male sexual function
and likely acts as a major modulator of the central
neuroregulatory control of penile erections.
b) Dopamine
The dopaminergic system has also been intensely
investigated as a likely major effector in the cen-
tral neuromediation of penile erection. The invol-
vement of dopamine in the control of penile erec-
tion followed the original discovery that low, but
not high, doses of the classical dopamine agonist
apomorphine, administered systemically to male
rats, induces penile erection [132]. Yawning and
seminal emission were also observed to accompa-
ny penile erections following dopamine adminis-
tration. These observations were subsequently
extended to investigations involving the low dose
systemic administration of other dopamine ago-
nists such as piribedil, lisuride and quinelorane in
rats and other animals [4]. The conclusion that the
erectile response was associated with the stimula-
tion of central dopamine receptors followed the
observation that the apomorphine effects were
attenuated with the application of centrally, but not
peripherally, acting dopamine receptor antago-
nists. Two main types of dopamine receptors, D1
and D2, are associated with erectile function cen-
trally with the latter perceived to predominate in
this effect.
Dopaminergic neurons comprise an incertohypo-
thalamic system with projections to the medial
preoptic area and paraventricular nucleus [133].
The injection of apomorphine into these central
nuclei has facilitatory effects on sexual behavior.
In the medial preoptic area, use of selective recep-
tor agonists has established that low levels of
dopaminergic stimulation, via D1 receptor in par-
ticular, facilitates erections [134]. In the paraven-
tricular nucleus, similar pharmacological experi-
ments have established that D2 rather than D1
receptors primarily facilitate erections [135]. The
mechanism of erection following paraventricular
D2 receptor stimulation apparently involves oxy-
tocinergic neurotransmission. Dopaminergic neu-
rons impinge on oxytocinergic cell bodies in the
paraventricular nucleus [136, 137] and apomor-
phine-induced penile erection is prevented dose-
dependently by oxytocin receptor antagonists
[138, 139] or by electrolytic lesions of the para-
ventricular nucleus that deplete central oxytocin
content [140, 141]. Conversely, injection of oxy-
tocin into the paraventricular nucleus induces
erections that are not attenuated by dopamine
receptor blockade, suggesting that dopaminergic
neurons activate oxytocinergic neurons in the
paraventricular nucleus and that released oxytocin
then accounts for the erectile response (see Oxyto-
cin section).
Dopaminergic neurons have also been identified
as traveling from the caudal hypothalamus within
the diencephalospinal dopamine pathway to inner-
vate the lumbosacral spinal cord [142, 143]. The
implication is that dopamine may participate in the
central nervous system regulation of autonomic
and somatic components that produce penile
reflexes. Indeed, low but not high dose systemi-
cally administered dopaminergic agonists enhance
spinally-mediated penile reflexes ex copula [144]
with a similar response observed following their
local injection into the medial preoptic area or into
the paraventricular nucleus [134, 145]. Converse-
ly, dopaminergic antagonists injected into the
medial preoptic area decrease the number of peni-
le reflexes [146]. The perception that the dopami-
nergic effect on penile reflexes converges on lum-
bar spinal cord dopamine receptors has been rein-
forced with the finding that injections of apomor-
phine into the lumbosacral subarachnoid space
impairs penile reflexes [147, 148]. The responses
appear to be D1 receptor-dependent although an
interaction between D1 and D2 receptors remains
possible. Thus, a seeming role for the dopaminer-
gic system in the control of spinal penile reflexes
as much as in the incertohypothalamic basis of
penile erection must also be recognized.
c) Noradrenaline
Evidence for noradrenergic effects in the central
neuromediation of penile erection is sparse.
However, the current data suggest that increased
noradrenergic activity stimulates, whereas decrea-
sed noradrenergic activity inhibits, sexual function
[122]. Insights have almost exclusively drawn
from experimental work involving the administra-
tion of agents that interact through α-AR path-
ways. Furthermore, accurate conclusions may
only draw from work that suggests that central
adrenergic receptors have been selectively stimu-
149
lated. In rats administered clonidine, an α2-AR
agonist, by direct injection into the medial preop-
tic area, male sexual behavior was suppressed
[149]. The suppression is inhibited by pretreat-
ment with selective α2-AR antagonists [150],
consistent with established facilitatory effects of
these agents on erectile responses in rats [150].
However, while several α2-AR antagonists most
notably yohimbine have been shown to increase
sexual responses in rats, the relatively poor thera-
peutic efficacy of yohimbine in clinical use among
men with erectile dysfunction [151], casts doubt
on the significance of central noradrenergic
mechanisms in erectile function.
d) Excitatory amino acids
Excitatory amino acids (eg., glutamic acid, aspartic
acid) appear to exert a role in penile erection in the
activation of central oxytocinergic neurotransmis-
sion of the response (see Oxytocin section). The
injection of N-methyl-D-aspartic acid (NMDA), a
selective agonist of the excitatory amino acid
NMDA receptor subtype, into the paraventricular
nucleus of rats induces penile erection, which is
prevented by the intracerebroventricular adminis-
tration of an oxytocin antagonist [152]. The NO
synthase signal transduction pathway is considered
to mediate the effect since the administration of
NOS inhibitors into the paraventricular nucleus and
intracerebroventricularly blocks the NMDA effect
[153, 154]. Further support is provided by findings
that NMDA injected into the paraventricular
nucleus also leads to the increased concentration of
NO metabolites in this region of the hypothalamus
[155]. The mechanism for NOS activation would
conceivably involve increased calcium influx
through previously described calcium channel-cou-
pled NMDAreceptors [156]. However, the ineffec-
tiveness of omega-conotoxin injected into the para-
ventricular nucleus in blocking erections induced
by NMDA conotoxin injected in this nucleus indi-
cates that omega-conotoxin sensitive N-type cal-
cium channels are not responsible for this mediation
[157].
e) Gamma-amino butyric acid
Cumulative data resulting from investigations on
the role of gamma-aminobutyric acid (GABA) in
penile erection indicate that this neurotransmitter
may function as an inhibitory modulator in the
autonomic and somatic reflex pathways involved
in penile erection [3]. In male rats, high concen-
trations of GABA have been measured in the
medial preoptic area of the hypothalamus [158],
and GABAergic fibers and receptor sites have
been localized to the sacral parasympathetic
nucleus and bulbocavernosus motor nucleus [159,
160]. The injection of GABAA agonists into the
medial preoptic area decreases [161], whereas the
injection of GABAA antagonists into this region
increases, copulatory behavior of male rats [162].
Systemic administration or intrathecal injection at
the lumbosacral level of the GABAB receptor ago-
nist baclofen decreased the frequency of erections
in male rats [122].
f) Oxytocin
Oxytocin is believed to be another spinal effector
of penile erection released from hypothalamic
supraoptic and paraventricular nuclei that project
to spinal centers influencing this function. Plasma
oxytocin concentrations are known to be elevated
in humans following sexual stimulation [163,
164]. When injected into the lateral cerebral ven-
tricle, the paraventricular nucleus, or hippocampus
in laboratory animals, oxytocin is found to be a
potent inducer of penile erection [165, 166, 167].
Oxytocin receptors are believed to mediate erec-
tions since the erectile response is blocked by the
administration of oxytocin antagonists and by
electrolytic lesion of the paraventricular nucleus
[138, 168]. Immunoreactive oxytocin-containing
spinal neurons associating with sacral preganglio-
nic neurons confirmed by retrograde labelling sup-
ports the role of oxytocin in the autonomic spinal
circuitry that mediates penile erection [126].
Oxytocin appears to exert an autoactivation
mechanism involving the stimulation of oxytoci-
nergic receptors located in the cell bodies of the
same oxytocinergic neurons in the paraventricular
nucleus [165, 166]. In support of this view, immu-
noreactive cell bodies of oxytocinergic synapses
have been found to impinge upon the cell bodies
of oxytocinergic neurons in both hypothalamic
supraoptic and paraventricular nuclei [169]. Seve-
ral central neurotransmitters may also converge
upon the oxytocinergic system as activators (e.g.,
dopamine) or inhibitors (e.g., opioid peptides) of
its transmission. Evidence supports calcium as a
second messenger mediating oxytocin-induced
penile erection in the paraventricular nucleus and
150
oxytocinergic receptor coupling with calcium
channels through a pertussis toxin-sensitive G pro-
tein [170, 171]. The oxytocinergic system may
also be influenced by the NO synthase signal
transduction pathway since inhibitors of this path-
way prevent penile erection and yawning in rats
induced by oxytocin, dopamine, and NMDA sti-
mulation [172, 173].
Recent studies have explored the physiologic basis
for central oxytocin release. Dorsal penile nerve
electrical stimulation in rats, presumed to repre-
sent physiological tactile stimulation during copu-
lation, elicits neurohypophyseal recordings from
oxytocinergic neurons [174].
g) ACTH and related peptides
Peptides derived from the common 31 kDa pre-
cursor pro-opiomelanocortin, including adreno-
corticotropic hormone (ACTH) and alpha-melano-
cyte stimulating hormone (alpha-MSH) [175,
176], have been associated with erectile responses
since it was early shown that ACTH induced peni-
le erection along with the ”stretching-yawning
syndrome” following its injection into the lateral
ventricles of several laboratory animals [177,
178]. Confirmation of the sites of action of ACTH-
MSH peptides in central neurotransmission has
been hindered by the failure to identify specific
binding sites (receptors) for these peptides in the
central nervous system. ACTH appears to exert its
effects through the hypothalamus and via calcium
channel mediation since the intracerebroventricu-
lar injection of the N-type calcium channel inhibi-
tor omega-conotoxin prevents the ACTH effect
[170]. However, the failure of both lesions of the
paraventricular nucleus [168] and injections of
omega-conotoxin into this same nucleus [179] to
alter erection induction by ACTH, combined with
evidence that excitatory amino acids do not affect
ACTH effects [180], have suggested that an alter-
native hypothalamic site or mechanism of action is
responsible for ACTH-induction of erection other
than that involving dopamine or oxytocin action in
the paraventricular nucleus [181].
h) Opioid peptides
Endogenous opioid peptides have long been assu-
med to be involved in the regulation of male
sexual responses, since sexual dysfunction has
been observed clinically in men chronically using
opiates [182, 183] and copulatory behavior in
male rats is depressed experimentally with the sys-
temic administration of morphine or other opioids
[184, 185]. β-Endorphin injection into the cerebral
ventricles or medial preoptic area of the hypotha-
lamus of male rats attenuates copulatory behavior
[184, 186]. Morphine, injected systemically or
into the paraventricular nucleus of male rats, pre-
vents penile erection induced by intracerebroven-
tricular administration of oxytocin or subcuta-
neous dopamine [187], or NMDAinjected into the
paraventricular nucleus [167]. However, similar
application of a selective agonist of the kappa
opioid receptor does not alter apomorphine- or
oxytocin-induced erectile responses [188]. This
evidence and the demonstration that the opiate
antagonist naloxone administered systemically
abolishes the central morphine preventative effect
on erections in rats have supported the belief that
µ receptors in the paraventricular nucleus account
for the morphine effect [188]. NO metabolite
concentrations that are increased in the paraventri-
cular nucleus following apomorphine, oxytocin, or
NMDA local administration become reduced fol-
lowing morphine administration also into the para-
ventricular nucleus, indicating that the morphine
effect depresses a NO-mediated erection induction
mechanism at this level [167, 188]. Current data
support the hypothesis that opioid µ receptor sti-
mulation centrally prevents penile erection by
inhibiting mechanisms that converge upon central
oxytocinergic neurotransmission of this function.
i) Acetylcholine
The role of acetylcholine at central levels in the
regulation of penile erection is mostly inferred
from limited neuropharmacologic studies invol-
ving primarily locally administered muscarinic
and nicotinic receptor antagonists and lesioning
studies in the brain [20, 189]. These studies have
suggested that acetylcholine operating seemingly
at the hippocampus may have a regulatory role in
erectile function.
j) Nitric oxide
The role of NO in the central neuromediation of
penile erection followed observations that the
injection of NOS inhibitors into the intracerebro-
ventricular nucleus or the paraventricular nucleus
of the hypothalamus prevented penile erectile res-
ponses induced by dopamine agonists, oxytocin,
and NMDA in rats 154, 172, 190]. The inhibitory
151
effect of NOS inhibitors was not observed when
these compounds were injected concomitantly
with L-arginine, the substrate for NO.
The paraventricular nucleus has been implicated
as a prime site for NO action mediating an oxyto-
cinergic mechanism for penile erection [173].
This brain nucleus was earlier identified to contain
one of the highest concentrations of NOS in the
brain [191]. Nitroglycerin, an NO donor, induces
penile erection in the rat with injection into the
paraventricular nucleus [192]. The medial preoptic
area is also purported to liberate NO with sexual
activity in rats, given direct measurement of its
release with copulatory behavior and its lack of
production following NOS inhibitor local admi-
nistration, which decreased copulatory behavior
[193].
Interestingly, since guanylate cyclase inhibitors
(e.g., methylene blue) injected into the paraventri-
cular nucleus fail to prevent drug-induced penile
erection, and 8-bromo-cGMP injected into the
paraventricular nucleus fails to elicit erections, it
has been proposed that the mechanism of NO
action is unassociated with the activation of gua-
nylate cyclase [131]. The additional finding that
the NO scavenger hemoglobin does not prevent
penile erection in spite of its ability to block NO
production in the paraventricular nucleus sugges-
ted that NO acts as an intracellular rather than an
intercellular modulator of erectile responses invol-
ving the paraventricular nucleus [131]. NO may
additionally mediate the actions of ACTH and 5-
HT1C agonists, which elicit erections when injec-
ted into the intracerebroventricular system accor-
ding to mechanisms unrelated to oxytocinergic
neurotransmission [131].
2. PERIPHERAL NEUROMEDIATION
The different structures of the penis receive sym-
pathetic, parasympathetic, somatic, and sensory
innervation. The distribution of autonomic nerves
within the corpora cavernosa has been studied by
several investigators [2, 3, 4], but the density of
nerves and the quantitative relations between the
number of nerve terminals and the number of
smooth muscle cells have not been established.
The nerves contain different transmitters and the
nerve populations have been categorized as adre-
nergic, cholinergic, and non-adrenergic, non-cho-
linergic (NANC). The latter nerves may contain
not only neuropeptides, but also transmitters and
transmitter/modulator generating enzymes, such
as NO synthase (NOS) and heme oxygenases
(HO). NANC transmitters/modulators may be
found in adrenergic and cholinergic nerves [194],
which should make it more meaningful to define
nerve populations based on their transmitter
content. Thus, it seems that one important popula-
tion of nerves in the corpora cavernosa contain not
only acetylcholine, but also NOS, VIP, and neuro-
peptide Y [195].
The nerves and vasculature of the penis produce
and release transmitters and modulators, produ-
cing contraction or relaxation (Figure 2). These
transmitters/ modulators interact in their control of
the contractile state of the corpus cavernosum
smooth muscle. In addition they may also have
other important functions, some of which are dis-
cussed below.
a) Contraction-mediating transmitters and recep -
tors
1. NORADRENALINE AND α-ADRENOCEPTORS
Penile arteries, cavernosal smooth muscle, and the
principal penile veins receive adrenergic innerva-
tion, and it is generally accepted that the penis is
kept in the flaccid state mainly via a tonic activity
in these nerves through release of NA (Figure 3).
NA stimulates α-ARs in the penile vasculature
contracting the helicine vessels, and in the corpus
cavernosum, contracting the trabecular smooth
muscle [4]. NA stimulates not only α-, but also β-
ARs. However, in the human corpus cavernosum,
receptor binding studies have revealed that the
density of α-ARs is almost 10 times higher than
Figure 2: The nerves and vasculature of the penis produce and release transmitters and modulators, producing contraction
or relaxation. These transmitters/ modulators interact in their control of the contractile state of the corpus cavernosum
smooth muscle.
152
that of β-ARs [196]; the number of α−AR binding
sites per cell was estimated to 650,000 [197]. Not
only the number of receptors is of importance.
Androgens may regulate the α-AR responsiveness
of cavernous smooth muscle. Compared to normal
rats, castrated animals showed an enhanced reacti-
vity to α1-AR stimulation [198].
Both α1-and α2-ARs have been demonstrated in
human corpus cavernosum tissue [4, 199, 200],
but available information supports the view of a
functional predominance of α1-ARs. This may be
the case also in the penile vasculature, although a
contribution of α2-ARs to the contraction induced
by NA and electrical stimulation of nerves cannot
be excluded (see below). In horse penile resistan-
ce arteries, NA activated predominantly α1-ARs,
whereas postjunctional α2-ARs seemed to play a
minor role [201].
An important question is whether or not one of the
α1-AR subtypes is more important than the others
for the contractile effects of NA. The subtypes of
α1-AR with high affinity for prazosin [202], cur-
rently designated as α1A, α1Band α1D (the cloned
counterparts are termed α1a α1b and α1d) have
been demonstrated in human corporal tissue. In a
preliminary communication, Price [203] reported
that in human corporal tissue, mRNAs for α1a,
α1b and, α1d (current terminology) could be iden-
tified, the α1a- and α1d-ARs predominating. This
was confirmed by other investigators [204, 205].
However, it is known that the levels of mRNA
expression do not always parallel the expression
of a functional receptor protein. Traish [200] cha-
racterized the functional α1-AR proteins in human
corpus cavernosum tissue, using receptor binding

Figure 3: The penis is kept in the flaccid state mainly via a
tonic activity in adrenergic nerves through release of nora -
drenaline (NA). Endothelin-1 may increase the sensitivity to
released NA, but may also by a direct action contribute to
the maintenance of tone in vascular and corporal smooth
muscle. The role of contraction-mediating prostanoids is
unclear.
and isometric tension experiments. Their results
demonstrated the presence of α1A-, α1B-, and
α1D-ARs, and they suggested that the NA-indu-
ced contraction in this tissue is mediated by two or
possibly three receptor subtypes.
There is increasing evidence that an additional α1-
AR subtype with low affinity for prazosin (α1L),
which is not yet fully characterized, may occur in,
for example, vascular smooth muscle [206]. The
possibility that the α1L-AR subtype may be of
importance in penile erectile tissues was recently
suggested [207]. Whether or not antagonists,
selectively acting at any of the α1-AR subtypes,
would offer any advantages over presently used
drugs (phentolamine, moxisylyte) in the treatment
of erectile dysfunction, remains to be established.
Traish et al. [199] demonstrated expression of
mRNA for α1A-, α1B-, and α1C-ARs in whole
human corpus cavernosum tissue. Radioligand
binding studies with a highly selective ligand for
α2-ARs revealed specific α2-AR binding sites,
and functional experiments showed that the selec-
tive α2-AR agonist, UK 14,304, induced concen-
tration-dependent contractions of isolated strips of
corpus cavernosum smooth muscle. These results
153
support previous data [4] suggesting the occurren-
ce of postjunctional α2-ARs in the human corpus
cavernosum. However, whether or not these α2-
ARs are of importance for the contractile regula-
tion of tone in corpus cavernosum smooth muscle
is still unclear. Prejunctional α2-ARs have been
shown to modulate stimulus-evoked release of NA
from nerves in the human corpus cavernosum, sti-
mulation inhibiting the release of the amine [208].
However, stimulation of prejunctional α2-ARs in
horse penile resistance arteries was shown also to
inhibit NANC-transmitter release [209]. This
might be one of the mechanisms by which NA
maintains detumescence.
2. ENDOTHELINS AND ENDOTHELIN RECEPTORS
Endothelins (ETs) have been demonstrated in
penile erectile tissues and suggested to contribute
to the maintenance of corporal smooth muscle
tone [4]. Three distinct ET peptides have been
demonstrated: ET-1, ET-2, and ET-3, all widely
distributed in the body. Two types of ET receptors
have been cloned and expressed: the ETA receptor
which is stimulated by ETs with the rank order
potency ET-1 = ET-2 > ET-3, and the ETB recep-
tor for which the rank order is ET-1 = ET-2 = ET-
3. ET-receptors are G-protein-coupled; they may
use various transduction systems in mediating
their actions [210].
Saenz de Tejada et al [211] showed that cultured
endothelial cells from the human corpus caverno-
sum, but not non-endothelial cells, expressed ET-1
mRNA. In the endothelium of human cavernous
tissue, intense ET-like immunoreactivity was
observed; immunoreactivity was observed also in
the cavernous smooth muscle [211]. Binding sites
for ET-1 were demonstrated by autoradiography in
the vasculature and cavernous tissue [212, 213].
Both ET A and ET B receptors have been found in
human corporal smooth muscle membranes, and it
cannot be excluded that both receptor subtypes are
functional [214]. In rat corpus cavernosum ET-1
and ETA receptor binding sites were primarily
localized to the endothelium lining the cavernosal
lacunar spaces [215].
ET-1 potently induces slowly developing, long-
lasting contractions in different penile smooth
muscles: corpus cavernosum, cavernous artery,
deep dorsal vein, and penile circumflex veins [4]
Contractions can be evoked in human corpus
cavernosus tissue also by ET-2 and ET-3, although
these peptides have a lower potency than ET-1
[211]. In bovine retractor penis muscle and penile
artery, the contraction induced by ET-1 was
mediated primarily by ETA-receptors [216]. The
contractions induced by ET-1 may be dependent
on both transmembrane calcium flux (through vol-
tage-dependent and/or receptor-operated calcium
channels) and on the mobilization of inositol tris-
phosphate (IP3-) sensitive intracellular calcium
stores [212, 217]. ET-1 may function not only as
a long-term regulator of corporal smooth muscle
tone, but also as modulator of the contractile effect
of other agents, e.g., NA [212, 214, 218], or as a
modulator of cellular proliferation and phenotypic
expression [219].
Ari et al [220] found that in the pithed rat, intrave-
nously injected ET-1 had a vasodilator action
(increase in corporal pressure) at low, but a vaso-
constrictor action at high doses. ET-3 had mainly
vasodilator effects. They suggested that the vaso-
dilator actions were mediated by activation of
ETB receptors on the endothelium and local relea-
se of NO, since these actions were inhibited by L-
NAME. Parkkisenniemi & Klinge [216] suggested
that the ETB receptors that could be demonstrated
on the bovine retractor penis muscle, at least part-
ly were located on the inhibitory nerves that
mediate relaxation via activation of the L-argini-
ne/NO/cGMP pathway.
Even if much available in vitro information sug-
gests that ETs may be of importance for erectile
physiology and pathophysiology, the role of the
peptides in vivo is unclear. Christ et al [214] found
no detectable age- or diabetes-related changes in
contractile effects in human corpus cavernosum tis-
sue. On the other hand, ET-1 and ETA receptor bin-
ding was found to be increased in diabetic rat caver-
nosal tissue [215]. Francavilla et al [221] found no
differences in plasma concentrations of ET-1 in dia-
betic and non-diabetic patients with erectile dys-
function, and the concentrations of ET-1 in caver-
nous body blood were no different following intra-
cavernous injection of PGE1. Further studies are
needed to define the role of ETs in erectile function
and dysfunction.
3. ANGIOTENSIN AND ANGIOTENSIN RECEPTORS
Human corpus cavernosum was found to produce
and secrete physiologically relevant amounts of
154
angiotensin II [222]. In vitro, angiotensin II
contracted canine corpus cavernosum smooth
muscle, an effect that was increased by NOS inhi-
bition [223]. Intracavernosal injection of angioten-
sin II caused contraction and terminated sponta-
neous erections in anesthetized dogs, whereas
administration of losartan, selectively blocking
angiotensin II receptors (type AT1), resulted in
smooth muscle relaxation and erection [222]. Also
in the rabbit corpus cavernosum, results were
obtained suggesting involvement of the renin-
angiotensin system in the regulation of corpus
cavernosum smooth muscle tone, and that the
angiotensin II receptor subtype AT1 is important
for mediation of the response [224].
Whether or not angiotensin II is an important regu-
lator of tone in penile erectile tissues, is unclear.
Studies using angiotensin II receptor antagonists,
for example losartan, designed to elucidate this
question, would be of interest.
b) Relaxation-mediating transmitters and
receptors
1. ACETYLCHOLINE AND CHOLINERGIC RECEPTORS
The importance of parasympathetic nerves for
producing penile erection has been well establi-
shed [7]. Penile tissues from humans and several
animal species are rich in nerves staining for ace-
tylcholine (ACh) esterase [239]. From these
nerves, ACh can be released by transmural electri-
cal field stimulation. Human corpus cavernosum
contains a high density of muscarinic receptors,
and Costa et al [197] calculated the number of bin-
ding sites on isolated corpus cavernosum smooth
muscle cells to be 45, 000, which was about 15
times less than the number of α-ARs. In these
cells, carbachol consistently produced contraction.
This means that relaxation induced by ACh can be
obtained either by inhibition of release of a
contractant factor, e.g., NA, and/or is produced by
the release of a relaxation-producing factor, e.g.,
NO (Figure 4). Four muscarinic receptor subtypes
(m1-m4) were shown to be expressed in human
corpus cavernosum tissue [225]; the receptor on
smooth muscle was suggested to be of the M2 sub-
type [225, 226], whereas that on the endothelium
was of the M 3 subtype [225].
It is important to stress that parasympathetic acti -
vity is not equivalent with the actions of ACh;
other transmitters may be released from choli -

Figure 4 : Relaxation induced by stimulation of cholinergic
nerves can be obtained either by acetylcholine (ACh) inhi -
bition of release of contractant factors, e.g., noradrenaline
(NA), and/or by the release of relaxation-producing factors,
e.g., nitric oxide (NO) and vasoactive intestinal polypeptide
(VIP). Prostanoids may act both prejunctionally (decrea -
sing the release of NA) and postjunctionally in producing
smooth muscle relaxation.
nergic nerves [194]. Parasympathetic activity may
produce penile tumescence and erection by inhibi-
ting the release of NAthrough stimulation of mus-
carinic receptors on adrenergic nerve terminals
[227], and/or by releasing NO and e.g., vasodila-
ting peptides from nerves and endothelium.
2. NITRIC OXIDE AND THE GUANYLATE CYCLASE
/CGMP PATHWAY
An important role for NO in the relaxation of cor-
pus cavernosum smooth muscle and vasculature is
widely accepted [4, 228]. In vitro, several investi-
gators have shown that both ACh- and neuronally
mediated relaxation in animal and human corpus
cavernosum (cc) involves release of NO, or a NO-
like substance [4]. Both the endothelium and/or
the nerves innervating the corpus cavernosum
(CC) may be the source of the NO, and thus, more
than one isoform of NOS can be involved. There
seems to be no doubt about the presence of NOS
in the cavernous nerves and their terminal endings
within the CC, and in the branches of the dorsal
penile nerves and nerve plexuses in the adventitia
of the deep cavernous arteries [228, 229, 230, 231,
232, 233]. In the rat, Dail et al [233] found that all
smooth muscle regions of the penis were richly
innervated by nerves containing neuronal NOS
(nNOS), and that the endothelium of vessels stai-
155
ned for both endothelial NOS (eNOS) and
NADPH diaphorase. However, the endothelium of
cavernous sinuses did not contain eNOS and did
not stain for NADPH-diaphorase. This is in
contrast to findings in both normal mice and in
mice with targeted deletion of nNOS [232]. In
both types, eNOS was present in the endothelium
of the penile vasculature and in sinusoidal endo-
thelium within the corpora cavernosa. These
observations are important for several reasons.
Species differences in the mechanisms of penile
erection have to be considered when evaluating
results from different animal models, and for
example the rat has been extensively used as
model for NO action in penile erection. Some of
the results obtained may not be valid for other spe-
cies, including humans, where there is functional
[4] evidence for the occurrence of eNOS in the
endothelium of the sinusoids.
Mice lacking nNOS [234] have erections, show
normal mating behaviour, and respond with erec-
tion to electrical stimulation of the cavernous
nerves [232]. Surprisingly, isolated corporal tissue
from both wild type and nNOS-deleted animals
showed similar responses to electrical stimulation
[232]. It was suggested that eNOS is essential for
erection, not only in nNOS deleted, but also in
normal mice. The importance of eNOS was stres-
sed by Bloch et al. [235]. They demonstrated that
eNOS is expressed in cavernosal smooth muscle
and they suggested that eNOS could be a main
source of NO alongside with nNOS. However, it
was shown that mice carrying a mutation in the
nNOS gene are still able to express an alternative-
ly spliced mRNA of nNOS, which could be the
source of NO in nNOS mutant mice [236]. Since
NO is produced, and the guanylyl/cGMP/cGKI
pathway apparently is intact in the CC of these
animals, they are not suitable to test whether or not
the NO/cGMP pathway is a prerequisite for nor-
mal penile erection.
cGMP signals via three different receptors in
eukaryotic cells, including ion channels, phospho-
diesterases, and protein kinases. At present, howe-
ver, the molecular targets which are activated by
cGMP and finally execute the relaxation of penile
smooth muscle are not known. Two different
cGMP-dependent protein kinases (cGK I and II)
have been identified in mammals. Inactivation of
cGKI in mice abolished both NO/cGMP-depen-
dent relaxation of vascular and intestinal smooth
muscle and inhibition of platelet aggregation, cau-
sing hypertension, intestinal dysmotility and
abnormal hemostasis [237].
cGKI-deficient (cGKI-/-) mice (see above) show a
very low ability to reproduce. CC tissue from
these mice has an inability or markedly reduced
ability to relax in response to neuronally or endo-
thelially released, or exogenously administered
NO [238]. The expression of cGKI in penile tissue
fom cGKI+/+ mice, as revealed by immunohisto-
chemistry, was confined to the smooth muscle of
the walls of the central and helicine arteries, and to
the smooth muscle of the trabecular septa surroun-
ding the cavernous spaces. This is in line with its
presumed role in the erectile events. The total
innervation (PGP immunoreactivity) and distribu -
tion of nerve populations containing transmitters
or transmitter-forming enzymes (vesicular acetyl-
choline transporter: VAChT: VIP, tyrosine
hydroxylase : TH, NOS) believed to be important
in the regulation of tone in CC tissue [4], were
similar in normal and cGKI-null mice. Analysis of
the NO/cGMP-induced relaxation clearly showed
that cGKI is the major mediator of the cGMP
signaling cascade in CC tissue. Its absence cannot
be compensated by the cAMP signaling cascade
that relaxes normal and cGKI-null penile erectile
tissue to a similar extent. Taken together, these fin-
dings suggest that activation of cGKI is a key step
in the signal cascade leading to penile erection.
3. VASOACTIVE INTESTINAL POLYPEPTIDE (VIP) AND
VIP RECEPTORS
The penis of humans as well as animals is richly
supplied with nerves containing VIP [239]. The
majority of these nerves also contain immunoreac-
tivity to NOS, and colocalization of NOS and VIP
within nerves innervating the penis of both animals
and humans has been demonstrated by many inves-
tigators [240, 241, 242, 243, 244, 245, 246, 247]. It
seems that most of these NO- and VIP-containing
neurons are cholinergic, since they also contain
VAChT [238], which is a specific marker for choli-
nergic neurons [248]. However, Tamura et al [243]
reported that in the human penis, NOS could be
found also in nerves containing TH, suggesting that
NO can be generated by adrenergic nerves. As poin-
ted out by the investigators, the physiological signi-
ficance of such a localization is presently unclear
and the finding has to be confirmed.
156
VIP receptors (types 1 and 2), linked via stimula-
tory G-proteins to adenylyl cyclase, are considered
to mediate the actions of the peptide [249]. The
importance of the different subtypes of VIP in
penile tissues have not been clarified. VIP related
peptides, e.g., pituitary adenylyl cyclase-activa-
ting peptide (PACAP), which has been found to be
colocalized with VIP in penile nerves [241], seem
to act through one of the VIP receptors.
The stimulatory effect of VIP on adenylyl cyclase
leads to an increase in cAMP, which in turn acti-
vates cAMP-dependent protein kinase. However,
VIP may increase not only cAMP, but also cGMP
concentrations in various smooth muscles [250].
On the other hand, this does not seem to be the
case in corporal tissue from humans [241], or rat
and rabbits [251], where VIP increased cAMP
concentrations without affecting the cGMP levels.
In experimental diabetes in rats, Maher et al [252]
found that the VIPcontent of the major pelvic gan-
glion and penis was markedly increased, whereas
intracavernous injection of VIP, which caused
erection in control rats, had no effect in diabetic
animals. Since forskolin, which directly activates
adenylyl cyclase, induced erection in both controls
and diabetic rats, it was concluded that there was a
defect at the level of the VIP receptor or of the
associated G-protein. This is in contrast to pre-
vious findings in diabetic rats, showing that VIP-
stimulated cAMP generation was significantly
increased [251]. They are also in contrast to obser-
vations in human diabetes [253, 254] showing that
in patients with impotence, there was a marked
reduction of VIP-like immunoreactivity in nerves
associated with the cavernous smooth muscle.
However, the latter observation has not been
confirmed by other investigators [255].
Undeniably, VIP has an inhibitory and relaxation-
producing effect on strips of human corpus caver-
nosum tissue and cavernosal vessels in vitro, but it
has been difficult to convincingly show that VIP
released from nerves is responsible for relaxation
of penile smooth muscle in vitro or in vivo [4].
VIP-antiserum [256] and chymotrypsin [257]
reduced or abolished the relaxant effect of exoge-
nous VIP on isolated human corpus cavernosum
tissue, but had no effect on relaxation induced by
electrical stimulation of nerves. Kim et al [258]
reported that in rabbit corpus cavernosum, a VIP-
antagonist inhibited electrically-induced contrac-
tions, suggesting that the peptide was released
from nerves during stimulation. They concluded
that VIP appeared to contribute to NANC-media-
ted corpus cavernosum relaxation, and that its
mechanism of relaxation was dependent on pros-
tanoids and involved the generation of NO. This is
in contrast to the conclusion drawn by Hayashida
et al [259], who found no evidence for a role of
VIP in the regulation of tone in the canine corpus
cavernosum.
As mentioned previously, many penile nerves
contain both NO and VIP and ACh, and the pos-
sible interactions between these agents should be
of particular interest. The effects of NO and the
NO donor linsidomine (SIN-1) were studied on
human isolated cavernous artery and corpus caver-
nosum [260]. A non-synergistic, independent
relaxant effect in both types of preparation was
observed. Suh et al [261] investigated the effect of
VIP and VIP combined with ACh given intraca-
vernously in rats. They found that VIP and ACh,
individually or in combination, did not produce
full erection, and concluded that neither VIP, nor,
ACh were likely to be principal transmitters.
Not only NOS, but also other peptides, seem to be
co-localized with VIP. Peptide histidine methionine
(PHM), which is derived from the same precursor
as VIP [262, 263, 264, 265], and the VIP-related
PACAP and helospectin [241, 264, 265, 266], have
been found to be colocalized with VIP. Even if Hed-
lund et al [241] demonstrated some of these pep-
tides to be effective relaxants of human CC prepa-
rations, a role for them as neurotransmitters and/or
neuromodulators has yet to be demonstrated.
Thus, whether or not VIP has a role as a neuro-
transmitter or modulator of neurotransmission in
the penis has not been established. Even if its phy-
siological role in penile erection and in erectile
dysfunction remains to be settled, VIP receptors in
the penis are an interesting therapeutic target. Par-
ticularly, the combination of VIP and phentolami-
ne seems to be effective in the treatment of erecti-
le dysfunction [267, 268].
4. PROSTANOIDS AND PROSTANOID RECEPTORS
Prostaglandins (PGs) and thromboxanes are local-
ly acting hormones derived from arachidonic acid
by the action of cyclooxygenases. Human corpus
157
cavernosum tissue has the ability to synthetize
various prostanoids [269, 270], and has also the
ability to locally metabolize them. The production
of prostanoids can be modulated by oxygen ten-
sion and suppressed by hypoxia [271, 272]. There
are five primary active prostanoid metabolites:
PGD2, PGE2, PGF2α, PGI2, and TXA2, and it has
been proposed that there are five major groups of
receptors, corresponding to these metabolites, that
mediate their effects, namely DP, EP, FP, IP, and
TP receptors [273, 274]. cDNAs encoding repre-
sentatives of each of these groups of receptors
have been cloned, including several subtypes of
EP receptors. The prostanoid receptors are G-pro-
tein-coupled receptors with differing transduction
systems [273].
Penile tissues may contain most of these groups of
receptors. However, their role in penile physiolo-
gy is still far from established. Prostanoids may be
involved in contraction of erectile tissues via
PGF2α and thromboxane A2, stimulating TX and
FPreceptors and initiating phosphoinositide turno-
ver, as well as in relaxation via PGE1 and PGE 2,
stimulating EP receptors (EP2/EP4) and initiating
an increase in the intracellular concentration of
cAMP. Prostanoids may also be involved in inhi-
bition of platelet aggregation and white cell adhe-
sion, and recent data suggest that prostanoids and
transforming growth factor-β1 (TGF-β1) may
have a role in modulation of collagen synthesis
and in the regulation of fibrosis of the corpus
cavernosum [275].
5. OTHER AGENTS
Adrenomedullin is a recently discovered vasodila-
tor peptide isolated from human phaeochromocy-
toma cells [276]. It consists of 52 amino acids and
has structural similarities to calcitonin-gene-rela-
ted peptide (CGRP). Adrenomedullin has been
suggested to serve as a circulating hormone regu-
lating systemic arterial pressure [276]. Champion
et al. [277, 278, 279] showed that adrenomedullin,
injected intracavernously in cats caused an increa-
se in intracavernous pressure and in penile length.
The increase in intracavernous pressure reached at
a dose of 1 nM adrenomedullin amounted to 75 %
of that induced by a triple drug combination of
papaverine, phentolamine and PGE1, or with the
response to CGRP at a 10 times lower dose [278].
The erectile responses to adrenomedullin or
CGRP were unaffected by NO-synthase inhibition
with L-NAME, or by KATP channel inhibition
with glibenclamide, suggesting that NO or KATP
channels were not involved in the response. Since
CGRP responses were reduced by the CGRPanta-
gonist CGRP (8-37) at doses having no effects on
the adrenomedullin response, it was suggested that
the peptides acted on different receptors. In the
highest doses used, both adrenomedullin and
CGRP (and the control triple combination) redu-
ced blood pressure. These results with CGRP are
in agreement with clinical experiences and support
the suggestion by Stief et al. [280] that CGRPmay
be useful in the treatment in erectile dysfunction.
In patients, intracavernosal injection of CGRP
induced dose-related increases in penile arterial
inflow, cavernous smooth muscle relaxation,
cavernous outflow occlusion, and in erectile res-
ponses. The combination of CGRPand PGE1 may
even be more effective than PGE1 alone [281,
282].
Nociceptin is a 17 aminoacid peptide that shares
structural homology with the dynorphine family of
peptides. It differs from other opioid peptides by
not having the NH2-terminal residue which is
essentail for activity at µ, δ, and κ opiod receptors
[283]. The drug is an endogenous ligand for the
orphan opioid receptor that has been identified in
several species: the human clone is called ORL1.
Its function is not established; it may be involved
in hyperalgesia or analgesia [283].
Champion et al. [277] compared the erectile res-
ponses to intracavernously given nociceptin with
those of a triple drug combination (see above),
VIP, adrenomedullin, and an NO-donor in cats.
Nociceptin in doses of 0.3 - 3 nM elicited dose-
related increases in intracavernous pressure and
penile length comparable to that of the triple drug
combination, but the duration of the response was
shorter.
These data on previously unknown receptors in
penile erectile tissues that on stimulation can indu-
ce erectile responses are exciting, and show that
the complex mechanisms involved in penile erec -
tion are far from clarified.
158
IV. SIGNAL TRANSDUCTION
1. THE S YNCYTIAL TISSUE TRIAD: THE
MECHANISTIC BASIS FOR THE LOCAL
COORDINATION OF PENILE ERECTION.
Coordination of activity among the corporal
smooth muscle cells is an important prerequisite to
normal erectile function. The autonomic nervous
system plays an important role in this process by
supplying a heterogeneous neural input to the
penis. The density, distribution and roles of the
various neuroeffector pathways are not complete-
ly understood, and in fact, may vary significantly
between individuals, as well as over time within
the same individual. For example, the activity of
the autonomic nervous system differs dramatically
during erection, detumescence and flaccidity. As
such, it is increasingly clear that the role of the
autonomic nervous system in normal penile func-
tion must be coordinated with the phenotype and
activity of the constituent corporal and arterial
myocytes. That is, the firing rate of the autonomic
nervous system, myocyte excitability and signal
transduction processes, and the extent of cell-to-
cell communication between corporal smooth
muscle cells must be carefully integrated to ensu-
re normal erectile function.
This integrative mechanism for the coordination
of tissue responses is referred to as the “Syncytial
Tissue Triad”, and furthermore, the principles that
govern its operation hold the key to understanding
the initiation and spread of stimuli among corporal
myocytes and its relationship to erectile physiolo-
gy and dysfunction. Simply put, the principles that
govern the coordination of corporal smooth
muscle responses exist at three levels:
1) The Signal: Direct activation of a fraction of the
corporal smooth muscle cells by 1st messengers;
i.e., neurotransmitters, neurohumors or hormones,
etc.
2) Signal Spread: Electrotonic current spread and
intercellular diffusion of relevant second messen-
ger molecules/ions via gap junctions; and
3) Signal Transduction: Intracellular signal trans-
duction within corporal smooth muscle cells
mediated by activation of transducer G-proteins,
i.e., 2nd and 3rd messengers etc. The inter-rela-
tionships that occur at these three distinct levels are
depicted in Figure 5. At the first level, innervation
and the mechanisms of action of neurotransmission
are still areas of rapidly expanding knowledge.
This is true also for the second and third levels,
where the variety of electrotonic and chemical
transduction mechanisms (2nd messengers, etc.)
extant in the corpora, as well as the mechanistic
basis for the rapid intercellular spread of these
signals, respectively, are areas that are just begin-
ning to be understood and more fully explored.
Recent experimental and theoretical studies sup-
port the supposition that the presence of the “Syn -
cytial Tissue Triad” in the human penis confers a
great deal of plasticity, flexibility and adaptability
to erectile function [284, 285, 286]. The presence
of such multiple, overlapping and apparently
redundant mechanisms for coordination of erectile
capacity is consistent with the proximal importan-
ce of penile erection to the survival of the species,
as well as the emotional well being of men and
their sexual partners. The supposition is advanced
that understanding autonomic neural control of
corporal smooth muscle tone needs to add a new
component, that is, the syncytial nature of corpo-
ral smooth muscle. These concepts, and the evi-
dence for their existence, are highlighted in the
context of new therapeutic approaches to the treat-
ment of erectile dysfunction (i.e., gene therapy)
that take advantage of their presence.
2. THE FLOW OF INFORMATION AND THE
DIVERSITY OF SIGNAL TRANSDUCTION
The intrinsic variability/diversity that is built into
the regulation of corporal smooth muscle contrac-
tion is a primary factor in understanding erectile
physiology, as well as the etiology and, ultimately,
the improved therapy of erectile dysfunction. The
exact nature of this diversity is reflected by the
relative contribution(s) of the numerous distinct
signal transduction pathway(s) present in these
cells (Figure 6). It is conceivable that corporal
myocytes from different individuals and under dif-
ferent conditions (i.e., age- or disease-related
changes) may have/express different complements
of membrane receptors (i.e., serotonergic, adrener-
159
gic, cholinergic, etc.), transducers (i.e., G proteins)
and effectors (i.e., enzymes and ion channels), and
therefore, heterogeneous pathways may be activa-
ted. Nonetheless, the three biochemical pathways
that have been most well documented and charac-
terized are outlined in Figure 6, which depicts how
information received from 1st messengers is trans-
lated into alterations in cellular biochemical activi-
ty, and finally, integrated over the entire tissue to
affect erectile capacity. However, as illustrated, it is
clear that despite the plethora of bifurcating signal
transduction pathways that are present and physio-
logically relevant in corporal smooth muscle, the
actions of most, if not all of the pathways, on cor-
poral smooth muscle tone, are exerted, at least in
part, via their respective effects on the ion channels
present in corporal smooth muscle.
3. I ONIC DISTRIBUTION ACROSS THE CORPO-
RAL SMOOTH MUSCLE CELL MEMBRANE
Critical to the understanding of ion channel func-
tion is the distribution of the relevant ions across
the cell membrane. The distribution of ions across
the corporal smooth muscle cell, in conjunction
with resting membrane potential of the corporal
smooth muscle cell, ultimately determines the
direction of ion flow during the opening of any
given ion channel. These ionic gradients are main-
tained by a series of active membrane ion pumps
and co-transporters, and are absolutely critical to
the normal function of the corporal smooth muscle
cell. Ionic movements associated with the opening
of various ion channels are discussed below in the
context of the individual ion channels thus far cha-
racterized in human corporal smooth muscle.
4. K+ CHANNELS IDENTIFIED IN HUMAN COR-
PORAL SMOOTH MUSCLE
To date, at least four distinct K+ currents have
been described in human corporal smooth muscle.
These are:
1. A calcium-sensitive maxi-K (i.e., KCa), channel.
2. A metabolically-regulated K channel (i.e.,
KATP).
3. A delayed rectifier K channel (i.e., KDR) and
4. An “A” type K current. The first two of these K
channel subtypes are the most well characterized,
and probably, the most physiologically relevant.
 Figure 5: Schematic depiction of
the expected impact of molecular
biology on the understanding,
diagnosis and treatment of erec -
tile dysfunction. The Molecular
Biology Quandrangle depicts the
four major arenas in which the
application of molecular techno -
logies will result in a significant
accumulation of new knowledge.
This knowledge will play a criti -
cal role in the development of
novel and more selective oral
and gene-based therapies for
erectile dysfunction.

Figure 6: Signal transduction pathway(s) present in penile vascular and corporal smooth muscle cells, mediating contraction
and relaxation. Prostaglandin E1 (PGE1) acts through stimulation of adenylyl cyclase, increasing the concentration of cyclic
AMP(cAMP), which via protein kinase A (PKA) decreases the intracellular Ca2+ concentration and thereby produces relaxa -
tion. Nitric oxide stimulates guanylyl cyclase, increasing the intracellular concentration of cyclic GMP(cGMP), which via pro -
tein kinase G (PKG) decreases the intracellular Ca2+ concentration with consequent relaxation of the smooth muscle cell.
160
The distribution of K + across the corporal smooth
muscle cell membrane ensures that the opening of
K channels will lead to efflux of K+ from the
smooth muscle cell, down their electrochemical
gradient. The movement of positive charge out of
the cell results in cellular hyperpolarization, or a
decrease in membrane potential. The main impli-
cation of K channels to erectile physiology/dys-
function is that their presence provides an impor-
tant hyperpolarizing mechanism for modulating
corporal smooth muscle tone and penile erection,
via their effects on transmembrane Ca2+-flux
through voltage-dependent Ca channels.
a) The K Ca channel
The calcium-sensitive K channel has been well
characterized in human corporal smooth muscle.
Briefly, KCa channel mRNA and protein have
been detected on both freshly isolated human cor-
poral tissues and cultured corporal smooth muscle
cells [287]. Consistent with such observations, the
single channel conductance (≈180 pS), whole cell
outward currents and voltage and calcium-sensiti-
vity of the KCa channel are remarkably similar
when comparing data collected with patch clamp
techniques on freshly isolated corporal smooth
muscle myocytes versus similar experiments on
short term explant cultured corporal smooth
muscle cells [288, 289].
Not surprisingly, the KCa channel appears to be an
important convergence point in modulating the
degree of corporal smooth muscle contraction.
That is, the activity of this channel is increased
quite dramatically following cellular activation of
either the cAMP pathway (8-Br-cAMP, PGE1
[289], or the cGMP pathway (nitroglycerin or 8-
Br-cGMP; Christ et al., unpublished observa-
tions). As such, it seems clear that the two most
physiologically relevant endogenous second mes-
senger pathways act to modulate corporal smooth
muscle tone (i.e., elicit relaxation), at least in part,
via activation of the KCa channel subtype. The
resulting hyperpolarization, in turn, is coupled to
decreased transmembrane calcium flux through L-
type voltage-dependent calcium channels (see
below), and ultimately, smooth muscle relaxation.
b) The metabolically-regulated K ATP channel
Western blots on isolated tissue strips, and immu-
nocytochemistry of cultured corporal smooth
muscle cells, using antibodies to the KATP chan-
161
nel, have documented the presence of the KATP-
channel protein [287]. Consistent with these
observations, several studies have documented
that K channel modulators, putative activators of
the K ATP channel subtype, elicit a concentration-
dependent relaxation of isolated human corporal
smooth muscle. Very recent experiments on fresh-
ly isolated corporal smooth muscle cells have
documented the presence of two distinct ATP-sen-
sitive K+ currents in cultured and freshly dissocia-
ted human corporal smooth muscle cells [290].
The two K ATP channel subtypes had conductance
values of ≈20 and ≈60 pS, respectively [290].
Consistent with observations at the single channel
level, whole cell patch clamp studies documented
a significant, glibenclamide-sensitive, increase in
the whole cell outward K+ currents in the presen-
ce of the K channel modulator levcromakalim
[290]. These data, ranging from the molecular,
through the cellular and whole tissue levels, clear-
ly document the presence and physiological rele-
vance of the KATP channel subtype(s) to the
modulation of human corporal smooth muscle
tone.
c) The L-type, voltage-dependent calcium chan -
nel
As illustrated in Figure 7, the distribution of cal-
cium ions across the corporal smooth muscle cell
membrane ensures that opening of calcium chan-
nels will lead to influx of calcium ions into the cor-
poral smooth muscle cell down their electroche-
mical gradient. The movement of positive charge
into the smooth muscle cell has the opposite effect
of the movement of K+ out of the cell, and there-
fore, will lead to an increase in membrane poten-
tial, or depolarization. Several studies have docu-
mented the importance of continuous transmem-
brane calcium flux through L-type voltage-depen-
dent calcium channels to the sustained contraction
of human corporal smooth muscle [291, 292, 293,
294, 295]. There is only one published report of
inward Ca2+ currents in corporal smooth muscle
using direct patch clamp methods [296]. However,
much of the most compelling mechanistic data
concerning the role of calcium channels in modu-
lating human corporal smooth muscle tone have
been established using digital imaging microscopy
of Fura-2 loaded cultured corporal smooth muscle
cells. These studies have provided strong evidence
for the presence and physiological relevance of
Figure 7: Signal transduction in corporal smooth muscle is more a network event than the simple activation of a physiologi -
cal cascade or pathway in individual myocytes. IP3 = inositoltrisphosphate; cGMP = cyclic AMP; cAMP= cyclic GMP

162
transmembrane calcium flux through the L-type
voltage-dependent calcium channel in response to
cellular activation with endothelin-1 (ET A/B
receptor subtype) and phenylephrine (α1-adrener-
gic receptor subtype [297, 298, 299].
d) Chloride channels in human corporal smooth
muscle.
The contribution of chloride channels/currents to
the modulation of human corporal smooth muscle
tone is less well understood than that of the other
ion channels. However, it seems clear that the dis-
tribution of the chloride ions across the corporal
smooth muscle cell membrane ensures that the
opening of chloride channels will result in the
efflux of Cl- from the smooth muscle cell. Moving
negative charge out of the cell will result in depo-
larization, or an increase in the membrane poten-
tial, presumably leading to increased cellular exci-
tability (i.e., contractility). Further complicating
study of these ion channels is that their presence
during patch clamp experiments on cultured myo-
cytes is relatively rare (i.e., ≈ 5% of cells actually
have any detectable chloride current [297, 300].
The precise reason for this fact is uncertain, but it
seems unlikely that their rarity in membrane
patches is an artifact of the cell culture conditions
per se, as there seems to be a similar infrequency
of their appearance on freshly isolated corporal
myocytes (Wang et al., unpublished observations).
Although rigorous analysis of Cl- channels is hin-
dered by the lack of truly selective channel bloc-
kers, there is still strong evidence for the presence
of at least two subtypes of Cl- channels on corpo-
ral myocytes. The first of these is a large conduc-
tance (i.e., 350 pS) [297], calcium-sensitive, chlo-
ride channel. The second detectable Cl- channel
subtype is a lower conductance (i.e., ≈ 150 pS),
stretch-sensitive chloride channel. The calcium-
sensitive Cl- channel has a very small open proba-
bility, making assessment of its potential physiolo-
gical significance a difficult task. However, as
recently discussed [300], the stretch-sensitive Cl-
channel may well provide an important servo-
mechanism for length maintenance of the corporal
smooth muscle cell in the face of differential
hydrostatic gradients, or additionally, during the
rapid corporal pressure changes that occur during
alterations in the flow of blood to and from the
penis during normal penile erection and detumes-
cence. For example, it is conceivable that increa-
sed stretch or deformation of the corporal smooth
163
muscle cell membrane would result in increased
activity of this Cl- channel. The ensuing depolari-
zation of the corporal smooth muscle cell, would
result in increased transmembrane Ca2+ flux due
to activation of L-type voltage-dependent calcium
channels, and concomitant elevations in corporal
smooth muscle tone/contractility to oppose the
imposed external force. Also, even if the stretch-
sensitive Cl- channels are present in low abundan-
ce in vivo, the presence of the intercellular path-
way provided by the gap junction network present
in the human corpora (see below), would still
ensure that effects of alterations in Cl- channel
function on some fraction of the corporal myo-
cytes would be transmitted to neighboring myo-
cytes. Thus, it is not unreasonable to assume that
activation of stretch-sensitive Cl- channels may
well contribute to global changes in corporal
smooth muscle cell tone.
e) The importance of intercellular communica -
tion through gap junctions.
Signal transduction in corporal smooth muscle is
more a network event than the simple activation of
a physiological cascade or pathway in individual
myocytes (Figure 7). Therein lies the true impor-
tance of the contribution of gap junctions to the
modulation of corporal smooth muscle tone, and
thus, erectile capacity. A logical extension of this
observation is that the presence of intercellular
communication through gap junctions provides
the corpora with a significant “safety factor” or
capacity for plasticity/adaptability of erectile res-
ponses. Thus, regardless of the precise mechanis-
tic components operant in the corporal myocytes,
intercellular communication through gap junctions
plays an important role in ensuring coordinated
smooth muscle responses among them.
Despite the identification of more than a dozen
mammalian connexins, connexin43 is the predo-
minant gap junction protein found in corporal
myocytes [301, 302, 303, 304, 305]. Thus, the fol-
lowing discussion pertains exclusively to
connexin43. Briefly, gap junctions represent
aggregates of intercellular channels where each
channel is formed by the union, across the extra-
cellular space, of two hemichannels or connexons,
one contributed by each cell of an adjacent pair
(Figure 8). Rafts of these individual channels (i.e.,
hundreds to thousands) aligned in adjacent cell
membranes form the structural basis for the gap

Figure 8 : Gap junctions represent aggregates of intercellu -
lar channels where each channel is formed by the union,
across the extracellular space, of two hemichannels or
connexons, one contributed by each cell of an adjacent pair.
IP3 = inositoltrisphosphate; cGMP = cyclic AMP; cAMP =
cyclic GMP
junctional plaques frequently, but not always,
observed between smooth muscle myocytes. The
functional correlate of these structures is that cor-
poral smooth muscle cells function as a network
(Figure 6).
Consistent with their proximal role in coordinating
responses among the diverse array of corporal
smooth muscle cells, recent publications have
shown that connexin43-derived gap junction chan-
nels have characteristically long open times (0.5-5
s) and high open probabilities (≈ 85%), coupled
with modest voltage sensitivity [302, 304]. In
addition, while subconducting states of the
connexin43 main state clearly do exist, the dwell
time(s) is too short to be of any physiological
significance, and therefore, the ≈100 pS main state
accounts for virtually all of the relevant unitary
activity of these channels [305]. Moreover, all of
the major modulators of corporal smooth muscle
tone are of the size (i.e., ≈1000 kD), or have alrea-
dy been shown to be gap junction permeant [295,
297, 306, 307]. As such, it is not surprising that
164
theoretical studies of junctional communication
have predicted that down regulation of intercellu-
lar communication is much more likely to be phy-
siologically relevant than up regulation of inter-
cellular communication [306]. In conclusion, the
presence of connexin43-derived gap junction
channels in corporal myocytes, ensures that there
are many distinct combinations of the individual
components of the “Syncytial Tissue Triad” which
are sufficient to ensure coordinated smooth muscle
function, and thus, the maintenance of erectile
capacity. The converse of this statement is that
erectile dysfunction would have to manifest at
multiple levels in order to overcome the extant
safety factor provided by the presence of the inter-
cellular pathway. In vivo support for these experi-
mental and theoretical suppositions derives from
the well documented clinical fact that organic
erectile dysfunction is indeed multifaceted. Fur-
ther evidence for these concepts is provided by
recents studies in a well documented rat model in
vivo, where the verity of these ideas has been
exquisitely tested and verified [308, 309]; see gene
therapy section for details).
V. SMOOTH MUSCLE FUNCTION
1. ELECTROMECHANICAL COUPLING
In electromechanical coupling, changes in the sar-
coplasmic Ca 2+ concentration, and thereby in the
contractile state of the smooth muscle cell, are
caused by changes in the membrane potential.
Action potentials or long-lasting changes in the
resting membrane depolarize the membrane
potential, thus opening voltage-gated L-type Ca 2+
channels [310]. Thus, Ca2+ enters the sarcoplasm
driven by the concentration gradient and triggers
contraction.
Changes in the membrane potential may also be
induced by membrane channels other than
Ca2+channels. Opening of K+channels (see
above) can produce hyperpolarization of the cell
membrane. This hyperpolarization inactivates the
L-type calcium channels, resulting in a decreased
Ca2+ influx and subsequent smooth muscle
relaxation.
2. PHARMACOMECHANICAL COUPLING resulting in Ca 2+ entry to the sarcoplasm down its
concentration gradient. A rather modest increase in
a) Contraction
the level of free sarcoplasmic Ca2+ by a factor 3-
Pharmacomechanical coupling describes the regu- 5 to 550-700 nM then triggers myosin phosphory-
lation of the sarcoplasmic Ca2+ concentration lation (see below) and subsequent smooth-muscle
without changing the membrane potential. The contraction.
major mechanisms of pharmacomechanical cou-
In the smooth muscle cell Ca 2+ binds to calmodu-
pling-induced smooth-muscle contractions are the
lin, which is in contrast to striated muscles, where
release of inositol 1,4,5-trisphosphate (IP3) and
Ca2+i binds to the thin-filament-associated protein
the regulation of Ca2+ sensitivity (see below). Fur-
troponin [314, 315]. The Ca-calmodulin complex
thermore, specific agonists may activate either L-
activates myosin light-chain kinase (MLCK) by
type calcium channels at a constant membrane
association with the catalytic subunit of the enzy-
potential or receptor-operated, nonspecific ion
me (Figure 9). The active MLCK catalyzes the
channels, resulting in an increase in intracellular
phosphorylation of the regulatory light-chain
levels of free Ca2+ and subsequent smooth-muscle
subunits of myosin (MCL 20). Phosphorylated
contraction. With regard to the physiologically
MCL20 activates myosin adenosine triphosphate
important phosphatidylinositol cascade, many
(ATPase), thus triggering cycling of the myosin
agonists (e.g., α1-AR agonists, ACh, angiotensin,
heads (cross-bridges) along the actin filaments,
vasopressin) bind to specific membrane-bound
resulting in contraction of the smooth muscle. A
receptors that are coupled to phosphoinositide-
decrease in the intracellular level of Ca2+ induces
specific phospholipase C via guanosine triphos-
a dissociation of the Ca-calmodulin MLCK com-
phate (GTP)-binding proteins. Phospholipase C
plex, resulting in dephosphorylation of the MLC20
then hydrolyzes phosphatidylinositol 4,5-biphos-
by myosin light-chain phosphatese and in relaxa-
phate (PIP2) to 1,2-diacylglycerol (DG; this acti-
tion of the smooth muscle [313, 314]. A specific
vates protein kinase C) and IP3. The water-soluble
long-lasting state of contraction with reduced
IP3 binds to its specific receptor [311, 312] on the
cycling frequency and low energy (ATP)
membrane of the sarcoplasmic reticulum (intracel-
consumption is termed a latch state. The mecha-
lular compartment for Ca2+ storage), thereby ope-
nism of this high-force and low-energy-consump-
ning this Ca2+ channel. Since the Ca2+ concen-
tion state is not known.
tration in the sarcoplasmic reticulum is about 1
mM, Ca2+ is thus driven into the sarcoplasm by
the concentration gradient, triggering smooth-
muscle contraction. This increase in sarcoplasmic
Ca2+ concentration may activate a distinct Ca2+
release channel of the sarcoplasmic reticulum (i.e.,
the ryanodine receptor-operated channel), leading
to a further increase in the Ca2+ concentration of
the sarcoplasm (muscle [313, 314].
b) Myosin phosphorylation and contraction
As in striated muscle, the amount of intracellular
free Ca2+ is the key to regulation of smooth-
muscle tone. In the resting state, the level of sar- Figure 9 : The Ca2+-calmodulin complex (Ca . CaM) acti -
vates myosin light-chain kinase (MLCK) by association
coplasmic free Ca2+ amounts to about ≈ 100 nM, with the catalytic subunit of the enzyme. Phosphorylated
whereas in the extracellular fluid the level of Ca2+ myosin (myosin – P) reacts with actin to form activated
is in the range of 1.5-2 mM. This 10,000-fold gra- actomyosin (actomyosin – P), which produces contraction.
dient is maintained by the cell-membrane Ca2+ Phosphorylated myosin (myosin – P) can be inactivated by
pump and the Na+/Ca2+ exchanger. Neuronal or myosin light-chain phosphatase (MLCP), which leads to
relaxation.
hormonal stimulation can open Ca2+ channels,

165
c) Regulation of Ca 2+ sensitivity and Ca2+-inde -
pendent contraction
In smooth muscle, the force/Ca2+ ratio is variable
and depends partly on specific activation mecha-
nisms. For example, α-AR agonists induce a
higher force/Ca2+ ratio than does a depolarization-
induced (i.e., KCl) increase in intracellular Ca2+,
suggesting a “Ca-sensitizing“ effect of agonists.
Furthermore, it has been shown that at a constant
sarcoplasmic Ca2+ level, decrease of force (”Ca-
desensitization”) can be observed.
The effect of Ca-sensitizing agonists are mediated
by guanosine triphosphate (GTP)-binding proteins
that generate protein kinase C or arachidonic acid
as second messengers [310, 314]. These inhibit the
myosin light-chain phosphatase (MLCP), thus
increasing MLC 20 phosphorylation by basal-level
activity of MLCK. The resulting myosin phospho-
rylation and subsequent smooth-muscle contrac-
tion therefore occurs without a change in sarco-
plasmic Ca2+ concentration.
Ca-desensitization occurs in vivo in the presence
of a sarcoplasmic Ca2+ concentration higher than
that required for the activation of the MLCK (its
affinity for the Ca-calmodulin complex is lower).
This high concentration of Ca2+ activates the Ca-
calmodulin-dependent protein kinase II, which
then reduces the affinity of MLCK for Ca-calmo-
dulin by phosphorylation of a specific site [316].
The resulting decrease in the activity of MLCK
leads to an increase in myosin dephosphorylation
by basal-level activity of MLCPand to subsequent
smooth-muscle relaxation.
Ca2+-independent contractions have been obser-
ved. Thus, phorbol-ester-induced contractions are
not accompanied by changes in the level of sarco-
plasmic free Ca2+ or in myosin phosphorylation
[317, 318]. Ca2+-independent contractions are
probably mediated via receptor-operated membra-
ne-bound GTP proteins that activate Ca2+-inde-
pendent protein kinase C (I-PKC). The subsequent
proteins responsible for further mediation of the
contractile response have not yet been elucidated.
3. RELAXATION
Pharmacomechanical coupling mechanisms of
smooth-muscle relaxation are mediated via the
intracellular cyclic nucleotide/ protein kinase/
166
second-messenger system. Via specific receptors,
β-AR agonists activate membrane-bound adenyla-
te cyclase, which generates cAMP. cAMP then
activates protein kinase A (PKA or cAK) and, to a
lesser extent, protein kinase G (PKG or cGK).
Atrial natriuretic factor (ANF) acts via the mem-
brane-bound guanylate cyclase, whereas NO sti-
mulates the soluble form of guanylate cyclase;
both generate cGMP, which activates PKG and, to
a lesser extent, PKA. Activated PKA and PKG
phosphorylate phospholamban, a protein that nor-
mally inhibits the Ca 2+ pump within the membra-
ne of the sarcoplasmic reticulum. The Ca2+ pump
is then activated and, consequently, the level of
free cytoplasmic Ca2+ is reduced, resulting in
smooth-muscle relaxation. Similarly, the protein
kinases activate the cell-membrane Ca2+ pump,
leading to a decreased sarcoplasmic Ca 2+ concen-
tration and to subsequent relaxation [313, 314].
As described above, cAMP and cGMP are synthe-
tized from the corresponding nucleoside triphos-
phates by their respective membrane-bound or
soluble adenylate or guanylate cyclases. cAMP
and cGMP are inactivated by phosphodiesterases
(PDEs) by hydrolytic cleavage of the 3’-ribose-
phosphate bond. Presently, more than 9 different
families of PDE are known, which differ in their
specificity for cAMP and cGMP, cofactor require-
ments and kinetic properties [319, 320, 321]. Each
family can again be divided into subfamilies.
Because of their central role in smooth-muscle
tone regulation and the considerable variation of
PDE isoenzymes with respect to species and tis-
sues PDEs have become an attractive target for
drug development. PDE 2, PDE 3, PDE 4, PDE 5
and several other isoenzymes have been identified
in human cavernous tissue [322, 323, 325, 326,
327]. Functionally, PDE 3 and PDE 5 seem to be
the most important [328, 329].
The identification of PDE families has been paral-
leled by the synthesis of selective or partially
selective inhibitors. Sildenafil is a highly selective
inhibitor of PDE type 5 [330, 331]. It enhances
NO-mediated relaxation of rabbit and human cor-
pus cavernosum in vitro, [326, 328, 329, 332, 333]
and increases dose-dependently the intracavernous
pressure in anesthetized dogs [334]. Sildenafil
increases the intracellular concentrations of cyclic
GMP[333, 335]. The effect of sildenafil may thus
be due to an amplification of the endogenous
NO-cyclic GMP pathway. This seems to involve a
novel cellular signal transduction pathway in
which force is dissociated from myosin light chain
phosphorylation [333].
VI. THERAPEUTIC ASPECTS :
GENE THERAPY & MOLECULAR
BIOLOGY: THE PROMISE OF
MOLECULAR SURGERY
1. WHAT IS MOLECULAR BIOLOGY?
The term “molecular biology” seems to have been
first used by Warren Weaver in his 1938 address to
the Rockefeller Foundation, where he stated:
“Among the studies to which the Foundation is
giving support is a relatively new field, which may
be called molecular biology...” [336]. Since that
seminal description, developments in many dis-
tinct scientific and clinical disciplines have been
tremendously impacted by the ever burgeoning
field of “molecular biology”. In the most broadly
conceived definition “molecular biology” includes
the study of the structure and function of biolo -
gically important macromolecules; ranging from
proteins to RNA and DNA. This rather broad
conceptualization explains why “molecular biolo-
gy” exists at the interface of crystallography, bio-
physics, biochemistry, biology and genetics. In
fact, many sophisticated techniques have been
developed as tools to assist in the more efficient
study of “molecular biology”. Some relevant
examples include the recent commercialization
and popularization of techniques, such as Nor-
thern, Western and Southern blots, and the poly-
merase chain reaction. The widespread availabili-
ty of this technology has moved “molecular biolo-
gy” to the forefront of scientific thought and deve-
lopment. Along the way many subdisciplines of
“molecular biology” have evolved. For the pur-
poses of this discussion the terms molecular bio -
logy, molecular genetics, and all related terms will
be used interchangeably.
Molecular biology, erectile physiology, and the
treatment of erectile dysfunction
The contribution of molecular technologies to the
improved understanding, treatment and diagnosis
of erectile dysfunction is expected to proceed
167
simultaneously in four major arenas as displayed
in the schematic Figure 5. The four arenas will be
referred to as the Molecular Biology Quadrangle,
and together they will serve as the foundation/cor-
nerstone for the genetic analysis and therapy of
erectile dysfunction. That is, the application of
molecular technologies to the field of erectile phy-
siology/dysfunction will permit the following:
1) Evaluation of the possibility that there may be
a genetic predisposition to erectile failure.
2) Evaluation of the possibility that there may be
genes or sets of genes/gene products whose
expression or function are themselves altered by
erectile dysfunction.
3) Evaluation of the possibility that there may be a
smooth muscle specific distribution of genes or
sets of genes/gene products that would allow one
to selectively modulate smooth muscle tone in the
penis, independent of other peripheral tissues.
4) Evaluation of the possibility that there may be
genes or sets of genes/gene products whose
expression or function can be stably and reprodu-
cibly altered so that erectile potency can be effec-
tively restored in the absence of the necessity for
any other form of treatment; i.e., somatic gene the-
rapy. Each of these four arenas will be considered
briefly below.
2. GENETIC PREDISPOSITION TO ERECTILE
FAILURE
Technologies exist for detecting mutations in, or
altered expression of, any gene(s)/gene product(s)
that might predispose one to erectile failure.
However, given the multifactorial, age-related
nature of erectile dysfunction, and the frequent
overlap between erectile dysfunction and, for
example, the presence of diabetes and/or vascular
disease (i.e., hypertension), it may take some time
to sort out a precise correlation between genetic
alterations and erectile dysfunction. Currently,
with the exception of Peyronie’s disease, which
seems to have a truly relevant gene-based compo-
nent (i.e., chromosomal instability), there is no
compelling evidence either for, or against, the pre-
sence of a significant genetic component to the
most common forms of organic erectile failure.
This will certainly be an area of much interest in
the future, and as with most other human diseases,
it would not be surprising to find a significant
genetic contribution to at least some aspects of
erectile dysfunction.
3. GENETIC/MOLECULAR ALTERATIONS AT-
TRIBUTABLE TO, OR wHICH ACCOMPANY,
ERECTILE FAILURE
The other side of the coin, with respect to the afo-
rementioned discussion, is whether or not the pre-
sence of organic disease and the ensuing erectile
dysfunction is correlated with detectable altera-
tions in the expression or function of a gene(s) or
gene product(s). That is, does advancing age, or
the presence of organic disease per se, result in
or produce any consistent alteration(s) in the
expression or function of a gene(s) or gene pro -
duct(s) that facilitates, or is associated with, erec -
tile failure ?. Not surprisingly [337], much of the
information collected to date has been obtained on
animal models of the human disease. These fin-
dings, and their similarities and differences with
respect to the human condition are the subject of
recent reviews, and will not be further discussed
here. As such, the data described below concerns
only findings on the molecular physiology and
pathophysiology of human corporal tissue.
4. DIFFERENTIALLY EXPRESSED TRANSCRIPT
IN CULTURED CORPORAL SMOOTH MUS-
CLE CELLS FROM DIABETIC PATIENTS
Because diabetic patients account for approxima-
tely half of all patients with erectile dysfunction,
one recent study utilized differential display tech-
nologies to examine the possibility of diabetes-
related alterations in molecular aspects of human
corporal smooth muscle cells. In this preliminary
study, a differentially expressed gene product was
detected in corporal tissue excised from diabetic
patients [338]. That is, differential display tech-
niques revealed that a transcript expressed in tis-
sue derived from a patient with impotence secon-
dary to a radical prostatectomy (i.e., nominally
neuronal in origin and free from organic disease)
was greatly reduced or absent in corporal tissue
from 3 diabetic patients. While no significant
homology was found between this transcript and
sequences deposited in GenBank, this was the first
evidence supporting the supposition that genetic
alterations may attend the manifestations of erec-
tile dysfunction in some patients.
168
5. AGE-RELATED DECLINE IN CONNEXIN43
(CX43) MRNA EXPRESSION IN HUMAN
CORPORAL TISSUE STRIPS
A series of recent publications has documented the
central role played by intercellular communication
through gap junctions in ensuring normal penile
erection [301, 302, 303, 304, 306]. Briefly, by vir-
tue of their presence in, and ubiquitous distribu-
tion among, corporal smooth muscle cells, these
aqueous intercellular channels help ensure the
coordinated relaxation and contraction responses
among corporal smooth muscle cells, that are an
absolute prerequisite to penile erection and detu-
mescence. Thus, molecular studies examined the
expression of the connexin43 transcript, to evalua-
te the hypothesis that altered intercellular commu-
nication may account for some aspects of the age-
related decline in erectile capacity [339]. A signi-
ficant, age-related (patient age ranged between 27-
89 years), a ≈ 3-fold decline in the expression of
the gap junction Cx43 transcript was detected in
frozen tissues excised from patients with organic
erectile dysfunction due to a diverse array of etio-
logies. It is important to emphasize that this relati-
vely modest decline occurred over virtually the
entire adult human life span. As such, this obser-
vation clearly indicates the relative plasticity of
intercellular communication through gap junc-
tions, although it certainly does rule out the possi-
bility that in any given patient, alterations in Cx43
mRNA levels may well contribute to the etiology
of erectile dysfunction.
6. MOLECULAR MECHANISMS OF CORPORAL
FIBROSIS
Immunostaining and densitometry techniques
have shown evidence for decreased smooth
muscle cell content in corporal tissue excised from
impotent men [340, 341], and thus, recent efforts
have been undertaken to understand the molecular
mechanisms that might account for such apparent
structural alterations [275, 342]. In trying to eva-
luate the putative mechanistic basis for corporal
fibrosis and ensuing erectile failure, recent inves-
tigations have centered around evaluating the rela-
tionship between collagen synthesis/deposition
and their relationship to transforming growth fac-
tor β1 (TGF-β1) mRNA and TGF-β1 membrane
receptor levels. The rationale is analogous to that
established as the etiologic basis for fibrosis in
other human disease states (e.g., hepatic cirrhosis
or pulmonary interstitial fibrosis), in which increa-
sed TGF-β1 levels have been documented to
contribute to increased extracellular matrix via
enhanced collagen deposition. In fact, molecular
studies conducted on cultured human corporal
smooth muscle cells have clearly established that
there may be an important reciprocal relationship
between the levels of, for example, prostaglandin
E1, NO and oxygen tension on the one and, and
TGF-β1-induced increases in collagen synthesis/
deposition on the other. Corresponding molecular
studies conducted on human corporal tissue biop-
sies, however, found no evidence for a physiologi-
cally relevant differential expression of either
TGF-β1 mRNA or TGF-β1 membrane receptor
levels in tissues excised from patients with a wide
range of organic etiologies, but which had signifi-
cant differences in the extent of corporal fibrosis.
Nonetheless, even when, as in this case the hypo-
thesized in vitro mechanism does not appear to
contribute to the in situ molecular/genetic altera-
tions, such studies still provide an important foun-
dation for identifying and evaluating the contribu-
tion of relevant molecular mechanisms to the etio-
logy of corporal fibrosis and the pathogenesis of
erectile dysfunction.
In summary then, while the number of molecular
studies in human corporal tissue are still relatively
few, this is clearly a promising area of research
with significant clinical potential. Many important
details concerning the physiological, pharmacolo-
gical and pathophysiological regulation of corpo-
ral smooth muscle tone have been gleaned in the
past few years, and it is only a matter of time befo-
re the rather robust techniques of molecular biolo-
gy begun to identify the most relevant molecular
alterations that contribute to the etiology of erecti-
le dysfunction. Certainly, a more precise identifi-
cation of the relevant molecular/genetic alterations
associated with erectile failure is a clear prerequi-
site to the improved diagnosis and treatment of
erectile dysfunction.
7. I DENTIFICATION OF SMOOTH MUSCLE SPE-
CIFIC GENES
The application of molecular technologies will
also be critical to the development of novel oral
and gene-based treatments for erectile dysfunc-
tion. For example, to really improve upon the suc-
169
cess of sildenafil, a much better characterization of
smooth muscle specific genes/gene products is
required. More specifically, consider the fact that
many of the documented side effects of sildenafil
(gastrointestinal distress, visual effects, facial flu-
shing, hypotension, etc.,) result from the fact that
the PDE 5 enzyme, the molecular target of silde-
nafil, is found not only in the smooth muscle cells
of the penis, but also smooth muscle cells in other
peripheral organs. Thus, the development of more
efficacious oral therapies with fewer systemic side
effects is dependent on the identification of even
more specific/selective molecular targets. The
later, in turn, awaits more precise details concer-
ning the distribution, relative stoichiometry, and
moreover, function, of genes or sets of genes/gene
products that are critical to the regulation of smoo-
th muscle cell tone/phenotype in physiologically
diverse smooth muscle tissues. The technologies
for making such comparisons already exist, and
must now be applied to this important medical
problem.
8. SOMATIC GENE THERAPY FOR THE TREAT-
MENT OF ERECTILE DYSFUNCTION
What specifically is gene therapy? The idea of
genetic therapy for human disease derives largely
from the application of molecular techniques to
clinical medicine [343, 344, 345, 346, 347]. Histo-
rically, and not surprisingly, genetic therapies
have been utilized to correct diseases/disorders
that have an underlying genetic component. In this
scenario, the introduction of foreign genetic infor-
mation into human cells either restores or supple-
ments defective functions, or conversely, functio-
nally antagonizes the effects of expression of a
mutant genetic phenotype. Thus, the term gene
therapy has been coined to describe the genetic
modification of a population of cells, and is the
term that will be used throughout this report.
Somatic gene therapy, in particular, refers to the
genetic modification of differentiated cells, as
opposed to modifying more pluripotent (less diffe-
rentiated) germ line cells. In fact, it is now pos-
sible for one to selectively express foreign genes
in specific target cells, and thus alter, in a measu-
rable fashion, a desired cellular response. A detai-
led description of all the methodologies involved
in gene therapy is well beyond the scope of this
report, suffice it to say that the identification, iso-
lation, sequencing, synthesis, cloning and expres-
sion of exogenous genes can now be accomplished
in relatively short order, and with great accuracy
and fidelity. The goal of this section of the report is
to highlight how these strategies will impact the
treatment of erectile dysfunction, and furthermore,
to outline several recent applications of such tech-
nologies to the genetic therapy of erectile dysfunc-
tion. Before so doing, a brief review of the evolu-
tion of gene therapy for the treatment of systemic
cardiovascular disease provides a nice encapsula-
tion of the strategies, limitations and overall goals
of any form of somatic gene therapy. A brief des-
cription is thus given below.
9. THE EVOLUTION OF CARDIOVASCULAR
GENE THERAPY
Exploration of the potential utility of gene therapy
to the treatment of cardiovascular disease dates
back to the beginning of this decade [348]. The
original intent was to utilize somatic gene therapy
to ameliorate the symptoms of cardiovascular
disorders such as atherosclerosis, vasculitis and
restenosis after balloon angioplasty [348, 349,
350, 351]. Since these seminal investigations, the
techniques for gene transfer into muscle cells have
continued to be developed and improved upon,
with the dual purpose of providing insights into
myocyte gene regulation (see above), as well as
providing novel therapeutic strategies for the treat-
ment of cardiovascular diseases. In fact, experi-
mental studies have elucidated some global boun-
dary conditions that govern the efficiency and
persistence of gene transfer into muscle cells, and
moreover, have indicated that muscle may be
unique in its ability to incorporate and express
naked DNA [344]. The efficiency of transfection
can vary widely depending on the muscle cell type
and the particular vector used, but has been repor-
ted to range from values as low as 0.01% in car-
diac myocytes following a single injection of
naked DNA [352, 353] to as high as 80% in vas-
cular wall cells using more aggressive strategies
such as adenovirus mediated gene transfer tech-
niques [354]. Following cellular incorporation of
the vector/DNA, the DNA is thought to remain
extrachromosomal (i.e., episomal), with persisten-
ce of exogenous DNAin vascular wall cells repor-
ted for up to 5 months post transfection [348].
Such results are quite exciting and encouraging,
170
given the relatively short time frame over which
these techniques have been utilized.
Notwithstanding the overall promise of gene the-
rapy, at least three significant obstacles to clinical
success still remain, and they are:
1) The specificity of gene transfer/incorporation
into one tissue or cell type, as opposed to others.
2) The efficiency and stability of gene incorpora-
tion after cellular uptake/invasion. That is, what
percentage of cells needs to be transfected, and for
how long?
3) Finding appropriate vectors so that the first two
conditions can be met without producing other
undesirable side effects, such as insertional muta-
genesis (i.e., as might be expected with retrovi-
ruses (e.g., Rous Sarcoma Virus (RSV)), or immu-
nogenic reactions, that is, as might be expected
from utilizing non-integrating, even non- replica-
ting viral vectors such as the adenovirus [343, 344,
345, 351, 355].
10. RATIONALE FOR GENE THERAPY AS A
TREATMENT OF ERECTILE DYSFUNCTION
In this regard, the anticipated successful utilization
of genetic therapy for the treatment of erectile dys-
function is based on the results of recent clinical,
experimental and theoretical studies, all of which
indicate that the coordination/homeostasis of corpo-
ral tissue responses exists at the intersection of:
1. the activity of peripheral neural pathways,
2. the subsequent activation of bifurcating intracel-
lular signal transduction pathways, and
3. the spread of such locally restricted neural signals
throughout the corpora via intercellular commu-
nication through gap junctions and/or regenerati-
ve electrical events (i.e., action potentials) [284,
286, 306, 307, 309]. This triumvirate of requisite
mechanisms for the coordination of tissue res-
ponses has been referred to as the “syncytial tis-
sue triad”, and serves as the foundation for inte-
grative tissue physiology in many other periphe-
ral organ systems composed primarily of smooth
muscle cells. This in mind, the salient evidence
supporting the supposition that genetic modifica-
tion of only a small fraction of the corporal
smooth muscle cells will be sufficient for the res-
toration of normal tissue function is summarized
below, and the overall strategy behind the thera-
py is conceptualized in Figures 10 - 12.
 Figure 10: Nonviral vector technology using
“naked DNA”. As illustrated in the lower panel,
a plasmid, in this case the commercially avai -
lable pcDNA plasmid (Invitrogen) is a circular
double stranded eukaryotic DNA that can be
used to obtain high-level, stable and nonreplica -
tive expression of the gene of interest in many
mammalian cell types. Specifically, using appro -
priate restriction enzymes, one can “cut” the
pcDNA vector between regions 1 & 2 (note that
the cross-hatched, darkened red area is actually
a blow-up of an underlying region which
contains the region encoding the T7-Sp6 promo -
ter, which flank the inserted sequence of interest.
Thus, this region is not on the same scale as the
rest of the molecule). As such, regions 1 & 2
demarcate the initiation and termination regions
for replication of the inserted DNAsequence. As
shown in this example, a linear double stranded
DNA sequence that encodes the pore forming
region of the human maxi-K channel (hSlo) is
routinely inserted. The top panel emphasizes that
the gene of interest in this study, the hSlo cDNA,
is nearly the same size as the vector itself.

Figure 11: Schematic depiction of the proposed use and putative corresponding sequence of events involved in gene therapy for
erectile dysfunction. As illustrated, a tourniquet could be placed at the base of the penis to restrict the outflow of blood from the
cavernous spaces. Aneedle injection of the “naked” DNAinto the penis would then result in diffusion of the DNAin the penis,
and uptake into the corporal smooth muscle cells by an as yet undetermined mechanism. The use of “naked” DNAas illustrated
in Figure 10, results in a nonintegrating or episomal DNA. The DNA then finds its way to the nucleus where it is able to take
advantage of the existing nuclear machinery to synthesize mRNA encoding the maxi-K channel protein. The mRNA exits the
nucleus, and protein is synthesized in the cytosol resulting in the incorporation of a functional maxi-K channel in the cell mem -
brane Clearly, as outlined in the text, other genes, that encode different proteins, can also be used.

171
Figure 12: The putative mechanistic basis for the observed in vivo efficacy of gene therapy with the maxi-K channel. As illustra -
ted, K+ channels and gap junctions are ubiquitously distributed throughout the corpora. The result is that the corporal smooth
muscle network behaves as an electrical syncytium. The main physiological implication is that not all of the cells need to be direct -
ly activated by an endogenous neural or humoral signal. In this scenario, intracellular second messenger signals (i.e., ions and
other small molecules such as Ca2+, K+, cAMP, cGMP) can quickly spread and equilibrate throughout the smooth muscle cell
network, without the necessity for direct activation of each smooth muscle cell. In fact, during erection, that is, syncytial relaxa -
tion of the corporal smooth muscle cells, it is believed that waves of hyperpolarization spread throughout the corpora. It is with
respect to this latter phenomenon that gene therapy with the maxi-K channel is thought to work. As illustrated in the upper panel,
K+ currents are equilibrated throughout the corporal smooth muscle network at some basal level, which, as illustrated in the bot -
tom panel, can be augmented by the over expression of the maxi-K channel on some fraction of the total cellular network (in this
example, the cells labeled A, B & C). In the example illustrated here, augmented K channel activity, due to over expression of the
maxi-K channel, essentially “drives” the rest of the tissue. Certainly, as reviewed in the text, other genetic strategies can also take
advantage the syncytial nature of the corporal smooth muscle cell network.

172
11. BRIEF REVIEW OF CURRENT GENE THE-
RAPY APPROACHES
Below 5 distinct reports of possible gene-based
strategies for the treatment of erectile dysfunction
are briefly described. Note that all of these reports
represent preclinical studies.
a) Gene therapy utilizing ex vivo-transformed
endothelial cells injected intracorporally.
Endothelial cells are an important source of vaso-
modulators (e.g., NO, prostacyclins and prosta-
glandins, etc.), thereby influencing the tone, and
perhaps the phenotype, of the underlying corporal
smooth muscle cells. As such, altered endothelial
cell function is thought to contribute to the etiolo-
gy of erectile dysfunction in some patients. In this
regard, two recent abstracts [356, 357] evaluated
the possibility of utilizing genetically modified
endothelial cells for the treatment of erectile dys-
function. That is, this proposed utilization of gene
therapy would involve genetic modification of the
endothelial cells ex vivo, and then the endothelial
cells would be injected into the penis.
In these preliminary studies, the investigators har-
vested microvascular endothelial cells from the rat
epididymal fat pad, fluorescently labeled them, and
subsequently injected the endothelial cells back into
the rat corpus cavernosum. Viable, fluorescently
labeled endothelial cells were identified within the
corporal sinusoids, adjacent to corporal smooth
muscle bundles at 48 hours post-injection. Labeled
endothelial cells were present for up to two weeks
after transplantation. Such observations indicate
that it is conceivable that one could harvest micro-
vascular endothelial cells, genetically manipulate
them, and place them back in the penis with the
expectation that they would remain viable. While
much more work clearly needs to be done, these
seminal studies provide “proof of principle” that
isogeneic (self) transplantation of genetically modi-
fied endothelial cells might assist with the restora-
tion of the normal balance between the effects of
local relaxing and constricting factors on the degree
of tone in the underlying smooth muscle cells.
b) Gene therapy with intracorporal injection of
inducible nitric oxide synthase (iNOS)/adeno -
viral constructs or intracorporal injection of
myoblasts transformed with iNOS/adenoviral
constructs.
173
There are three major isoforms of the nitric oxide
synthase (NOS) enzyme [358]. Two of these are
constitutive (the neuronal (nNOS or NOS 1) and
endothelial (eNOS or NOS 3) isoforms), and one
of these is inducible (iNOS or NOS 2). Two
recently published abstracts [359, 360] examined
the ability of gene therapy with iNOS to enhance
erectile capacity in a rat model. The utilization of
iNOS is based on the rationale that, in contrast to
the constitutive NOS isoforms, iNOS could provi-
de “on demand” increases in NO levels. Thus,
nerve-stimulated intracavernous pressure response
(ICP) responses were evaluated in the rat in vivo as
well as in vitro. In one series of in vitro studies
[360] it was shown that cultured myoblasts trans-
fected with iNOS elaborated NO into culture
medium. In another series of in vivo studies [359],
iNOS was expressed in adenovirus, and then either
the iNOS/adenoviral vector itself, or transformed
myoblasts containing the adenoviral/iNOS
construct were directly injected into the rat penis.
iNOS gene expression in the rat penis was found
to be time-dependent, being maximal at day 4,
with lower levels at days 2 and 7. The maximal
nerve-stimulated ICPresponse was elevated 2-fold
as expected. However, of major significance was
the observations that the basal, or resting, ICP was
also 10-fold greater in those animals containing
the iNOS transgene. The former is encouraging,
but the latter would be an extremely undesirable
side effect. Nonetheless, these initial studies docu-
ment that physiologically relevant amounts of
iNOS can be delivered either directly packaged
with adenovirus (and presumably subsequently
incorporated in corporal smooth muscle cells), or
indirectly via a shuttle vector/cell type (i.e., the
myoblast cells), and then injected into the penis.
c) Gene therapy with rat penile iNOS (i.e., RPi -
NOS).
Garban et al [361], also in the rat model, described
in great detail another elegant strategy, which is
also designed to take advantage of the prominent
role played by NO in erectile function. These stu-
dies utilized the rat penile iNOS gene that the
authors cloned themselves. The goal was to deter-
mine if gene therapy could restore the age-related
decline in the intracavernous pressure response
(ICP) observed in 20 month old rats, when com-
pared to 5 month old rats. To this end, 10 µg of the
rat penile iNOS cDNA (i.e., RPiNOS / pcDNA;
i.e., “naked” DNA) was injected intracorporally in
a 100 µl volume. Transcript and protein for RPi-
NOS were both detected following the intracaver-
nous injection of RPiNOS/pcDNA, and moreover,
a significant enhancement in the cavernous nerve
stimulated intracavernous pressure response (ICP)
was noted for up to 10 days post injection of the
RPiNOS/pcDNA construct. By 21 days, however,
the effects were no longer significant. Clearly
these studies provide further evidence for potential
utility of a gene therapy strategy for the treatment
of human erectile dysfunction.
d) Gene therapy with the hSlo/pcDNA encoding
the human calcium-sensitive potassium (K)
channel subtype.
Christ et al [309] applied the principles of integra-
tive tissue physiology [284, 285, 286] to test the
hypothesis that low efficiency gene transfer is an
attractive therapeutic option for correcting dimini-
shed erectile capacity. The specific rationale for
the approach was as follows. Heightened contrac-
tility and/or impaired relaxation of the corporal
smooth muscle is a primary cause of erectile dys-
function in many impotent men [4, 303, 362]. The-
refore, any therapy that increases either the “dri-
ving” force for relaxation (i.e., the gene therapy
techniques designed to enhance NO signals, as
described above), or the “sensitivity” of the smoo-
th muscle cells to vasorelaxants, would be expec-
ted to improve erectile capacity. Recent publica-
tions have documented that potassium (K) chan-
nels are important modulators of human corporal
smooth muscle tone and erectile capacity, by vir-
tue of their ability to modulate corporal smooth
muscle membrane potential, transmembrane cal-
cium flux, and therefore, the free intracellular cal-
cium concentration [288, 290, 296, 297, 303].
Thus, the initial gene therapy approach was desi-
gned around one of the most prominent K currents
present in human corporal smooth muscle cells,
that is, the calcium-sensitive, maxi-K channel
[288, 290]. Consistent with the important role of K
channels as mediators/modulators of the effects of
a vast array of physiologically relevant vasomodu-
lators, it was documented that a single bolus intra-
cavernous injection of naked hSlo cDNA (which
encodes the pore forming subunit of the large
conductance calcium-sensitive maxi-K channel,
KCa) [363] was sufficient to prevent the age-rela-
ted decline in erectile capacity normally observed
174
in older animals [309]. That is, hSlo cDNA/ pc
DNA transfection was sustained for at least 2
months, but perhaps as long as 4 months in vivo,
and was associated with measurable and physiolo-
gically relevant alterations in the mean amplitude
of the cavernous nerve-stimulated intracavernous
pressure response (ICP); an objective index of
erectile capacity. However, since more than 50%
of impotent men are diabetic, a second series of
studies was more recently conducted to determine
if KCa gene therapy would also be sufficient to
prevent the decline in erectile capacity that is
known to be associated with streptozotocin (STZ)-
induced experimental diabetes in rats [364]. Thus,
47 rats were made diabetic by a single subcuta-
neous injection of STZ (35 mg/kg). Two months
after the diabetic state was established (when
significant neuropathy is known to occur) [365],
all animals received a single intracorporal injec-
tion of naked pcDNA/hSlo cDNA (again, 100 ∝g
in 200 ∝l final volume).
The ICP response to cavernous nerve stimulation
was studied 1-2 months later, and the results for
several levels of current stimulation clearly indi-
cated that the presence of the hSlo transcript was
sufficient to restore the nerve-stimulated ICP res-
ponse to levels that were statistically significantly
greater than STZ-diabetic animals that did not
receive an hSlo injection, but indistinguishable
from age-matched control animals. Taken together
with previously published work, these studies
clearly document that KCa gene therapy can resto-
re both the age-related [309] and the STZ-induced
[364] decline in erectile capacity observed in rats
in vivo, and the putative mechanistic basis for this
effect is depicted in the schematic diagram shown
in Figure 12. Such observations provide further
support for the possibility that a similar genetic
strategy will be useful in treating men with erecti-
le dysfunction due to diverse organic causes.
e) Gene therapy with vascular endothelial grow -
th factor (VEGF).
Another recent study [366] seeks to take advanta-
ge of the fact that erectile dysfunction is often
associated with alterations in the flow of blood to
or from the penis, and moreover, that problems
with vascular perfusion to the erectile tissue of the
penis may be a proximal cause. Several endoge-
nous growth factors are known to regulate/induce
angiogensis/vasculogenesis, that is, the formation
and growth of new blood vessels. Vascular endo -
thelial derived growth factor (VEGF) is among the
most potent of the known angiogenic/vasculoge-
nic factors, and thus, was chosen as the initial
molecular target for these studies. Since VEGF
therapies in laboratory animals and/or humans
with peripheral vascular disease have been shown
to produce measurable increases in tissue vascula-
rity, the investigators sought to identify the VEGF
transcript(s) present in the adult rat and human
penis, as a prelude to the identification of the best
therapeutic agent. Thus, penile tissue was obtained
from adult rats, as well as human patients under-
going penile prosthesis implantation.
Analysis of the VEGF transcript isoforms was per-
formed using reverse-transcriptase polymerase
chain reaction (i.e., RT-PCR). In short, four pre-
viously described VEGF isoforms were detected
in both rat and human corporal tissue. Again, the
identification of the relevant and predominant
human VEGF isoforms is the first step toward
genetic manipulation of VEGF in the penis as a
therapy for erectile dysfunction related to compro-
mised vascular perfusion. The proposed advantage
of such a therapy, is related to the fact that all cur-
rently available forms of therapy for erectile dys-
function treat the symptoms of erectile failure and
not the cause. That is, current therapeutic options
are available “on demand”, and thus, represent lar-
gely palliative, and not curative, therapies. If vali-
dated in an appropriate animal model, and moreo-
ver, in clinical trials, this would indeed represent a
significant advance in the treatment of human
erectile dysfunction in that subset of patients in
whom vascular disease is a proximal etiologic fac-
tor in their disease.
f) Summary and conclusions concerning gene
therapy for the treatment of erectile dysfunction.
In short, the field of gene therapy for erectile dys-
function is still in its infancy. Clearly, divergent
genetic strategies are plausible.
To summarize, there are several reasons for sus-
pecting that utilization of a relevant molecular tar-
get(s) will lead to a genetic therapy of erectile dys-
function that will be inherently more successful
than gene based strategies for the treatment of
diseases such as cancer, systemic cardiovascular
175
disease and cystic fibrosis. First, preclinical stu-
dies have illustrated that the intracavernous
injection and cellular incorporation of naked
DNA [309, 359, 361, 364], leads to the subse-
quent expression of transcript, and finally, of
functional protein in vivo. Since physiologically
relevant alterations in erectile capacity have been
documented following such genetic strategies,
these exciting data would nominally obviate the
necessity for utilizing an adenoviral or retroviral
vector for the treatment of erectile dysfunction.
In turn then, the use of “naked” DNA would
have the additional benefit of minimizing the two
most prominent side effects of gene therapy, that
is, insertional mutagenesis and immune res-
ponses [367].
The fact that a tourniquet can be placed around the
base of the penis for several minutes, under the
low blood flow conditions of flaccidity, will ensu-
re the maximum possible restriction of the intra-
corporally injected naked DNA within the penis;
minimizing the presence of naked DNAin the sys-
temic circulation and other peripheral tissues.
Furthermore, the presence of intercellular commu-
nication through gap junctions ensures that only a
fraction of the total corporal smooth muscle cell
population needs to be genetically modified in
order to affect rather global changes in erectile
function; as such, the efficiency of cellular trans-
fection is not likely to be an important limitation.
Lastly, preliminary preclinical observations in the
rat model in vivo have indicated that the expres-
sion of the gene of interest can last for up to four
months [309].
That is, three intracavernous injections of the hSlo
cDNA per year may be sufficient to restore erecti-
le potency in men, in the absence of a need for any
other form of therapy. Such a therapeutic strategy
stands in stark contrast to the currently tolerated 3-
4 intracavernous injections per week that some
men are willing to endure. Unequivocally then, if
the specificity, physiology and duration of the
effect of gene transfection are similarly robust in
man, gene therapy would represent a major advan-
ce in the treatment of erectile dysfunction. Based
on the encouraging preclinical data reviewed
herein, the future of gene therapy for the treatment
of human erectile dysfunction seems bright
indeed.

VII. THERAPEUTIC ASPECTS :
PHARMACOLOGICAL BASIS
FOR CURRENT AND FUTURE
THERAPIES
1. DRUGS FOR INTRACAVERNOUS ADMINIS-
TRATION
Among the many drugs and/or drug combinations
tested [368, 369, 370, 371], only three, used alone
or in combination, have become widely clinically
accepted and administered on a long-term basis,
namely papaverine, phentolamine, and prostaglan-
din PGE1 (alprostadil). The experimental and cli-
nical experiences with several other agents, used
for treatment and discussed below, are limited.
a) Papaverine
Papaverine is often classified as a phosphodieste-
rase inhibitor, but the drug has a very complex
mode of action and may be regarded as a «multi-
level acting drug» [373]. Which of its several pos-
sible mechanisms of action is the one that predo-
minates at the high concentrations that can be
expected when the drug is injected intracaver-
nously is difficult to establish. In vitro, it has been
shown that papaverine relaxes the penile arteries,
the cavernous sinusoids, and the penile veins
[374]. In dogs, Juenemann et al. [375] demonstra-
ted that papaverine had a dual hemodynamic
effect, decreasing the resistance to arterial inflow
and increasing the resistance to venous outflow.
The latter effect, which has been demonstrated
also in man [376], may be related to activation by
papaverine of the veno-occlusive mechanism.
Since a main mechanisms of action of papaverine
is non-selective PDE inhibition, and the main PDE
activities in the human CC appears to be PDE3
and PDE 5, PDE inhibitors with actions on these
isoenzymes, but which lack the ”non-specific”
side effects of papaverine would be an interesting
alternative.
b) -Adrenoceptor antagonists
1. PHENTOLAMINE
Beside being a competitive α-AR antagonist with
similar affinity for α1- and α2-ARs, which is its
main mechanism of action, phentolamine can also
176
block receptors for 5-hydroxytryptamine (5-HT,
serotonin) and cause release of histamine from
mast cells. Phentolamine also seems to have ano-
ther action, possibly involving NOS activation
[377]. Since phentolamine non-selectively blocks
α-ARs, it can be expected that by blocking pre-
junctional α2-ARs, it would increase the NA
release from adrenergic nerves, thus counteracting
its own post-junctional α1-AR blocking actions.
Whether or not such an action contributes to the
limited efficacy of intracavernosally administered
phentolamine to produce erection, is not known.
In dogs, phentolamine like papaverine decreased
the resistance to arterial inflow to the penis.
However, papaverine, but not phentolamine,
increased the resistance to venous outflow [375].
Lack of effect on venous outflow by intracaver-
nous phentolamine has also been demonstrated in
man [378].
There is a general lack of information about the
pharmacokinetics of phentolamine. The drug has a
reduced efficacy when given orally, probably due
to extensive first-pass metabolism. A discrepancy
between the plasma half-life (30 min) and effect
duration (2.5-4 h) has been demonstrated [379];
whether this can be attributed to active metabolites
is not known. When the drug is given intracaver-
nosally, the serum concentration of phentolamine
will reach a maximum within 20-30 minutes, and
then rapidly decline to undetectable levels [380].
The most common side effects of phentolamine
after intravenous administration are orthostatic
hypotension and tachycardia. Cardiac arrhytmias
and myocardial infarction have been reported, but
these are very rare events. Theoretically, such
effects may be encountered also after intracorporal
administration, but so far this does not seem to be
the case. Since a single intracavernous phentola-
mine injection does not result in a satisfactory
erectile response in most cases, the drug is widely
used in combination with papaverine [368, 381],
or with VIP [382].
2. THYMOXAMINE
Thymoxamine (moxisylyte) has a competitive and
relatively selective blocking action on α1-ARs. In
addition, it may have antihistaminic actions. Little
is known about its pharmacokinetics, but after sys-
temic administration, it has an effect duration of 3-
4 h. Moxisylyte is a prodrug, rapidly transformed
into an active metabolite in plasma (deacetylmoxi-
sylyte or DAM). Elimination of the active meta-
bolite occurs by N-demethylation, sulpho- and
glucuroconjugation. The N-demethylated metabo-
lite is sulphoconjugated only. Urine is the main
route of excretion [383]. In vitro, moxisylyte
relaxed NA-contracted human corpus cavernosum
preparations [384], but was less potent than prazo-
sin and phentolamine.
Moxisylyte was shown to produce erection when
injected intracavernosally [385], and in a double-
blind crossover study Buvat et al. [386] showed it
to be more active than saline, but less active than
papaverine. Buvat et al. [386] reported on the
experiences of intracavernous injections of moxi-
sylyte in 170 patients with impotence, and pointed
out that the drug did not produce, but facilitated,
erection by inducing prolonged tumescence. They
also stressed that the main advantage of the drug
was its safety. Only 2 out of the 170 patients injec-
ted had prolonged erections. Buvat et al. [387],
comparing papaverine and moxisylyte, also found
that moxisylyte had less tendency to produce cor-
poral fibrosis than papaverine (1.3% vs 32%). The
positive safety aspects were underlined by Arvis et
al. [388], who reported no serious side effects
among 104 men followed for 11 months and per-
forming 7507 self-adminstrations.
In a comparative study between moxisylyte and
PGE1, Buvat et al. [389] showed that PGE1 was
significantly more effective than moxisylyte (71%
vs 50% responders), especially in patients with
arteriogenic dysfunction (96% vs 46%). However,
moxisylyte was significantly better tolerated than
PGE1, causing fewer prolonged erections and
fewer painful reactions.
As a facilitating drug, moxisylyte may be a reaso-
nable alternative for treatment of erectile dysfunc-
tion.
An interesting development is nitrosylated moxi-
sylyte, which may act as as combined NO-donor
and α1-AR antagonist [390]. Clinical studies
experiences are so far lacking.
c) Prostaglandin E 1 (alprostadil)
PGE1, injected intracavernously or administered
intraurethrally, is currently one of the most widely
used drugs for treatment of erectile dysfunction
[371, 372, 391, 392], and several aspects of its
177
effects and clinical use have recently been revie-
wed [371, 372]. PGE1 is metabolized in penile tis-
sue to PHE0 [393], which is biologically active,
and may contribute to the effect of PGE1 [394].
PGE1 may act partly by inhibiting the release of
NA [395], but the main action of PGE1 and PGE0
is probably to increase the intracellular concentra-
tions of cAMP in the corpus cavernosum smooth
muscle cells through EPreceptor stimulation [394,
396, 397, 398].
PGE1 is known to have a variety of pharmacolo-
gical effects. For instance, it produces systemic
vasodilatation, prevents platelet aggregation, and
stimulates intestinal activity. Administered syste-
mically, the drug has been used clinically to a limi-
ted extent. Little is known about its pharmacoki-
netics, but it has a short duration of action and is
extensively metabolized. As much as 70% may be
metabolized in one pass through the lungs [399],
which may partly explain why it seldom causes
circulatory side effects when injected intracaver-
nosally
Palmer et al [396] found that forskolin, which
directly stimulates adenylate cyclase, was a potent
stimulant of intracellular cAMP formation in cul-
tured human corporal smooth muscle cells. Thre-
shold forskolin doses were found to significantly
increase the production of cAMP by PGE1, which
suggested a possible synergistic effect. Traish et al
[394]confirmed this synergistic effects of forsko-
lin and PGE1 in cultured human corpus caverno-
sum cells. They also demonstrated that the aug-
mentation of the forskolin-induced cAMP genera-
tion by PGE1 and PGE0 was mediated by EP
receptors and attributable to interactions at the
adenylyl cyclase and G-protein levels.
Both forskolin and PGE1 elicited concentration-
dependent increases in the magnitude and duration
of intracorporal pressure in dogs without systemic
effects [398] and Mulhall et al [400] reported that
intracorporal administration of forskolin to
patients with erectile dysfunction and not respon-
ding to triple-drug therapy, responded when fors-
kolin was added. These results suggest that it is
possible to enhance the relaxant corporal effects of
PGE1, and may be other vasodilators, by forskolin
and analogues [401], and it cannot be excluded
that this may provide new strategies for pharma-
cologic treatment of erectile dysfunction.
d) Other drugs
1. VASOACTIVE INTESTINAL POLYPEPTIDE (VIP)
A role for VIP as neurotransmitter and/or neuro-
modulator in the penis has been postulated by
several investigators, but its importance for penile
erection has not been established [4, 402]. Howe-
ver, the inability of VIP to produce erection when
injected intracavernosally in potent [403] or impo-
tent men [404, 405, 406], indicates that it cannot
be the main NANC mediator for relaxation of
penile erectile tissues.
VIP has been shown to produce a wide range of
effects. It is a potent vasodilator, inhibits contrac-
tile activity in many types of smooth muscle, sti-
mulates cardiac contractility, and many exocrine
secretions. It stimulates adenylate cyclase and the
formation of cyclic AMP.
Wagner and Gerstenberg [403] found that even in
high doses (60 ug), VIPwas unable to induce erec-
tion on intracavernous injection in potent men. On
the other hand, when used in conjunction with
visual or vibratory stimulation, intracavernous
VIP facilitated normal erection. Kiely et al. [405]
injected VIP, papaverine, and combinations of
these drugs with phentolamine intracorporally in
twelve men with impotence of varying etiology.
They confirmed that VIP alone is poor at inducing
human penile erections. However, in combination
with papaverine, VIP produced penile rigidity
similar to that obtained with papaverine and phen-
tolamine. Gerstenberg et al. [407] administered
VIP together with phentolamine intracavernously
to 52 patients with erectile failure. Forty percent of
the patients had previously received treatment
with papaverine, alone or with papaverine together
with phentolamine. After sexual stimulation, all
patients obtained erection sufficient for penetra-
tion. Those patients previously treated with papa-
verine or papaverine/phentolamine stated that the
action of the VIP combination was more like the
normal coital cycle. No patient developed pria-
pism, corporal fibrosis, or any other serious com-
plication [407]. McMahon [408] performed a
pilot study in 20 men with erectile dysfunction of
various etiology using a VIP/phentolamine combi-
nation. Sixteen of the patients responded favora-
bly, and side effects were few.
VIPgiven intravenously can produce hypotension,
178
tachycardia and flushing [409, 410]. However, the
plasma half-life of the peptide is short, which may
contribute to the fact that systemic side effects are
rare when it is administered intracavernosally.
It seems that VIP administered intracavernously
together with phentolamine may be an alternative
to the more established treatments with papaveri-
ne/phentolamine or PGE 1, but more experience is
needed to give a fair evaluation of the advantages
and disadvantages of this combination.
2. CALCITONIN GENE-RELATED PEPTIDE (CGRP)
Stief et al. [411] demonstrated CGRP in nerves of
the human corpus cavernosum, and suggested its
use in erectile dysfunction. In human blood ves-
sels from various regions, CGRP is known to be a
potent vasodilator. Its effect may be dependent or
independent of the vascular endothelium [412,
413]. The peptide relaxed the bovine penile artery
by a direct action on the smooth muscle cells
[414], which suggests that it may have important
effects on the penile vasculature.
In patients, intracavernosal injection of CGRP
induced dose-related increases in penile arterial
inflow, cavernous smooth muscle relaxation,
cavernous outflow occlusion, and in erectile res-
ponses. The combination of CGRP and PGE1 may
be more effective than PGE 1 alone [415, 416].
It cannot be excluded that CGRP, alone as a facili-
tating drug, or in combination with with other
drugs as an initiator of erection, can be useful for
therapeutic purposes, but to assess its potential,
more experience is needed.
3. LINSIDOMINE CHLORHYDRATE (SIN-1)
It is reasonable to assume that drugs acting via NO
may be useful for treatment of erectile dysfunc-
tion. Linsidomine, the active metabolite of the
antianginal drug molsidomine, is believed to act
by non-enzymatic liberation of NO [417, 418],
which by stimulating soluble guanylate cyclase
increases the content of cyclic GMP in the smooth
muscle cells and produces relaxation. Linsidomine
also inhibits platelet aggregation [419], and in
some countries it is registered for treatment of
coronary vasospasm and coronary angiography.
The drug was reported to have a plasma half-life
of approximately 1-2 h [418, 420].
Linsidomine was found to effectively relax prepa-
rations of rabbit and human corpus cavernosum
contracted by NA or endothelin-1 in a concentra-
tion-dependent way [212, 213]. In preliminary stu-
dies, Stief et al. [421, 422], and Truss et al. [423]
studied the effect of linsidomine injected intracor -
porally in impotent patients and found that the
drug induced an erectile response by increasing
the arterial inflow and relaxing cavernous smooth
muscle. There were no systemic or local side
effects, and no patient had a prolonged erection.
These promising results have not been confirmed
by other investigators [424, 425]. Placebo-control-
led, randomized clinical trials must be performed
to ascertain whether linsidomine is a useful thera-
peutic alternative to existing drugs available for
intracorporal injection.
Another NO donor, sodium nitroprusside (SNP),
have been given intracorporally for treatment of
erectile dysfunction, but has been shown not to be
effective [426, 427], and caused profound hypo-
tension. These rather discouraging results with
donors of NO do not rule out that drugs acting
through the L-arginine/ NO/ guanylate cyclase/
cGMP pathway can be effective for treatment of
erectile dysfunction (see below).
2. DRUGS FOR NON-INTRACAVERNOUS ADMI-
NISTRATION
There is a generally a high placebo response (40-
50%) to non-intracavernously administered drugs.
Therefore, placebo-controlled trials and valid ins-
truments to measure response are mandatory to
adequately assess effects.
a) Organic nitrates
Nitroglycerin and other organic nitrates are belie-
ved to cause smooth muscle relaxation by stimula-
ting soluble guanylate cyclase via enzymatic libe-
ration of NO [417]. Both nitroglycerin and isosor -
bide nitrate were found to relax isolated strips of
human corpus cavernosum [428].
Transdermal administration of nitroglycerin is
well established in the treatment of angina pecto-
ris. The observation that topical application of
nitroglycerin to the penis may lead to erection
adequate for sexual intercourse [429], has stimula-
ted several investigations on the efficacy of this
potential mode of treatment of erectile dysfunc-
tion.
179
Owen et al. [430] performed a placebo-controlled,
double-blind study on the effect of nitroglycerin
ointment applied on the penis of 26 impotent
patients with a diagnosis of organic, psychogenic,
or mixed-type impotence. Nitroglycerin increased,
relative to placebo, penile circumference signifi-
cantly in 18 out of 26 patients, and in 7 out of 20
patients it increased blood flow in the cavernous
arteries. Hypotension and headache was observed
in one patient. In a double-blind, randomized, pla-
cebo-controlled trial, Claes and Bart [431] treated
26 impotent men with nitroglycerin patches. They
observed a positive response to nitroglycerin with
return to satisfactory sexual function in 12 (46%)
patients, and some erectile improvement in 9
(35%). Only one patient of the 26 reported restora-
tion of potency with placebo patches. Twelve of the
patients reported mild to moderate headache during
nitroglycerin treatment.
The effects of nitroglycerin plaster applied to the
penis were also investigated in 10 impotent
patients by Meyhoff et al. [432]. They found that
when tested in the laboratory, all patients achieved
an erectile response. When the plaster was self-
administered, potency was restored in 4, semirigi-
dity insufficient for intercourse was seen in 2,
tumescence in 3 and no effect in 1. Seven patients
complained of headache. A sufficent erectile res-
ponse to the same nitroglycerin plaster was found
in 5 out of 17 patients with spinal cord injury
[433].
Comparing transdermal nitroglycerin and intraca-
vernous injection of papaverine in 28 patients with
spinal cord lesions and erectile dysfunction, Ren-
ganathan et al. [434] found that 61% responded to
nitroglycerin and 93% to papaverine. Nine
patients had complications with papaverine, while
the only side effect of transdermal nitroglycerine
was mild headache (21%).
Even if the efficacy of transdermal nitroglycerin is
limited, and headache seems to be a common side
effect, it may be an effective treatment in selected
patients.
b) Phosphodiesterase inhibitors
The L-arginine/NO/guanylate cyclase/cGMP path-
way seems to be the most important for penile erec-
tion in some species (see above), and recent results
with sildenafil, a selective inhibitor of the cGMP-
specific phosphodiesterase (PDE 5), found in the
human corpus cavernosum [323, 331] further sup-
port the view that this may be the case also in
humans [331]. Sildenalfil is 4000 more selective for
PDE 5 than for PDE 3, 70 times more selective for
PDE 5 than PDE 4, but only 10 times more selecti-
ve for PDE 5 than for PDE 6 [329]. Sildenafil is
rapidly absorbed after oral adminstration (bioavai-
lability 41%) and has a plasma half-life of 3-5 h.
A large number of placebo-controlled, randomi-
zed, double-blind trials have shown that sildenafil
can improve erections in men with erectile dys-
function, regardless of whether the cause is due to
psychogenic, organic, or mixed factors [435].
Since PDE 5 is not restricted to the penis, but can
be found in other tissues as well, side effects such
as nasal congestions, dyspepsia, headache, facial
and chest flushing, and diarrhea may develop.
Dominating in the safety discussions have been
possible cardiovascular and visual side effects. An
absolute contraindication to sildenafil is the use of
nitrates and several, but not all, of the deaths asso-
ciated with sildenafil use have been attributed to
concomitant use of nitrates. However, based on
experiences so far, sildenafil must be considered a
safe drug [435, 436, 437].
Sildenafil appears to be one of the most promising
orally active agents for treatment of erectile dys-
function. The high response rate and good toleran-
ce makes it an attractive first alternative to patients
who would previously have been considered can-
didates for injection therapy.
Other selective PDE 5 inhibitors are in clinical
development (e.g.IC351, [438], but data are not
yet available for evaluation.
c) Prostaglandin E1
Vasoactive agents can be administered topically to
the urethral mucosa and can apparently be absor-
bed into the corpus spongiosum and transferred to
the corpora cavernosa. PGE1 (alprostadil) and a
PGE1/prazosin combination were demonstrated to
produce erections in a majority of patients with
chronic, organic erectile dysfunction [439]. In a
prospective, multicenter, double-blind, placebo-
controlled study on 68 patients with long-standing
erectile dysfunction of primarily organic origin
[391], transurethrally administered alprostadil
produced full enlargement of the penis in 75,4%,
and 63.6% of the patients reported intercourse.
180
However, the frequency of intercourse or ability to
perform in men that had no erection prior to drug
therapy was not addressed. The most common side
effect was penile pain, experienced by 9.1% to
18.3% of the patients receiving alprostadil. There
were no episodes of priapism. In another double-
blind, placebo-controlled study on 1511 men with
chronic erectile dysfunction from various organic
causes, 64.9% had intercourse successfully when
taking transurethral alprostadil compared to 18.6%
on placebo [392]. Again the most common side
effect was mild penile pain (10.8%).
Despite early encouraging results, some suggest
the true efficacy is nearer to 30-40% and the qua-
lity of erection deteriorates over time. Penile pain
remains a problem in many patients. For men fin-
ding intracavernous injections problematic, the
ease of intraurethral administration is an option.
However, optimism should be tempered in those
with severe dysfunction and who have failed intra-
cavernous therapy.
d) K+ Channel openers
Several K+channel openers (pinacidil, cromaka-
lim, lemakalim, and nicorandil) have been shown
to be effective in causing relaxation of isolated
cavernous tissue from both animals and man, and
to produce erection when injected intracavernosal-
ly in monkeys and humans [440, 441]. However,
only minoxidil, an arteriolar vasodilatator used as
an antihypertensive agents in patients with severe
hypertension, seems to have been tried in man.
Minoxidil is a prodrug, not active in vitro, but is
metabolized in the liver to the active molecule,
minoxidil N-O sulfate [442]. It has been shown that
minoxidil sulfate has the properties of a K+
channel opener. Minoxidil is well absorbed, both
from the gastrointestinal tract and transdermally,
but its biotransformation to the active metabolite
has not been evaluated in man. The drug has a half-
life in plasma of 3 to 4 hours, but the duration of its
vascular effects is 24 hours or even longer.
In a double-blind trial, minoxidil was given to 33
patients with neurogenic and/or arterial impoten-
ce, and compared with placebo (lubricating gel)
and nitroglycerin (2.5 g 10% ointment). Minoxidil
was applied on the glans penis as 1 ml of a 2%
solution. Minoxidil was superior to both placebo
and nitroglycerin in increasing penile rigidity, and
it was suggested that the drug might be considered
for long-term treatment of organic impotence
[443].
The main side effects of the drug, when used in the
treatment of hypertension, are fluid and salt reten-
tion, cardiovascular effects secondary to barore-
flex activation, and hypertrichosis. Side effects
have so far not been reported when the drug is
used for treatment of erectile dysfunction, but the
experiences are limited.
The principle of K+ channel openening is interes-
ting, and the preliminary experiences with minoxi-
dil seem promising, but further controlled clinical
trials are needed to confirm and assess the effica-
cy and side effects of the drug in patients with
erectile dysfunction.
e) - Adrenoceptor antagonists
1. PHENTOLAMINE
Early studies with oral phentolamine showed
some success in patients with non-specific erectile
insufficiency [444, 445], Zorgniotti [445] conside-
red non-intracavernous, ”on demand” administra-
tion of phentolamine a promising approach for
treatment of impotence. Becker et al. [446] per-
formed a double-blind placebo-controlled trial
with oral phentolamine 20, 40, and 60 mg in
patients with erectile dysfunction and a high like-
lihood of organogenic etiology, and found the drug
to be of benefit. There were no serious complica-
tions, but some circulatory side effects were seen
after 60 mg.
Whether or not phentolamine is a competitive
alternative to other oral treatments of erectile dys-
function has to be demonstrated in comparative
clinical trials.
2. YOHIMBINE
In man, yohimbine has for a long time been consi-
dered as an aphrodisiac. Yohimbine is a relative
selective antagonist of α2-ARs, and even if other
actions have been demonstrated [447], these can
be demonstrated only in concentrations that most
probably cannot be obtained in man. The site of
action of yohimbine is most probably not periphe-
ral, since the predominant subtype of α-adreno-
ceptos in penile erectile tissue is of α1-type [7],
and since intracavernosal injection of another,
more potent, α2-AR antagonist, idazoxan, did not
produce penile erection in man [385]. In normal
healthy volunteers, Danjou et al. [448] found that
181
intravenous infusion of yohimbine had no erecto-
genic effects. This does not exclude that orally
administered yohimbine may be effective (see
below). In a randomized, double-blind, placebo-
controlled study, Montorsi et al. [449] found that
combination treatment with yohimbine and trazo-
done was more effective than placebo for the treat-
ment of psychogenic impotence. Jacobsen [450]
found in a pilot study that eight out of nine patients
with impotence associated with antidepressive
treatment with the serotonin reuptake blocker,
fluoxetine, responded favorably to oral yohimbi-
ne. A potentiation of yohimbine effects by the
opioid receptor antagonist naltrexone has been
demonstrated [451].
The effects of yohimbine have been investigated
in controlled trials on patients with organic [452],
psychogenic [453] , and mixed [454, 455] etiolo-
gy to their impotence. In organically impotent
patients, marginal effect of the drug demonstrated,
i.e., 43% responded (complete or partial response)
to yohimbine and 28% to placebo (difference n.s.)
[452]. In studies of the same design in patients
with psychogenic impotence, similar figures were
obtained, although this time the difference bet-
ween active treatment and placebo was significant
[452, 453]. Positive responses in patients with
impotence of mixed etiologies were reported in
approximately 1/3 of the cases [454, 455].
A cross-over, double blind study on 62 patients
with impotence, where the efficacy of yohimbine
ointment administered locally on the penis was
compared with that of placebo, suggested positive
results in a subgroup of patients [456], but in the
total material no significant effects were found.
High dose yohimbine (36 mg per day) was found
to have no positive effect in a prospective, rando-
mized, controlled double-blind, cross-over study
of 29 patients with mixed-type erectile dysfunc-
tion [457]. Another double-blind, placebo-control-
led study of 86 patients without clearly detectable
organic or psychologic causes [458], revealed that
yohimbine was significantly more effective than
placebo (71 vs 45%) in terms of response rate.
The plasma half-life of yohimbine was found to be
0.6 h [459], whereas the plasma NA-increasing
effects of the drug lasted for 12 h [460]. This dis-
crepancy may be explained by the presence of an
active metabolite [459]. The side effects reported
included increases in heart rate and blood pressu-
re, but also orthostatic hypotension, anxiety, agita-
tion, and manic reactions have been described
[461, 462, 463].
It cannot be excluded that orally administered
yohimbine can have a beneficial effect in some
patients with erectile dysfunction. The conflicting
results available may be attributed to differences
in drug design, patient selection and definitions of
positive response. However, generally, available
results of treatment are not impressive.
f) Opioid receptor antagonists
In man, it is well known that chronic injection of
opioids can lead to impotence [464, 465]. It has
also been suggested that endogenous opioids can
be involved in sexual dysfunction, and that opioid
antagonists would be effective as a treatment
[466].
Intravenous naloxone, which is a pure antagonist
at opioid receptors, was found to have no effect on
arousal in normal subjects [467]. Naltrexone has
effects similar to those of naloxone, but can be
given orally, and has a higher potency and a longer
duration of action (24-72 h) than naloxone. It is
well absorbed from the gastrointestinal tract, but is
subject to an extensive first-pass metabolism,
metabolized in the liver and recycled by enterohe-
patic circulation. The major metabolite of nal-
trexone, 6-ß-naltrexone, also possesses opioid
receptor antagonist activity and probably contri-
butes to the effects of naltrexone. The plasma half-
life of naltrexone is about 4 h and that of 6-ß-nal-
trexone 13 h.
In an open pilot study, Goldstein [468] found that
naltrexone (25-50 mg/day) restored erectile func-
tion in 6 out of 7 men with «idiopathic» erectile
dysfunction. Fabbri et al. [466] compared in a
single-blind randomised study naltrexone to place-
bo in 30 men with idiopathic erectile impotence. It
was found that sexual performance was improved
in 11 out of the 15 naltrexone-treated patients,
whereas placebo had no significant effects. Libido
was not affected and there were no side effects. In
general, the adverse effects of naltrexone are tran-
sient and mild, but hepatocellular injury may be
produced with high doses.
In a randomized, placebo-controlled, double-blind
pilot study of 20 patients with idiopathic, non-vas-
cular, non-neurogenic erectile dysfunction, van
Ahlen et al. [469] found no significant effect on
182
libido or frequency of sexual intercourse, but early
morning erections increased significantly.
It cannot be excluded that increased inhibition by
opioid peptides may be a factor contributing to
non-organic erectile failure, and that naltrexone
therapy in these cases may be a useful therapeutic
agent. However, well-controlled studies confir-
ming this are lacking.
g) Dopamine receptor agonists
It is well established that dopaminergic mecha-
nisms may be involved in the regulation of male
sexual behavior in animals [122, 470]. Apomor-
phine, a dopamine receptor agonist which stimu-
lates both dopamine D1 and D2 receptors, has
been shown to induce penile erection in rats [471,
472] as well as in normal [473] and impotent [474,
475] men. L-dopa may also stimulate erection in
patients with Parkinson´s disease [476]. It has
been suggested that dopamine D2 receptor stimu-
lation may induce penile erection in rats, while
activation of D1 receptors have the opposite effect
[477]. In rhesus monkeys, quinelorane, a dopami-
ne D2 receptor agonist produced penile erection
[478], favoring the view that D2 receptor stimula-
tion is important for this response. This may be the
case also in man [475]. However, clinical trials
with quinelorane were discontinued prematurely
before its efficacy could be assessed.
1. INJECTED APOMORPHINE
Lal et al. [473] showed in a placebo-controlled,
double-blind study on healthy volunteers, that
apomorphine, injected subcutaneously (0.25-0.75
mg), was able to induce erection. This was confir-
med by Danjou et al. [448], showing that apomor-
phine induced erection and potentiated the erec-
tion induced by visual erotic stimulation. There
was no increase in libido, which was in agreement
with previous observations [479]. In 28 patients
with impotence, Lal et al. [475] found that 17
responded with erection after subcutaneous apo-
morphine (0.25-1.0 g); no erection developed after
placebo. Segraves et al. [480] also administered
apomorphine subcutaneously (0.25-1.0 g) to 12
men with psychogenic impotence in a double-
blind and placebo-controlled study. They found a
dose-related increase in maximal penile circumfe-
rence. An erection exceeding 1 cm was obtained in
11 of the 12 patients.
It cannot be excluded that a subgroup of impotent
patients may have an impairment of central dopa-
minergic functions, and that the principle of dopa-
mine receptor stimulation may be used not only
diagnostically, but also therapeutically. The thera-
peutic potential of apomorphine, however, seems
to be limited mainly because of frequently occur-
ring side effects. High doses (i.e., up to 5-6 mg in
adult patients) may cause respiratory depression,
and in the low dose range (0.25-0.75 mg) where
effects on penile erection can be demonstrated,
emesis, yawning, drowsiness, transient nausea,
lacrimation, flushing, and dizziness [473, 480]
may occur. Even if Lal et al. [474] observed that
non-responders, but not responders, experienced
side effects, agents other than apomorphine repre-
senting the principle of dopamine stimulation,
may be useful.
2. ORAL APOMORPHINE
Heaton and coworkers [481] reported that apo-
morphine, absorbed through the oral mucusa will
act as an erectogenic agent. In twelve impotent
patients with no documentable organic disease,
but with proven erectile potential, 3 or 4 mg apo-
morphine in a sublingual controlled release form
produced significantly durable erections in 67%
without adverse effects.
These results have been largely confirmed in a
randomized, double-blind study including 520
patients [482]. Doses of 2, 4, 5 and 6 mg were
investigated, with optimum effects (best effect and
less side effects) obtained with 4 mg (apomorphi-
ne 58.1% vs placebo 36.6%). The occurrence of
nausea (not severe) with 4 mg was 21.4 %.
Similar results were obtained in two randomized
double-blind studies including 977 patients with
hypertension [483].
These results suggest that sublingual apomorphine
has a potential to be an effective agent for patients
with erectile dysfunction.
h) Trazodone
Trazodone is an «atypical» antidepressive agent,
which has been shown to selectively inhibit cen-
tral 5-HT uptake. It increases the turnover of brain
dopamine, but does not prevent the peripheral re-
uptake of NA [484]. In addition, trazodone has
been demonstrated to block receptors for 5-HT
and dopamine, whereas its major metabolite, m-
chlorophenylpiperazine (m-CCP), has agonist
activity at 5-HT2C receptors [485]. This metaboli-
183
te induces erection in rats and selectively increases
the spontaneous firing rate of the cavernous nerves
[486]. The mode of action of trazodone in depres-
sion is not fully understood; it has a marked seda-
tive action. Trazodone has a serum half-life of
about 6 h and is extensively metabolized.
Blanco and Azadzoi [487] showed that trazodone
and its major metabolite had an α−AR blocking
effect in isolated human cavernous tissue. Later
investigations confirmed that trazodone, in
concentrations obtained in blood after intake of
clinically relevant doses, had an inhibitory effect
on isolated corpus cavernosum preparations
contracted by NA or electrical stimulation [488].
However, the active metabolite, m-CCP, seemed
to have no significant peripheral effects.
Orally administered trazodone has been associated
with priapism in potent men [489], and with increa-
sed nocturnal erectile activity in healthy volunteers
[488]. When injected intracavernosally to patients
with impotence, trazodone caused tumescence, but
not full erection [489]. Intracavernosal trazodone
acted as an α-AR antagonist, but was not as effecti-
ve as papaverine or a combination of papaverine
and phentolamine [489]. Positive clinical experien-
ce with the drug has been reported [490]. However,
In a double-blind, placebo controlled trial, on 69
patients with different etiology of their erectile dys-
function, no effect of trazodone (150 mg/d) could
be demonstrated [491].
The potential of trazodone in the treatment of
penile erectile dysfunction has not been fully
explored. The drug may be an alternative in some
anxious or depressed men.
i) Future aspects
Even if intracavernous treatment of erectile dys-
function has made great progress since the intro-
duction of papaverine and phenoxybenzamine,
there is still room for improvement. Local, non-
injection administration may be developed to an
effective on demand therapy for inducing erection.
Oral treatment with apomorphine, and particularly
with sildenafil, is promising, and these drugs may
be important in the strategy of future treatment of
erectile dysfunction. One could look forward to a
rational approach to erectile disorders based on the
proposed etiology of dysfunction. Following failu-
re of one or more oral agents, intraurethral or
intracavernous drug treatment could be tried.
 VIII. RECOMMENDATIONS
1. MODELS OF ERECTION AND NEURAL
CONTROL
a) Rat is a suitable model. However, mice
models are needed for molecular biology
purposes.
b) Behavioral assessments should be further
persued.
c) The anatomical interrelationships and inter-
actions among the different brain nuclei that
modulate erectile capacity and sexual func-
tion should be further explored.
d) New and reliable animal models of erectile
dysfunction should be developed.
2. TRANSMITTERS AND RECEPTORS
a) The potential of new neuronal and non-neu-
ronal transmitters/modulators (e.g., - JARDIN, A.: Neural control of penile erection, Urol.
MSH, adrenomedullin, angiotensin II, noci-
ceptin) should be further investigated.
b) The interactions among the established neu-
rotransmitters/modulators need to be fur-
ther investigated, centrally and peripherally.
3. SIGNAL TRANSDUCTION
a) The signal pathways for different transmit-
ters/modulators should be studied in detail.
Distribution and roles of e.g., receptors,
cyclases, phosphodiesterases and protein
kinases need further study.
4. SMOOTH MUSCLE FUNCTION
a) Excitation-contraction coupling, cell to cell
transmission of activation, ion channels, and
changes in contractile proteins with erectile
dysfunction should be further studied.
5. THERAPEUTIC ASPECTS I: GENE THE-
RAPY & MOLECULAR BIOLOGY
a) Strategies to prevent cavernosal degenera-
tion and/or restore cavernosal function need
to be investigated.
b) The potential of intracavernosal somatic
gene therapy should be further explored.
6. THERAPEUTIC ASPECTS II: PHARMA-
COLOGICAL BASIS FOR FUTURE THE-
RAPIES
Based on findings in basic experimental
research, new molecular targets for drug
treatments should be defined and explored.
184
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2. STEERS, W.D.: Neural control of penile erection.
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3. DE GROAT, W.C. AND BOOTH, A.M.: Neural control
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Vol. 6, Chapter 13, Nervous Control of the Urogenital
System, edited by C A Maggi, Harwood Academic
Publishers, London, UK, p465, 1993.
4. ANDERSSON, K.-E, AND WAGNER, G.: Physiology
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203
204
 Committee 7

Endocrine and Metabolic Aspect

Including Treatment

Chairman
Y. C. K IM

Members
J. BUVAT,
C.C. CARSON,
L.J GOOREN,
J. JAROW,
J. RAJFER,
A. V ERMEULEN

205
 CONTENTS

A. PATHOPHYSIOLOGY C. TREATMENT

I .HYPOGONADISM IN PATIENTS I. TESTOSTERONE EFFECTS ON

WITH ERECTILE DYSFUNCTION THE BODILY SYSTEMS IN MALE

II. HYPOGONADISM IN AGING II. TESTOSTERONE TREATMENT

MALE AND ITS PREVALENCE IN PATIENT WITH ERECTILE
DYSFUNCTION
III. DIABETES MELLITUS
III. AVAILABLE PREPARATION OF
IV. HYPERCHOLESTEROLEMIA TESTOSTERONE

V. OBESITY, RENAL DISEASE AND IV. COMPLICATION OF TESTOSTE-

THYROID DISEASE RONE SUPPLEMENTATION

V. CLINICAL RECOMMENDATIONS
VI. HYPERPROLACTINEMIA
FOR TESTOSTERONE
SUPPLEMENTATION

B. CLINICAL MANIFESTA-
TIONS AND DIAGNOSIS OF VI. RECOMMENDATIONS
HYPOGONADISM

APPENDIX
I. SYMPTOMS OF HYPOGONADISM

II. DIAGNOSIS OF
HYPOGONADISM

206
 Endocrine and Metabolic Aspect
Including Treatment
YOUNG CHAN KIM
J. BUVAT C.C CARSON, L.J G OOREN, J. J AROW, J. R AJFER, A.VERMEULEN
A. PATHOPHYSIOLOGY
I . HYPOGONADISM IN PATIENTS
WITH ERECTILE DYSFUNCTION
The association between hypogonadism and erec-
tile dysfunction (ED) has not been clearly clari-
fied. There appears to be a direct relationship bet-
ween serum androgen levels and libido but the
association with sexual function is less clear. It is
well known that libido can have a significant
impact as a ‘conditioner’ for sexual function, and
thus androgens may play an important role in both
libido and the pathophysiology of erectile dys-
function.
1. PREVALENCE OF HYPOGONADISM IN THE
PATIENTS REFERRED FOR ERECTILE DYS-
FUNCTION
Total testosterone is usually normal in these
patients. Its average value does not differ from that
of men with normal erectile function [1-5] or is
only slightly decreased [6-11]. In 7 series totaling
2722 patients referred for impotence, 2.1 to 21% of
them according to the series (making a total of 227,
thus in average 8.3%) were found to have a serum
total testosterone lower than 300 ng/dl [12-18]. The
prevalence of the low testosterone levels increases
with age. For example in a series of 1022 unselec-
ted impotent patients, 9% of those over 50 years old
had a serum testosterone < 300 ng/dl, including
2,6% < 200 ng/dl, compared to respectively 4 and
0.8% of those less than 50 years [18].
207
Free testosterone (FT) or at least non Sex Hormo-
ne Binding Globulin (SHBG)-bound testosterone
(bioavailable testosterone) are considered as the
only fractions of serum testosterone available to
the target cells. Buvat et al [19] assessed the pre-
valence of the decreases of both fractions in over
400 impotent patients according to their age. Free
testosterone was decreased in 22.6% before the
age of 50 and in 37.1% after age 50. Non SHBG-
bound testosterone was reduced in 3.9% before
and in 24.4% after age 50. Korenman et al [20]
also reported on a substantial prevalence of low
levels of non SHBG-bound testosterone in the
older men with impotence.
Pirke et al[5] found, however, no difference bet-
ween their groups of impotent patients and
controls as regards the mean value of serum free
testosterone. Moreover, in the studies of Koren-
man et al[20], the decrease in the levels of non
SHBG-bound testosterone was not different whe-
ther the older men were impotent or not. On the
other hand Buvat-Herbaut et al [7] found a signifi-
cant decrease in the mean value of both free and
non SHBG-bound testosterones in impotent
patients compared with age-matched controls.
Therefore, there are inconsistent results with dif -
ferences in the levels of bioavailable testosterone
between normal and erectile dysfunction
patients.
2. TESTOSTERONE AND SEXUAL INTEREST
Androgens are clearly required for sexual inter -
est in men. In hypogonadal men supplemented
with androgens, cessation of supplementation
results in a progressive decline of sexual interest,
sexual fantasies and arousal, starting after 2 or 3
weeks after withdrawal. Surgical or drug-induced
castration following the administration of LHRH-
agonists [21,22] or antagonists [23], result in the
same effects. Sexual interest and arousal return to
the previous level about 2 weeks after reintroduc-
tion of androgens or cessation of anti-LHRH or
anti-androgen therapy. These observations sug -
gest that the effect of testosterone upon sexual
function in man is centrally mediated through
libido.
3. TESTOSTERONE AND ERECTIONS
Relationships are more complex. Spontaneous
erections, either nocturnal or morning, are clear -
ly androgen-dependant. Nocturnal Penile Tumes-
cence and Rigidity (NPTR) monitoring using a
Rigiscan device shows a significant reduction in
frequency, amplitude and rigidity of the erections
in men with marked hypogonadism while they are
not reduced in moderate decrease of serum testos-
terone [24,25]. In the former case, NPTR signifi-
cantly increases upon administration of andro-
gens. Nocturnal erections are highly, significantly
correlated with the serum testosterone level, and
constitute the most sensitive clinical criterion of
well-balanced androgen production. However
nocturnal erections may require up to 6 to 12
months of androgen supplementation to regain
complete normality [26]. Nocturnal erections are
also highly correlated with sexual interest. Studies
in paraphilic men [25] or sexual aggressors [27]
treated with anti-androgens report a significant
decrease of erections parallel with that of sexual
interest.
Psychogenic erections, i.e. induced by visual sti -
muli or fantasies, are only partly androgen-
dependant. In young hypogonadal men, several
studies reported complete erectile response to a
strong audio-visual sexual stimulation (AVSS) as
induced with erotic movies despite cessation of
androgen supplementation, without increase of the
response after restarting androgens. However
several other studies conclude to some partial
dependence on androgens The penile rigidity
induced by visual erotic stimulation (VES) did not
differ between hypogonadal men and controls.
However, in terms of both duration and maximum
level of rigidity, there was a significant increase
following androgen replacement in the hypogona-
208
dal men, suggesting that erectile response to VES
may also be influenced by androgen sensitive
mechanisms [24]. Lange et al [28] also found a
borderline significant relationship between the
erectile response to AVSS and the serum testoste-
rone level. All together, these studies support the
fact that the psychogenic erections are only part -
ly androgen-dependant, although the level of evi-
dence is lower than that of the studies having esta-
blished the androgen-dependence of the nocturnal
erections, due to a less rigorous methodology.
4. TESTOSTERONE, EJACULATION AND
ORGASM
Castration or removal of androgen supplementa -
tion results in delayed ejaculation and a reduc -
tion of the ejaculated volume. Subsequently eja-
culation and orgasm disappear in many cases.
They return to normal on androgen replace-
ment[29, 30].
5. RELATIONSHIP BETWEEN SERUM LEVEL OF
TESTOSTERONE AND ERECTILE FUNCTION
a) The threshold value of serum testosterone in
relation to erectile functions
Research indicates the following levels of testos-
terone as minimum values for erectile functions;
Levels below which sexual behaviour is impaired
but there are normal night erections (i.e. 350 ng/dl)
and there are still lower threshold values below
which night erections are also impaired (i.e. 150
ng/dl) [31]. Others have suggested a level of 200
ng/dl as threshold for sleep related erection[32]. It
appears that the plasma testosterone levels requi -
red for normal libido and sexual activity are
rather low.
b) Upper limit of the effects of testosterone upon
male sexual function
It is generally believed that the effects of testoste-
rone on sexual function are maximal as soon as
plasma level gets close to the lower limit of the
normal adult range, and that no additional effect
would occur following further increase over this
limit. In controlled studies, the effects of testoste-
rone injections upon sexual function definitely
correlate with the serum testosterone level only up
to a certain level. Salminies et al [33] suggested
that between 200 and 450 ng/dl effect is maximal.
No marked increase in sexual interest or activity
occurred over this limit. Buena et al[34] did not
observe changes in sexual function when the
serum testosterone levels of normal men were
pharmacologically changed by means of testoste-
rone injections following pituitary desensitization
with a LHRH-agonist. Indeed, after suppressing
testosterone levels with GnRH analogues, which
resulted in a marked decrease in frequency of
sexual desire and activity, androgen replacement
at a dose maintaining testosterone levels approxi-
mately half the basal levels, was found to be
appropriate for sustaining normal libido and
sexual activity [23].
Other data, however, support the probability of a
stimulating effect of increases of the serum testos-
terone level from values exceeding 4 ng/ml. Diffe-
rent methodological flaws could explain the dis-
cordant results of these studies, including: small
number of patients in certain series, limited infor-
mation resulting from only single testosterone
determinations. Several studies also reported a
significant increase in sexual interest and arousal
following injection of large doses of androgens to
eugonadal males [35,36], including males referred
for lack of sexual interest [37], though in all these
studies this effect was too modest to lead to an
increase in sexual activity. In eugonadal men,
amplitude and duration of NPTR proved to be
modestly but significantly increased following
injection of large doses of testosterone esters [24].
Lastly, Buvat et al [38] observed a borderline
significant improvement in satisfying sexual inter-
course by increasing the circulating level of tes-
tosterone with injections of chorionic gonadotro-
pins in eugonadal males referred for erectile dys-
function or low sexual interest.
This body of data thus supports a highly signifi -
cant relationship between the serum testosterone
level and sexual interest and activity up to a cer -
tain limit, probably individually different, but
with values not exceeding 200 to 450 ng/dl.
Beyond this level, a weaker relationship may
exist, but the most extensive studies[36,37] sug-
gest no therapeutic effect of androgen administra-
tion in eugonadal men can be expected.
6. SITE OF ACTION OF TESTOSTERONE;
CENTRAL AND/OR LOCAL
Testosterone seems to act centrally and at
local level, at least in animals (Figure 1).
209
a) Brain centers
In rodents, the neurons of anterior hypothala -
mus , and more specifically of the median preop -
tic area (mPOA) have the capacity of accumula -
ting isotopically labeled sex steroids as evidenced
by auto-historadiographic studies. These neurons
play an essential role in male sexual behavior
(sexual performance) since these are stimulated
when the corresponding neurons are electrically sti-
mulated and abolished when they are des-
troyed[39]. The appetitive elements of sexual beha-
vior (sexual motivation) would be under control of
other neuronal systems, also able to accumulate sex
steroids (amygdala, lateral septum ,ventral stria-
tum) [39], although other data suggests that mPOA
is also involved in these appetitive aspects[40].
According to Clark[41], steroids would act on both
motivational and consummatory aspects of sexual
behavior by modulating a central alpha 2 adrenergic
tone permanently inhibiting it. Steroids would also
act through their impact on different peptidergic
systems colocalized with the adrenergic transmis-
sion, especially neuropeptide Y, somatostatin and
angiotensin which all strongly inhibit the copulato-
ry behavior. Less data is available in humans.
However androgen receptors have been detected in
the human temporal cortex [42].
b) Peripheral control (spinal cord centers and
pelvic autonomous nervous system)
In spinal animals, postural reactions to sexual sti-
mulation are facilitated by testosterone [30,43].
Certain spinal motor neurons accumulate andro -
gens [44]. The major pelvic ganglion, which is an
important intermediary of the autonomic innerva-
tion to the penis, is also a target for androgens
[45]. Testosterone stimulates the tyroxine hydro-
xylase and choline acetyl-transferase activities in
its neurons [46]. Recent animal model data sug -
gests that androgens may have a direct effect
upon the penis [47,48]. Reilly and colleagues
demonstrate that castration obliterates the penile
erectile response to pelvic ganglionic stimulation
via both nitric oxide and non-nitric oxide depen-
dent pathways in a rat model [49,50]. They repor-
ted that androgen mediated the erectile response
by stimulating the expression of the neuronal iso-
form of nitric (NO) and by alternative pathway,
including one that is independent of NO but
involves the synthesis of cyclic GMP.
Figure 1: Sites of action of testosterone: Testosterone appears to act centrally and at local level.

210

II. HYPOGONADISM IN AGING
MALE AND ITS PREVALENCE
Recent studies have shown an increased preva -
lence of erectile dysfunction in the aged where
hypogonadism is more frequent than in young
men. It has increased awareness to hypogona -
dism itself in the aging male, regardless of their
status of sexual function, because of the nume-
rous benefits of testosterone on the whole bodily
systems, such as body composition and sense of
well-being.
1. PADAM(PARTIAL ANDROGEN DEFICIENCY
OF THE AGING MALE)
Unlike women, there is no sharp decline or break
off point in serum sex steroid levels. In contrast,
cross-sectional studies have documented a gradual
age-related decline in serum testosterone concen-
trations in healthy adult men [51]. Furthermore,
the occurrence of an age associated gradual
decline in bioactive testosterone levels is now
generally accepted, being now confirmed by lon -
gitudinal data [52,53]. Highest plasma levels are
observed in the age group 20-30 yrs, levels star-
ting to decrease around age 35 yrs and at age
75yrs, mean free testosterone (FT) levels are only
50% (0.22 nMol/l) of levels at age 25yrs (0.45
nMol/l) [54].
It is not clear how to define “hypogonadism” in
aging men. Should hypogonadism be defined
based upon the criterion of normal levels of young
men, older men, or as a specific decrease from
levels measured earlier in life? For instance, a hal-
ving of serum testosterone within the normal
range from 800 ng/dl to 400 ng/dl (both are within
the normal range) may represent a physiologically
significant decline in androgen levels for that indi-
vidual and may respond to androgen replacement
therapy. In the absence of longitudinal data it is
impossible to state with certainty whether or not
this is the case. The exact prevalence of hypogo -
nadism amongst aged men is not known and is
dependent upon the definition of hypogonadism
that is utilized. One definition that has been utili-
zed is to select the population with the lowest
quintile of serum testosterone and the highest
quintile of gonadotropins. Using this definition,
211
the prevalence of hypogonadism in the Massachu-
setts Male Aging Study is 4% amongst men aged
40 to 70 years old [51]. The prevalence of hypo-
gonadism amongst men over 55 years increases to
20% when hypogonadism is defined as having a
serum testosterone concentration below the nor-
mal range of serum testosterone for healthy young
adult men. The major part of serum testosterone is
tightly bound to SHBG produced by the liver. The
serum testosterone fractions that are free or loose-
ly bound to albumin are considered to be bioavai-
lable to target organs. Cross-sectional and longitu-
dinal studies have also demonstrated a significant
increase in SHBG concentrations in aging male.
Thus, not only does total testosterone decline but a
higher percentage of the remaining testosterone is
tightly bound to SHBG, further reducing the
amount of bioavailable testosterone. The prevalen-
ce of testosterone deficiency amongst older men
increases dramatically if hypogonadism is defined
by the amount of bioavailable testosterone in the
serum and has been estimated by some authors to
be as high as 50%[51]. In an investigation of 300
healthy men applying a definition of hypogona-
dism as a morning level of testosterone below the
lower limit of normal (12 nmol/L), Vermeulen and
Kaufman [55] reported that none of the men aged
20-40 years had testosterone levels within the
hypogonadal range, but 7% of those aged 40-60
year, 21% of those aged 60-80 years and 35% of
those over the age had hypogonadism. The elderly
men who meet these criteria might be good candi-
dates for testosterone supplementation, and expect
improvement of age-related symptoms.
There exists, however, at any age a wide interin -
dividual variation in free testosterone (FT)
levels,and, while at age 75 yrs, 20 % have FT
levels which even for young male would be in the
highest quartile (> 0.6 nMol/l or 17 ng/dl), at least
25 % have levels below the normal limit for young
adults (0.2 nMol/l or 6 ng/dl) and, hence, can be
considered to be hypogonadal [56]. The important
large interindividual variability of androgen levels
in healthy men is attributable to genetic, socioeco-
nomic and environmental factors. Meikle et al [57]
attributes about 30 % of the variability to genetic
factors. Circadian and ultradian pulsatile varia-
tions in androgen levels also play a role in the
variability of the measured values. Among the
more personal factors, obesity, probably via the
induced hyperpinsulinemia and low SHBG levels,
is accompanied by decreased testosterone levels
and in morbid obesity even decreased FT level
[58] whereas several studies suggest that a vegeta-
rian diet is accompanied by lower FT levels. Smo-
kers on the other hand have higher FT levels than
non smokers. Physical or psychological stress are
generally accompanied by decreased testosterone
levels. It should be mentioned moreover that most
acute or chronic illnesses such as myocardial
infarction, acute infectious diseases, diabetes mel-
litus, chronic rheumatoid arthritis, renal, hepatic or
pulmonary insufficiency, respectively, are accom-
panied by decreased testosterone levels.
This androgen deficiency in elderly men is gene-
rally moderate and some authors suggest to use the
term: Partial Androgen Deficiency of the Aging
Male, or PADAM. More importantly, it should be
realized that the normal testosterone levels for our
aging males are defined on the basis of data obtai-
ned in young men. It is, however, not certain that
the same criteria can be used for our elderly men.
Indeed the tissular sensitivity to androgens may be
different in young and elderly men , whereas it
might moreover vary between the different tissues.
There is, for example, good evidence that the
hypothalamo-pituitary system of the elderly is
more sensitive to sex hormone feed back [59-61],
whereas the decrease of the androgen receptor
concentration in the corpora cavernosa or pubic
skin suggests a decreased sensitivity at this level
[62,63]. Unfortunately, a more reliable parameter
of androgen action is not available and, hence, the
required testosterone concentration in elderly
males remains questionable.
2. ETIOLOGY OF AGE-RELATED
HYPOGONADISM
The cause of hypogonadism amongst aging men is
unclear. The preponderance of evidence points
towards a primary Leydig cell defect. Quantitati-
ve histological studies in man demonstrate decrea-
sed number and volume of Leydig cells [55]. Zir -
kin and colleagues [64] observed similar findings
in a Brown-Norway aging rat model where both
spermatogenesis and steroidogenesis decrease in
an age-dependent manner similar to that observed
in the human condition. The primary defect in
these aged rats is Leydig cell dysfunction. In
contrast, several human studies have demonstrated
212
abnormalities in the hypothalamo-pituitary axis
[55,65], showing an increased SHBG level was a
primary event leading to low levels of bioavailable
testosterone in older men. Therefore, it appears
that, the hypogonadism present in elderly men is
multifactorial.
3. RELATIONSHIP OF HYPOGONADISM WITH
IMPOTENCE IN THE AGING MALE
Male hypogonadism is defined by decreased
androgen effect which is most commonly due to
impaired testicular secretion of testosterone but
may also be due to decreased bioavailability of cir-
culating androgens through an increase in serum
binding proteins. Normal serum androgen levels
are critical for the maintenance of normal bone
and muscle mass, erythropoiesis, cognition, and
libido. As stated previously, studies have shown an
increased prevalence of erectile dysfunction in the
aged [66]. This finding is also associated with
age-related sexual changes which include reduced
libido, delays in achieving erection and orgasm,
and prolonged latency time [67-70]. Current evi-
dence documents an age - related decrease in
serum androgen levels which is associated with an
age - related decrease in sexual function. Pfeiffer
and associates documented an inverse relationship
between age and coital frequency and sexual inter-
est [71]. These observations correspond with a
well described decline in serum androgen levels
with age [51,53,67,72]. However, it is unclear
whether or not there is a causal relationship bet-
ween these two phenomena. Yet there is a paucity
of data on the human male sexual response with
age and its relationship with hypogonadism.
Korenman and associates addressed this issue in a
cohort controlled study of 267 men with erectile
dysfunction and 107 controls equally divided
amongst potent young and older men [65]. They
observed an increased prevalence of hypogona-
dism amongst older men as compared to young
controls. However, when corrected for age, there
was no association between hypogonadism and
erectile dysfunction in the older population. In
other words, both hypogonadism and erectile
dysfunction are common conditions in the aging
male but they may not be causally related.
Currently available evidence suggests that endo -
crine factors do not play a substantial role in the
age-associated increased prevalence of erectile
dysfunction observed in man. Many other causes
of erectile dysfunction increase with age. The
predominant etiological factor of erectile dys -
function in older men appears to be atheroscle -
rotic vascular disease. The diminution of libido
associated with age most likely has an endocrino-
logic basis, yet androgen replacement therapy may
not be sufficient to restore normal sexual function
in aging men due to the presence of other etiologic
factors (ie, atherosclerosis).
III. DIABETES MELLITUS
Diabetes mellitus has been the most common
cause of erectile dysfunction(ED) seen in men
throughout the world. As many as 28% of men
presenting with ED have diabetes mellitus as the
principal cause of their erectile dysfunction. Most
often, ED develops during the course of diabetes
with 50% of diabetic men being impotent after 10
years of diabetes [73]. Occasionally, however, ED
is the first symptom of diabetes and is its presen-
ting symptom. Although the severity of diabetes
has been suggested as a predictor of ED, there
appears to be little difference in the likelihood of
ED in patients treated with oral hypoglycemics or
those who require insulin. Age, duration of dia-
betes and other diabetic complications, however,
appear to predict ED in most diabetic patients.
Because ED in younger diabetics is most com-
monly caused by microangiopathy, retinopathy
and other complications of diabetes are the most
accurate predictors of the development of ED in
diabetic patients. While glycosylated hemoglobin
has been suggested as a predictor of the associa-
tion of ED and diabetes, other factors, such as
alcohol intake, age and anti-hypertensive medica-
tions are more accurate predictors [74-76].
The pathophysiology of erectile dysfunction in
diabetics is dependent upon neuropathy, microan-
giopathy and generalized vascular disease [77].
Specifically, animal studies have provided eviden-
ce that diabetes produces endothelial cell dysfunc-
tion that leads to smooth muscle dysfunction in the
microvascular beds in the penis producing ED. A
number of animal studies have confirmed this
association [78-80]. Diabetic changes are not iso-
lated to microvascular abnormalities, but also
include significant peripheral neuropathy in the
213
corpora cavernosa [81]. These changes may pro-
gress to involve larger myelinated fibers with the
classic peripheral sensory abnormalities associa-
ted with peripheral neuropathy. The use of corpus
cavernosum electromyography, while controver-
sial, may provide some evidence for early per-
ipheral neuropathy affecting diabetic men [82].
Diabetic men are also at high risk for associated
conditions that increase risk for ED. These inclu-
de hypercholesterolemia, hypercoagulability,
hypertension, and cardiac disease [83-86]. Each
of these conditions increases the risk of micro-
vascular and major vessel vascular disease inhi-
biting endothelial, smooth muscle function, and
vascular flow [87-89].
Because diabetes is the most common single cause
of ED, all men who present with newly diagnosed
ED should be evaluated for undiagnosed dia -
betes [73]. A strong family history of diabetes or
history of associated symptoms of diabetes should
be elicited. Laboratory studies should include ran-
dom blood sugar and a glycosylated hemoglobin
to identify diabetes and to assess control if dia-
betes has been previously diagnosed [77]. Since
diabetes is associated with a risk of hypogona-
dism, a serum testosterone should also be evalua-
ted routinely.
Initial improvements in diabetic control should be
initiated to optimize treatment outcomes. While
few patients will realize restored erections from
diabetes control alone, improvement in overall
health status may improve patients sexual respon-
se and response to other treatment. A goal-oriented
approach to patients with erectile dysfunction cau-
sed by diabetes is essential. Treatment with the
most conservative method for restoration of erec-
tions will provide the best clinical outcome. Expe-
rimental treatment with aldose reductase inhibi-
ting medications for patients with significant pe-
ripheral neuropathy have demonstrated some
improvement in erectile dysfunction as well as
restoration of peripheral nerve function. A number
of these agents continue in clinical studies but
have not yet been approved for clinical use. Most
available treatment modalities for impotence, such
as oral medications, intracavernosal injections,
vaccum erection device and prosthetic surgery can
be applied to the treatment of diabetic impotent
patients.

IV. HYPERCHOLESTEROLEMIA
Atherosclerosis is a significant risk factor for erec-
tile dysfunction. It has been estimated that athe-
rosclerotic vascular disease is an associated risk
factor for as many as half of all men over 50 with
ED[90]. Because the penis is a high flow system
during erectile function, ED may be an early sign
of atherosclerotic disease, which subsequently
may appear as cardiac disease or peripheral vascu-
lar disease. Thus, systemic conditions such as
atherosclerosis, myocardial infarction, hyperten-
sion, peripheral vascular disease, may be precur-
sors or sequelae of erectile dysfunction in the
aging male. Hypercholesterolemia as well as
hypertriglyceridemia are clearly important risk
factors for atherosclerosis [91]. These risk factors
are enhanced by the presence of other risk factors
such as smoking [92]. There is little question that
hypercholesterolemia is associated with ischemic
heart disease and increased incidence of vascu -
lar dysfunction and heart disease with increasing
age. In the multiple risk factor intervention trial
(MRFIT), men were investigated with elevated
cholesterols for risk of ischemic heart disease [93].
Hypercholesterolemia, hyperlipidemia and other
risk factors for vascular disease are closely asso -
ciated with erectile dysfunction. These risk fac -
tors from hypercholesterolemia are associated
with both atherosclerosis in the hypogastric
cavernous arterial bed as well as endothelial and
smooth muscle dysfunction in the corpus caver -
nosum. Studies reporting an association of corpo-
ral venous leakage and veno-occlusive dysfunc-
tion are the clinical end result of this smooth
muscle dysfunction. Animal studies have clearly
documented the impairment of endothelium
dependent vascular relaxation in a variety of ani-
mal models and vascular environments. Studies by
Kim et al demonstrated that cavernosal hyperlipi-
demia produces not only endothelial changes but
also smooth muscle dysfunction and structural
destruction of endothelial cells in the corpus
cavernosum [94]. These same authors documented
reversal of these changes with the addition of L-
Arginine, the nitric oxide precursor [95]. Thorne
and colleagues [96] have used L-Arginine clinical-
ly to improve nitric oxide production in smooth
muscle relaxation in patients with clinical atheros-
214
clerosis. It appears that high cholesterol produces
not only endothelial cell dysfunction but smooth
muscle dysfunction and a net decrease in produc-
tion and effectiveness of the neurotransmitter
nitric oxide. In animal modes, these effects can be
ameliorated by reversal of serum cholesterol
levels, addition of dietary L-Arginine to increase
nitric oxide precursor, and addition of antioxidants
such as vitamin C and vitamin E [97-100].
Treatment of erectile dysfunction associated with
hypercholesterolemia begins with dietary counse-
ling to restore normal weight and decrease intake
of saturated fat and cholesterol [101]. Drug thera-
py, in addition to lifestyle changes such as diet,
increased physical activity, and smoking cessa-
tion; however, many patients require drug therapy
to normalize cholesterol and lipid levels [102].
Agents such as nicotinic acid, cholestyramine and
HMG-CoA reductase inhibitors (vastatins) block
the rate limiting step in cholesterol synthesis and
increase LDLcatabolism, thus lowering LDL cho-
lesterol levels. While these agents have not been
studied in large trials of patients with erectile dys-
function, they have been widely and carefully stu-
died in patients with atherosclerotic and choleste-
rol related cardiac disease with substantial impro-
vement or stabilization of cardiac disease. The
combination of a low cholesterol diet, lipid lowe-
ring agents other than clofibrate, and perhaps, the
addition of dietary L-Arginine, vitamin C, or other
anti-oxidants may improve erectile dysfunction in
these patients [103].
V. OBESITY, RENAL DISEASE AND
THYROID DISEASE
1. OBESITY
Obese men who are otherwise healthy have
been found to have low serum testosterone
levels with a progressive fall in serum testoste -
rone [104]. Despite this low serum testosterone,
obese men might not display clinical evidences
of hypogonadism [105]. They have normal libi-
do, potency, testicular size and spermatogenesis.
This paradox is partially explained by the fin -
ding that most obese men have normal free tes -
tosterone (non-protein bound) levels. This is due
to a decrease in the sex hormone binding globu-
lin (SHBG) which reduces the protein-bound tes-
tosterone. There are some men with marked obe-
sity (> 250% of ideal body weight) that has sub-
normal free testosterone levels. Obese men have
elevated estradiol and estrone levels [106]. The
high estrogen levels may reflect the ability of the
adipose tissue to convert androgens to estrogens.
When these obese men lose weight and their adi-
pose tissue, the abnormal androgen and estrogen
levels revert to normal [107]. Serum gonadotro-
pins are normal in obese men.
2. R ENAL DISEASE
Chronic renal failure impairs sexual function in
about 50% of the men[108] and hemodialysis
does not seem to improve it. Men with renal fai -
lure have elevations of LH and FSH and some
decrease in serum testosterone, hormone levels
that are characteristic of a primary testicular
dysfunction [109,110]. This is supported by the
observation that hCG stimulation testing in these
patients fails to elevate serum testosterone levels
[111]. Elevated prolactin levels may also be seen
in men with chronic renal failure [112,113],
although the impact of this endocrinopathy in the
dysfunction seen in these patients is unclear.
However, renal failure patients may also have
accelerated changes in their vascular system
and an autonomic neuropathy, two non-endo -
crine causes of erectile dysfunction. Vascular
testing demonstrate cavernous artery occlusive
disease in 78% and corporeal veno-occlusive
dysfunction in 90% of patients with chronic renal
failure [114]. In addition, these patients have a
lot of psychological issues regarding their
disease and the many medications they have to
take for hypertension etc. that may affect sexual
function [115].
In some patients, renal transplantation may rever-
se the low serum testosterone levels seen pre-
transplant and improve sexual function in about
80% of patients [116]. Dialysis rarely improves
the sexual dysfunction [117]. If potency does not
improve posttransplantation, the etiology of the
dysfunction is most likely non-endocrine such as
an abnormal vascular supply to the penis. There-
fore, in patients with chronic renal failure, a
lowered serum testosterone level may be the
cause of the sexual dysfunction and these patients
may be candidates for exogenous androgen the-
215
rapy. If exogenous testosterone fails to improve
the dysfunction that is usually what occurs in this
setting [118], then a vasculopathy and/or neuro-
pathy as the etiology of the dysfunction should be
addressed.
3. THYROID DISEASE
Thyroxin can affect the male reproductive sys-
tem. Increased thyroid hormone secretion has
been associated with an increase in total testoste-
rone but with normal unbound testosterone. This
is due to the increase in the sex hormone binding
globulin (SHBG) or as it is occasionally referred
to as testosterone-estrogen binding globulin
(TEBG) associated with hyperthyroidism. The
increase in SHBG causes a relative decrease in
the free testosterone levels which cause an eleva-
tion of serum LH (negative feedback) and further
increase in serum testosterone and by peripheral
conversion, an increase in serum estradiol. As a
result of the increase in circulating estrogens,
these men with hyperthyroidism may complain
or present with gynecomastia, spider angiomas
and a decrease in libido [119]. The libido does
not respond to exogenous testosterone that may
also make the gynecomastia worse. Treatment of
the thyrotoxicosis reverses the symptoms and
signs of the disorder.
In hypothyroidism, LH and FSH are usually ele-
vated, which is consistent with testicular resis-
tance to gonadotropins. Serum testosterone and
SHBG are usually decreased. Free testosterone
has been reported to be either increased, decrea-
sed or normal. Potency is usually normal in
hypothyroidism but erectile dysfunction and
decrease in libido were reported in some men. If
hypothyroid men complain of impotence, repla-
cement with thyroxin rarely improves the poten-
cy [120].
VI. HYPERPROLACTINEMIA
Hyperprolactinemia is a common endocrine
cause of erectile dysfunction. Men with hyper -
prolactinemia tend to have reduced libido and
have erectile dysfunction. Some of men with
hyperprolactinemia have galactorrhea, which is
important physical sign for this abnormality.
Serum gonadotropins and testosterone are
usually decreased in men with hyperprolactine-
mia. Hyperprolactinemia can decrease gonado-
tropins [121] by inhibition of GnRH secretion,
and larger nonfunctioning tumors cause hypogo-
nadism by direct damage to the gonadotrophs.
The abnormalities of testosterone metabolism
have been reported in hyperprolactinemia[ 122].
Other mechanisms which are proposed to be
responsible for diminishing erectile activity in
hyperprolactinemia are direct suppression of
the libido center or decreased relaxation of the
corpus cavernosum through mechanisms that
are independent of testosterone action [123].
Men with acquired hypogonadotropic hypogona-
dism (i.e. pituitary tumor) commonly complain
of decreased erectile function. Signs of this type
of tumor include decreased facial hair, decreased
muscle strength, central obesity, premature facial
wrinkling and abnormal visual fields, the result
of a mass lesion causing hypogonadism. These
tumors commonly secrete prolactin and high
serum prolactin levels can interfere with the
reproductive axis at many levels. Prolactin also
interferes with brain neurotransmission and may
impair libido.
Treatment of these pituitary tumors, if small
(microadenomas), usually respond to dopamine
agonist therapy. With large tumors (macroadeno-
mas), the LH and FSH deficiency are not always
restored to normal upon the dopamine agonist
treatment even if the prolactin levels return to
normal. In addition, prolactin may also have
adverse effects on sexual function in men separa-
te from that of testosterone suppression since
treatment of these patients with exogenous tes-
tosterone does not always reverse erectile dys-
function until the prolactin levels have been
returned to normal levels [124]. If medical thera-
py fails to control the effects of the tumor, trans-
phenoidal adenectomy may be indicated. Depres-
sion and anxiety are common in men with pitui-
tary secreting hyperprolactinomas independent
of the lowered testosterone levels and may play a
role in the decreased libido seen in these men
[125].
Besides an ademona, hyperprolactinemia may
also be caused by certain drugs and is seen in
some patients with chronic renal failure [126].
216
B. CLINICAL MANIFESTA-
TIONS AND DIAGNOSIS OF
HYPOGONADISM
I. SYMPTOMS OF HYPOGONADISM
1. HYPOGONADISM IN THE RELATIVELY
YOUNGER MEN
The clinical manifestations of hypogonadism
depends on the time of onset of hypogonadism.
Prepubertal androgen deficiency is associated with
small- sized testes and/or phallus, abnormality of
secondary sex characteristcs, abnormal skeletal
proportions with long legs, and infertility (Figure
2). Hypogonadism, which occur after puberty,
often accompanies sexual dysfunction( i.e. decrea-
sed libido and increased erectile dysfunction), the
changed body hair patterns, decreases in bone and
muscle mass, and a loss of aggressive behaviour
(Figure 3).
2. AGING AND HYPOGONADISM IN THE AGED
MEN
Many of the clinical features, accompanying
the aging proces in men, are reminescent of the
symptomatology of hypogonadism: decrease of
libido and sexual activity, decrease of signs of
virilism such as decreased sexual pilosity or
beard growth, decrease in muscle mass and
strength, lack of energy, ostopenia, decrease of
cognitive functions, irritability, excessive swea-
ting with, occasionnally hot flushes, decrease of
the feeling of general well-being (Table 1).
Hence, it is tempting to attribute, at least part of
these symptoms to an age associated decrease in
testosterone levels.
a) Sexual functions
Coital frequency declines rapidly with age from,
according to Masters, a mean maximal coital fre-
quency of about 4 times a week at age 25 yrs, to
once a week at age 50, 3 times a month at age 70
yrs and 1.7 times a month between age 75 and 79
yrs [127]. Moreover ED increases dramatically
with age: rare before age 30 yrs, it is observed in 8
Figure 2: Clinical manifestations of prepubertal androgen deficiency:

Figure 3: Clinical manifestations of postpubertal hypogonadism:

217
Table 1: Clinical manifestations which may be associated determinant of free testosterone(FT) levels, glu-
with hypogonadism in the aging male teal fat and lean body mass affect the FT levels
PSYCHOLOGICAL
very little.
Lack of mental energy The ratio of subcutaneous over visceral fat
Decreased of cognitive functions decreases significantly with age and this indepen-
Decrease of the feeling of general well-being. dently of body mass index. These data suggest -
Irritability that elderly men, similar to hypogonadal men,
Inablity of concentration accumulate visceral fat preferentially. This fat
Depressive symptoms accumulation is the major cause of insulin resis -
Nervousness tance and the atherogenic lipid profile, this sug -
gests that obesity in elderly men is a more impor -
PHYSICAL tant health hazard than in young men. It is pro-
Generalized weakness bable that the atherogenic effect of androgen defi-
Lack of physical energy ciency is largely mediated via this fat accumula-
Decrease in muscle mass and strength tion. Androgen substitution decreases abdominal
Ostopenia fat mass and increases the insulin sensitivity
Gynecomastia [132,133]. As obesity is a cause of decreased free
Decreased body hair and total testosterone levels, it could be hypothesi-
Abdominal obesity zed that the decrease in testosterone levels in aging
males is the consequence of the increase in fat
VASOMOTOR mass. Multiple regression analysis showed howe-
Excessive sweating ver, that age and fat mass are independent deter-
Occasional hot flushes minants of free and total testosterone levels. Age is
Insomnia also accompanied by an important decrease of
Palpitation muscle mass and there exists a highly significant
correlation between muscle mass and FT levels,
SEXUAL
which persits after correction for age; moreover
Decrease in sexual activity
testosterone supplementation increases muscle
Loss of libido
mass [133].
Erectile dysfunction
Lengthening of refractory period It is evident, however, that the changes in body
Less-well defined quality of orgasm composition in elderly men are not uniquely the
Poor intensity of ejaculation consequence of the decreased FT levels but that
Decrease in volume of ejaculate other factors such as the somatopause and the
decrease in physical activity are important co-
determinants of these changes.
Bone mass decreases with age in both males and
% subjects age 50 yrs, 20 % at age 65 yrs, 40 % at
females even if osteoporosis manifests itself at a
age 70 yrs and ± 60 % in men over 70yrs old
later age in men than in women. There exists a
[128,129]. This might however be related to the
negative correlation between bone mass and tes -
aging process itself, as the hormonal differences
tosterone levels [134]. Senile hypogonadism is a
lost their significance after correction for age.
risk factor for hip fractures, although instability,
b) Body composition and others secondary to the reduction in muscle mass and
Aging is accompanied by a decrease of lean body strength, plays the major role.
mass (LBM) and an important increase in fat mass Aging is accompanied by a decrease in cognitive
[130,131] and, although aging itself is an impor- functions and androgen substitution improves spa-
tant determinant of body composition, plasma tes- tial abilities and mathematical reasoning[135]. As
tosterone levels are negatively correlated to fat far as memory is concerned, the age associated
mass, independently of age. Moreover, it has been impairment is evident, but the role, if any, of sex
shown that the abdominal fat mass is the major hormones in the loss of memory is questionable.

218
 II. DIAGNOSIS OF
HYPOGONADISM
1. THE HYPOTHALAMIC-PITUITARY-
GONADAL (HPG) AXIS
An understanding of the HPG axis is essential for
the proper hormonal evaluations and treatment of
androgen in the male (Figure 4).
2. DIAGNOSIS OF HYPOGONADISM
While hormonal status is usually evaluated by
measurements of serum hormone levels, determi -
nation of total testosterone has been regarded as
a universally accepted diagnostic method of
serum hormonal level to date. However, there are
increasing evidences that the serum concentration
of total testosterone may not be an accurate mar-
ker for the levels that exert their action on target
organs. Androgen deficiency can be better
demonstrated by measuring bioavailable testoste-
rone, i.e. free and albumin-bound fractions of cir-
culating testosterone. Therefore, measuring total
testosterone in aging men may not be adequate to
determine whether they have testosterone defi-
ciency because levels of circulating SHBG increa-
se with age [136] and that measurement of bio-
available or free fractions of testosterone is needed
to correctly diagnose hypogonadism in men over
age 50. However, this approach may not be ade-
quate in terms of cost effective diagnostic para-
digm, and has not been used in a large populations
of normal aging males as well as impotent men. To
make accurate diagnosis of hypogonadism, dia -
gnostic criteria using bioavailable testosterone
should be established in the future especially in
the aging male.
It has been suggested that measurement of testos-
terone is reserved to the patients with positive phy-
sical findings of hypogonadal symptoms. Howe-
ver, determination of total testosterone is stron-
gly recommended for all patients with erectile
dysfunction as the first line endocrine evalua-
tion because libido which is the principal symp-
tom of hypogonadism may be a nonspecific fin-
ding, and physical examinations is usually normal
in postpubertal hypogonadism.
219
When patients have low or borderline testostero -
ne level, repeat measurement of testosterone is
generally recommended because there is evidence
that a substantial number of impotent patients
found to have a low serum testosterone level at a
first determination had a normal level when the
test was repeated [15]. At this time, measurement
of bioavailable fraction of serum testosterone,
LH, and prolactin can be done to verify whether
there is low testosterone and what its causes
might be. Total testosterone and SHBG can be
checked for evaluation of bioavailable testostero -
ne levels [137]. It should be realized that direct
measurement of free testosterone by RIA using an
testosterone analogue may give falsely low free
testosterone levels[138], whereas the free andro-
gen index (100T/SHBG) is relatively unreliable
[139].
Measuring gonadotropin is necessary to avoid
missing many states of compensated testicular fai-
lure in which the serum testosterone level is usual-
ly normal [140,141]. One more reason for measu-
ring gonadotropin is to detect secondary hypogo-
nadism, which requires specific diagnosis and
treatment. It should be realized that in hypogona-
dism of the elderly males, plasma LH levels are
often not increased. Single determination of LH is
preferable in terms of cost effective approach.
However, it has been suggested that measurement
of both gonadotropins including FSH can be help-
ful in certain clinical situations.
In the secondary hypogonadism where the serum
LH and FSH levels are low or normal with conco-
mitant low level of serum testosterone, the evalua-
tion for identifying a cause of secondary hypogo-
nadism should be mandatory including serum iron
study, thyroid function tests, and an evaluation for
pituitary macroadenoma.(Figure 5. Algorithm)
The routine use of prolactin is less well defined
because isolated hyperprolactinemia is rare and
most patients with hyperprolactinemia have
abnormally low testosterone levels. Patients who
present the symptoms of hyperprolactinemia such
as decreased libido and headache with depressed
testosterone levels, are suggestive of prolactin
abnormality.
Figure 4: Hormonal control of testosterone secretion: The hypothalamic-pituitary-gonadal (HPG) axis consists of a closed-
loop feedback control mechanism. The hypothalamus is a pulse generator for the cyclic secretion of pituitary and gonadal hor -
mones. The portal vascular system provides a direct communication for pulsatile delivery of hypothalamic hormone to the
pituitary gland, avoiding the systemic circulation delete. The function of GnRH is to stimulate the secretion of LH and FSH
from the anterior pituitary. LH stimulate testosterone secretion while FSH stimulate Sertoli cell function with production of
inhibin. Testosterone is a strong regulator of its own production through negative feedback mechanism on the HPG axis and
inhibin is important in the feedback regulation of FSH.

220
 HISTORY AND PHYSICAL EXAMINATION

NORMAL POSITIVE FINDINGS APPROPRIATE ENDOCRINE TESTING

TESTOSTERONE
PROLACTIN
THYROID STUDY
CORTISOL

TOTAL TESTOSTERONE NORMAL OTHER TESTS FOR IMPOTENCE

ABNORMAL OR
BORDERLINE
NORMAL

REPEAT TOTAL TESTOSTERONE,

NORMAL TESTOSTERONE
SHBG,
LH,
PROLACTIN EVALUATION FOR
AND PROLACTIN ELEVATION HYPERPROLACTINEMIA

LH
LH DECREASE OR
ELEVATION
NORMAL

TESTS FOR IDENTIFYING

TESTOSTERONE NO ENDOCRINE ETIOLOGIES OF SECONDARY
TREATMENT DISORDER HYPOGONADISM
(I.E. IRON STUDY, THYROID FUNCTION
TESTS, G NRH S TIMULATION TEST)

ENDOCRINE RELATED
DISORDER

SPECIFIC TREATMENT
Figure 5: Basic diagnostic algorithm for hormonal evaluation in men

221

C. TREATMENT
I. TESTOSTERONE EFFECTS ON
THE BODILY SYSTEMS IN MALE
Hypogonadism in men is associated with decrea -
sed bone mineral density and decreased muscle
mass and androgen replacement certainly ame -
liorates these symptoms. Apart from its evident
effects on libido, testosterone improves also
cognitive functioning of men, notably of spatial
abilities. Both testosterone levels and bone mine-
ral density decline with aging. Indices of bone
mass have been and plasma testosterone levels
have been found to be positively correlated. Hypo-
gonadism is a risk factor in hip fracture in aging
men. The first data on the effects of androgen
administration to aging men on bone mass are cer-
tainly encouraging [142]. The cause of the decrea-
se in muscle mass and strength in elder men is pro-
bably multifactorial, with a decrease in physical
activity and a decrease in growth hormone as
contributing factors. The first studies of the effects
of androgens on muscle mass and/or strength are
encouraging particularly since the administration
of androgens may also decrease fat mass.
There is male predominance in cardiovascular
morbidity/mortality compared to premenopausal
women which is generally attributed to the effects
of androgens on lipid metabolism as one of the
risk factors in cardiovascular disease. But it has
been found that men suffering from cardiovascu -
lar disease have lower-than-normal androgen
levels. The explanation could possibly lie in the
so-called syndrome X, the association that has
been found between visceral obesity, hyperlipide-
mia, hypertension and cardiovascular disease and
non-insulin dependent diabetes mellitus. Men with
a large degree of visceral obesity tend to have low
androgen levels. So, in reality, it could rather be
the lowered androgen status, which explains the
higher cardiovascular disease / mortality rate in
middle aged men [143]. There are some reports
now that androgen administration indeed
decreases visceral obesity [144].
Prescribing androgens to aging men is considered
a responsible decision by most physicians. Most
222
experts agree that in cases of evident hypogona-
dism in the aging male, testosterone replacement
is as much warranted as in younger men. In all
likelihood not only libido will improve but also
bone mineral density and muscle mass therewith
helping the locomotion of the aging male. Side
effects are acceptable [145]. So far there is no
solid evidence that there is a relationship bet -
ween circulating androgens and prostate disease
[146]. This notwithstanding, androgen administra-
tion to men above 50 years requires careful moni-
toring of the prostate.
Nevertheless, epidemiological studies show that
hypogonadal men are at higher risk of cardiovas-
cular incidents than normal men and there exists
generally an inverse correlation between testoste-
rone levels and the atherogenic lipid profile, athe-
romatosis [147,148] or the degree of coronary
artery stenosis [149], whereas androgens supple -
mentation within the physiological range, nor -
malizes the lipid profile, probably via increasing
insulin sensitivity and decreases Lp(a) levels
[150], a well known risk factor for atheromathosis.
Notwithstanding the apparently favorable effects on
the lipid profile and atherogenesis, the testosterone-
mia is not correlated with the risk of cardiovascular
mortality [151,152], suggesting that besides the
effects on the lipid profile, testosterone has direct
unfavorable effects on the blood vessels [153,154].
Moreover, testosterone has complex effects on both
coagulation and fibrinolysis. It is, finally, evident,
that supraphysiological levels of testosterone, non
aromatizable anabolic steroids or alpha alkylated
androgens are clearly atherogenic and often cause
cardiovascular accidents [155].
II. TESTOSTERONE TREATMENT
IN IMPOTENT PATIENT
1. MECHANISM OF HYPOGONADISM IN THE
PATIENTS REFERRED FOR IMPOTENCE
In 155 impotent patients with total serum testoste-
rone < 300 ng/dl coming from 5 different studies
[12-14,16,18], serum LH was low or normal in 98
(hypogonadotropic hypogonadism) and it was
elevated in 57 (peripheral hypogonadism). The
most frequent identified causes were Leydig cell
failure, and, in a minority of the cases, hyperpro-
lactinemia or hemochromatosis. In many cases no
organic cause was found. For example in the 8
cases with markedly decreased serum LH (< 2.5
mIU/ml) of Buvat and Lemaire [18], 3 times the
hypogonadism resulted from a pituitary adenoma,
but in the 5 other cases it seemed to result from a
functional hypothalamic abnormality. Such cases,
in whom clomifene citrate was able to increase
serum testosterone to normal, have also been
reported by Guay et al [156]. They could result
from psychosomatic mechanisms like stress and
depression that are often present in impotent
patients and can induce a mild hypogonadotropic
hypogonadism [157,158]. The reduction in
sexual activity could also play a role in the
decreased testosterone levels of the impotent
patients since several studies have observed an
increase in testosterone secretion following sexual
activity in men [159-162]. Lastly the variability of
serum testosterone could be responsible for some
false hypogonadism. Indeed 6 of the 22 impotent
patients of Maatman and Montague [15] who were
found a low serum testosterone level at a first
determination had a normal level when the test
was repeated. The same was observed by Buvat
and Lemaire in 39 of their 98 cases, thus in 35% of
the cases of these 2 series.
2. C ANDIDATES FOR TESTOSTERONE
TREATMENT
a) Relatively young patients with erectile dys -
function
Impotent patients either with low level of testos -
terone or borderline normal level can be candi -
dates for the testosterone treatment. With respect
to exact serum level of testosterone, there is a pro-
blem with establishing a universal lower limit for
normal serum testosterone. Serum testosterone
levels vary based upon time of day that the sample
is obtained, method of preparation of the sample
and the antibody utilized in the RIA assay. These
variations make it impossible to accurately esta-
blish a universal lower limit for normal testostero-
ne level.
b) Elderly men with hypogonadism
High prevalence of hypogonadism and sexual
dysfunction is observed in men over age of 50.
Impotent patients with hypogonadism may expe-
rience a decline in not only sexual function but
223
also physical capacity. Also they may experience
various symptoms related to hypogonadism; such
as nervousness, depression, impaired memory,
inability to concentrate, easy fatigability, insom-
nia, hot flashes, periodic sweating, reduction of
muscle mass and power, aching bones, and sexual
dysfunction. Treatment of hypogonadism in the
aging male has a special clinical value. In addi -
tion to sexual function, testosterone treatment
produce numerous beneficial effects on whole
body systems including body composition and
sense of well being. Therefore, physicians are
encouraged to prescribe testosterone preparations
in the older patients with hypogonadism.
1) Elderly men with clearly decreased plasma tes -
tosterone levels:
Age-related decreases in androgen level vary
widely between the individuals. The favorable
effects of hormonal replacement therapy can be
expected in men with clearly decreased serum
level of testosterone [163]. The reported propor-
tion of the population who are considered hypogo-
nadal differs between several studies and depends
on how the term hypogonadism is defined. The
proportion of the patients who fit these criteria was
intensively discussed on chapter A-II. “Hypogona-
dism in aging male and its prevalence ”. The crite-
ria of the serum levels of testosterone for hypogo-
nadism in the aging male might be different from
the reference values of young men. Empirical cri-
teria of hypogonadism in which testosterone sup-
plementation might produce beneficial effects in
the aged men would be higher than that of young
men.
2) Elderly men with symptoms that are associated
with hypogonadism, but normal testosterone
levels and those with marginally lowered testos -
terone levels:
Testosterone supplementation might be considered
in these situations, although this has been debated.
The rationale supporting its use in such patients is
as follows:
• Elderly men with symptoms but plasma testos -
terone levels in the normal range:
Frequently, men are encountered who do not meet
the criteria for diagnosis of hypogonadism by
plasma testosterone determinations, but who
respond to testosterone treatment with improve-
ments in physiological and biochemical parame-
ters. The reasons for this have not yet been fully
elucidated, but the explanation may be similar to
that for men with marginally lowered plasma tes-
tosterone levels (see below).
• Elderly men with marginally lowered plasma
testosterone levels:
There is increasing evidence that men in this cate-
gory respond to testosterone treatment [164]. The
rationale for supporting hormonal treatment in
these men is that the plasma level of testosterone
does not reflect the intensity of androgenic
effects in target tissues. Moreover, despite plasma
testosterone being in the normal range, its effects
in target tissues may not be adequate. In such
situations, it is possible that testosterone treatment
may produce desirable effects, the rationale for
which includes the following:
➦ Classical parameters such as the plasma testos -
terone level do not always accurately detect
hypogonadism. Therefore, a man with a total
testosterone level in the normal range may still
be considered to have hypogonadism in terms
of androgen actions in the target tissues.
➦ Since the definition of hypogonadism is not
well established, clinicians may miss the pro-
portion of the population in whom testosterone
treatment may be of benefit. There is increa-
sing evidence that testosterone supplementa-
tion in aging men has a great chance of impro-
ving age-related symptoms, especially in the
hypogonadal state, and this may be particularly
relevant to men with borderline biochemical
abnormalities [165].
➦ There is evidence in animal studies that the sen-
sitivity to androgens may be affected, decrea-
sing the effect of testosterone in target tissues
[166,167].
From these observations, it might be proposed that
even though plasma level of testosterone is not in
the abnormal range, hypogonadism may still exist.
In view of all these situations in which the plasma
level of testosterone may not accurately reflect
androgen actions in the body, it is evident that elder-
ly men with testosterone levels in the normal range
could be carefully considered for hormone supple-
mentation. Questions that need to be answered in
such cases are whether exogenous testosterone pro-
duces down-regulation of androgen receptors in
224
those with normal testosterone levels, and what
effects in target tissues are achieved by increasing
plasma testosterone levels in older men with mild
degrees of androgen insensitivity.
3. EFFECTS OF TESTOSTERONE ON SEXUAL
FUNCTION
a) Effects of testosterone treatment on the sexual
function of the patients with hypogonadism
primarily referred for hypogonadism who are
usually relatively young:
Many studies with a control group receiving a pla-
cebo have shown that in such men testosterone
constantly and significantly increases sexual
interest and arousal, the frequency of sexual
acts, and nocturnal and morning erections
[24,25,33,168-172]. Conversely no study was able
to objectively demonstrate an improvement of coi-
tal erections, a concept that is methodologically
more difficult to prove. The effect of testosterone
on sexual function appear to be clearer in the
patients with more severe hypogonadism.
b) Effects of testosterone treatment in impotent
patients with hypogonadism primarily referred
for impotence:
These effects are markedly less clear-cut and
constant than in the young patients primarily
referred for hypogonadism. On the other hand
very few controlled studies were done in hypogo-
nadal men referred for impotence.
1) Marked hypogonadism
Six studies reported on the results of androgen the-
rapy in men referred for impotence and in whom
serum testosterone was found consistently
< 300 ng/dl or 11.5 nmol/l [14,16,18,173-175].
Several modalities of androgen therapy had been
used, including injections of testosterone esters or
in one study of chorionic gonadotropins (which
stimulate testosterone secretion by the Leydig
cells) when serum LH was not elevated [18], and
oral administration of testosterone undecanoate or
in one study of methyl-testosterone [173]. No
study was placebo controlled. The total number of
treated patients was 162. Only 60 of the 162
(37%) had definite erections (Table 2). Sexual
interest was improved in some additional cases
without simultaneous improvement of erections.
For example, 5 of the 23 patients of Morales et al
[175] had improved libido in addition to the 10
improved in both the erections and the sexual
Table 2: Positive effect of androgen therapy in 162 men referred for erectile dysfunction
AUTHORS NO. SUBJECTS
Keogh et al 22
Kropman et al 15
Morales et al (1994) 27
Morales et al (1997) 23
Rakic et al 31
Buvat and Lemaire 44
Total 162
T: Testosterone HCG : Human Chorionic Gonadotropin
interest. Guay et al [176] also reported a placebo-
controlled trial of clomifene citrate in 17 patients
with impotence and functional hypogonadotropic
hypogonadism. They found that nocturnal penile
tumescence and rigidity testing, as well as the
number of intercourse and the sexual satisfaction
index significantly increased on clomifene compa-
red to placebo in the younger subgroup.
2) Mild hypogonadism:
Nankin et al [177] found that testosterone cypio -
nate had significant, although modest, effects on
the sexual function of impotent men with serum
testosterone levels within the range of 300 to 400
ng/dl. Conversely, using chorionic gonadotropins,
or testosterone undecanoate when the serum LH
level was high, Buvat et al [19] were able to defi-
nitely improve the erectile function of only 1 out
of 21 impotent men with decreased free testostero-
ne and normal total serum testosterone and 2 of 19
impotent men with decreased non SHBG-bound
testosterone.
Reason for this low effectiveness of testosterone
treatment in the impotent men with mild hypogo -
nadism:
Young hypogonadal men where testosterone treat-
ment produce significant effects on sexual func-
tion, are rarely referred for impotence since their
hypogonadism was diagnosed and treated from
puberty. The lesser correlation between testostero-
ne and sexual behavior in the often older patients
referred for erectile dysfunction could result from
the fact that sexual behavior progressively
becomes less dependant on hormones in men, like
in animals, in proportion to time of exposure to
androgens and to previous sexual experience.
TYPE OFANDROGEN NO. OF SUBJECTS
IMPROVED (%)
T pellets 11 (50%)
NA 2 (13%)
Methyltestosterone 2 (7%)
T Undecanoate 14 (61%)
T propionate 15 (48%)
HCG, T Undecanoate 16 (36%)
60 (37%)
Moreover, in some men with erectile impotence,
low testosterone could be more a consequence of
impotence rather than its cause. As previously dis-
cussed, low testosterone could result from reduc-
tion in sexual activity, stress and depression, all of
which can inhibit testosterone secretion [158].
Lastly low testosterone is often only one of seve-
ral consequences of aging, supported by the high
rate of associated other organic abnormalities in
the series of 60 impotent patients with hypogona-
dism thoroughly investigated by Buvat and
Lemaire [18]: 25 (41,6%) could be classified as
vasculogenic according to significant arterial
abnormalities in 17, a pattern of veno-occlusive
dysfunction at pharmaco-cavernosometry in 8,
while 4 had in addition significant neurological
abnormalities. Such multifactorial cases were also
reported by Kropman et al [16].
3) Effects of testosterone treatment in the impotent
patients with normal testosterone levels:
Although testosterone treatment has been widely
used for decades in eugonadal impotent men, very
few studies have compared its effects to those of a
placebo according to double-blind designs. Benkert
et al [178] did not find any superiority of testoste-
rone undecanoate over placebo in such impotent
men. However, serum testosterone could have not
been really increased because of the feedback
control, operational in these men. Conversely,
Buvat et al[38] found a borderline significant super-
iority of injections of chorionic gonadotropins (2 x
5000 IU per week) over placebo in increasing the
number of satisfying intercourse of eugonadal
males with erectile impotence or low sexual desire.
In addition, Carani et al [24] observed a modest but
225
significant increase in the extent and duration of the
nocturnal penile rigidity of eugonadal impotent
men following injection of supraphysiological
doses of testosterone enanthate. O’Carroll and
Bancroft [37] also reported on a significant but
modest increase in sexual interest following tes-
tosterone treatment in males with low sexual inter-
est and erectile dysfunction, but this improvement
did not result in an increase in the number of
sexual intercourse. In a single blind study compa-
ring injections of high doses of testosterone with a
placebo in normal young males, Anderson et al
[36] also observed a significant increase in sexual
interest and arousal without subsequent increase in
the number of intercourse. Lastly Moss et al [179]
reported on a significant increase in the number of
sexual intercourse and orgasms, and in the sexual
satisfaction, in male anabolic steroid abusers com-
pared with other athletes not using steroids.
These data are consistent with a modest stimula -
tory effect of increasing the serum testosterone
level with testosterone injections upon sexual
interest of the eugonadal men, including those
with low sexual interest and perhaps erectile dys-
function. But this effect is too small to have a the-
rapeutic interest, especially in erectile dysfunction
III. AVAILABLE PREPARATION OF
TESTOSTERONE
Testosterone has been used to forestall the effects
of aging in middle-age men for many years.
Brown-Sequard reported in 1889 that a self-admi-
nistered watery testicular extract improved his
work capacity and overall vigor. Testosterone,
however, was not isolated as a substance until the
mid-1930’s, but since that time attempts have been
made to physiologically replace testosterone and
raise testosterone levels to normal using exoge-
nous testosterone and its metabolites. These agents
are also used in excessively high doses to improve
athletic performance and strength [180].
Because androgen replacement therapy is necessa-
rily of long duration and testosterone’s serum half-
life is short, pharmacologic preparations have
been developed to provide sustained testosterone
blood levels and prolong androgenic activity. The
ideal testosterone replacement agent should:
226
1) mimic diurnal patterns of endogenous hormone
secretion,
2) produce physiologic levels of not only testoste-
rone but also its metabolites of dihydrotestostero-
ne (DHT) and estradiol (E2),
3) should be well tolerated, comfortable, conve-
nient and cost effective.
Agents available currently include oral, sublin-
gual, implantable testosterone pellets, intramuscu-
lar, and transdermal agents (Table 3).
Table 3 : Available testosterone preparations
PREPARATION USUAL DOSAGE
ORAL
Methyl Testosterone 10 –15 mg daily
Fluoxymesterone 5 mg 1-4 times daily
Testosterone undecanoate 120-240 mg daily
PARENTERAL
Testosterone cypionate 200 mg Q 2 wk
Testosterone enanthate 200 mg Q 2 wk
TRANSDERMAL
Androderm 1 - 2 patch daily
Testoderm TTS 1 patch daily
Testoderm (Scrotal) 1 patch daily
Oral agents for testosterone replacement are clear-
ly convenient and comfortably used. Oral testoste-
rone, however, is rapidly absorbed from the GI
tract and circulated through the portal blood [181].
Because of this portal circulation and rapid hepa-
tic metabolism, only a small volume of testostero -
ne is circulated and only serum testosterone
metabolites are raised. Most importantly, these
agents have been reported to produce significant
long-term hepatic toxicity. Oral testosterone does
not reproduce the circadian pattern of testosterone
production of the testes nor does it achieve normal
physiologic levels of dihydrotestosterone or estra-
diol. As to oral preparations, only testosterone-
undecanote is orally active, due to its partial
absorption via the lymph, thus escaping first pass
hepatic inactivation. Testosterone undecanoate is
available in areas other than the US [175]. The
usual dose is 120-240 mg/d dived over 2 of 3
doses. Absorption and plasma levels achieved are
rather variable but others reported that it restores
serum testosterone levels and improves libido in
hypogonadal men. Plasma estradiol levels also
rise to physiologic levels with oral testosterone
undecanoate treatment [175]. The most effective
of these oral agents are the 17 alpha alkylated tes-
tosterones such as methyl testosterone. These may
be administered either orally or bucally. Because
of their high cost, minimal potency, and risk of
hepatotoxicity, these kinds of oral androgens
should not be used for androgen replacement in
hypogonadal men.
Parenteral preparations for intramuscular testoste-
rone replacement are clearly effective in increa-
sing serum testosterone levels, but produce signi-
ficant elevations in serum testosterone levels
immediately after administration and a very low
nadir before repeat injection. Intramuscular andro-
gens do not provide the normal circadian pattern
of testosterone and the injections are somewhat
uncomfortable [182]. Similarly, while restoring
serum DHT levels, estradiol levels may be exces-
sive in patients with high testosterone levels after
injection. Intramuscular 17 beta hydroxyl esters of
testosterone are widely used. These esters of tes-
tosterone lack inherent androgenic activity and
must be hydrolyzed to testosterone before they
become active. Parenteral testosterone is usually
administered in an oil-based vehicle such has cot-
tonseed or sesame oil. The 17 beta hydroxyl esters
of testosterone include the short acting testostero-
ne propionate, and longer acting testosterone
enanthate and cypionate. Because of the short
activity of testosterone propionate, it is impractical
to use as it must be injected every second day to
maintain serum testosterone levels. In hypogona-
dal men, however, testosterone enanthate and
cypionate may be administered every 2-3 weeks to
maintain normal average testosterone levels.
There are, however, surges in testosterone from 1-
2 days following administration with supraphysio-
logic serum levels as high as 1400 ng/dl which
then decline over 14-21 days reaching a nadir in
approximately 21 days. Because of these signifi-
cant peaks and valleys in serum testosterone,
patients may have mood swings and significant
changes in sexual function. Long acting parenteral
testosterone may be administered in 200, 300, or
400 mg every 2-4 weeks. 200 mg injections main-
tain normal testosterone levels for approximately
two weeks while 300 mg levels will maintain tes-
227
tosterone levels in the eugonadal range for
approximately 3 weeks. 400 mg doses, while
obtaining higher peak values, will not maintain
eugonadal levels beyond the 3 week limit. These
agents in hypogonadal men produce an improve-
ment in libido, sexual function, potency, energy
level, and mood if these abnormalities are caused
by androgen depletion. Reports of increased
sexual aggressiveness and overall aggressive
behavior during peak levels of injectable testoste-
rone levels have been reported [182]. Careful
counseling about these mood and behavioral
changes in patients undergoing injectable testoste-
rone therapy are essential. These adverse effects
are, however, rare and testosterone enanthate is the
most widely used agent for exogenous testostero-
ne replacement in the US. It is cost effective and
convenient.
However, there is good evidence that injectable
testosterone preparations induce plasma levels of
testosterone, which are supraphysiological, and
may be a cause of important side effects such as
an atherogenic lipid profile, insulin resistance,
polycythemia, sleep apnea, fluid retention, hyper-
tension. Furthermore, supraphysiologic testoste -
rone levels with testosterone result in aromatiza -
tion to estradiol or its esters which may produce
gynecomastia or erectile dysfunction. These side
effects are most pronounced with supraphysiolo-
gic doses in eugonadal men taking androgen sup-
plements. Hence it is important when administe-
ring testosterone to avoid even transient supraphy-
siological levels. As a result of these concerns,
transdermal patches and oral undecanoate form
of testosterone, notwithstanding their high cost,
will probably become the treatment of choice
because they avoid supra-physiologic levels and
restore the normal diurnal testosterone pattern.
They have, moreover, the advantage that, when
side effects occur, the patches can be immediately
removed.
Transdermal testosterone is the newest approved
replacement modality and is currently available as
a scrotal or non-scrotal patch [172, 183]. Trans-
dermal administration utilizes unmodified testos-
terone and is an alternative to intramuscular or oral
medications. These transdermal patch systems
provide normal testosterone levels with diurnal
variations in a physiologic fashion when the
patches are applied prior to bedtime. Peak testos-
terones are achieved in the early morning with a
nadir prior to bedtime. While the scrotal patch
(Testoderm®) requires scrotal shaving weekly and
increases DHT levels beyond the normal range,
normal physiologic serum testosterone ranges can
be obtained. The non-scrotal transdermal patch
(Androderm®), however, also maintains a diurnal
serum concentration curve with normal testostero-
ne levels and normal estradiol and dihydrotestos-
terone levels. Because the testosterone levels do
not increase beyond normal as with intramuscular
testosterone, the mood and aggressiveness occa-
sionally occurring with intramuscular testosterone
should not be seen with transdermal preparations.
While long-term studies are still unavailable on
these issues, a smoother more natural serum tes-
tosterone level can be obtained with these prepara-
tions. Clearly, transdermal systems are of higher
cost and in some patients inappropriate because of
compliance and motivation. Clinical studies with
transdermal preparations have, however, demons-
trated improved sexual function, libido, and noc-
turnal penile tumescence (NPT) response, with
normal hematocrit, lipid, and PSA levels. Local
side effects of dermatitis make these agents inap-
propriate for some men.
Administration of testosterone by long acting
implantable tablets has been investigated in Euro-
pe [180]. These subcutaneous capsules are fused
pellets of unmodified testosterone and can be
implanted every 4-6 months. Because these pel-
lets require percutaneous trochar or minor surgical
administration, they are infrequently used. Further
development of these pellets to decrease invasive-
ness of administration may lead to their use for
long term therapy.
IV. COMPLICATION OF TESTOSTE-
RONE SUPPLEMENTATION
The risks of this therapy depends on the age and
medical condition of the patient and the type of
testosterone preparation used. Not all androgens
are metabolized the same and each may have dif -
ferent side effects. For example, testosterone can
be metabolized to estrogen whereas other prepara-
tions of DHT that do not have this capability will
not have any feminizing effects. This summary
228
will focus only on the adult male treated with
parenteral or transdermal testosterone and not with
any oral androgen preparations.
Testosterone therapy in adult men can cause an
increase in red blood cell production, stimulate
prostate growth, exacerbate sleep apnea, alter
hepatic function and induce gynecomastia and
acne.
1. LIPID PROFILE
There is no strong supporting data that the major
serum cholesterol profiles are adversely affected
by exogenous androgen treatment [51,184]. This
is most likely mediated through the androgen
effects upon serum lipoproteins but other factors
such as vascular reactivity may also play a role.
There is limited long term data in man but all avai-
lable data demonstrate little or no adverse effect of
androgen replacement upon serum cholesterol
levels in aged men. All studies reported to date
demonstrate either no change or even a decrease in
both total cholesterol and low-density lipopro-
teins. However, androgens was reported to be
associated with decreases in HDL cholesterol and
apolipoprotein A-I levels and reduced LDL cho-
lesterol and apolipoprotein B levels
2. ERYTHROPOIESIS
Androgens are known to stimulate an increase in
the hematocrit and hemoglobin levels [185] due
to stimulation of erythropoietin production [186].
The increase in erythropoiesis in these aged
patients may be exacerbated by sleep apnea and an
elevated body mass which may necessitate
changes in the way the testosterone is administe-
red. It can be minimized by using lower and more
frequent dosing, such as with transdermal prepara-
tions. Polycythemia may increase blood viscosity
and lead to diminished cerebral blood flow with
the possibility of a cerebrovascular event [187].
Some patients may even require phlebotomy to
reduce the erythrocytosis [188].
3. SLEEP APNEA
Sleep apnea can be exacerbated by exogenous
testosterone therapy [189] and, with the additio-
nal possibility of erythropoiesis, decreased cere-
bral blood flow may result. The mechanism of
this disordered breathing could be an increased
sensitivity to hypoxia.
4. PROSTATE
Both benign prostatic hyperplasia and prostate
cancer are highly prevalent diseases in older men.
The prostate is dependent upon androgens for nor-
mal growth and function. Prostate volume
decreases with castration and is restored by andro-
gen replacement. In addition, castration has a tem-
porary palliative effect upon prostate cancer. The
limited studies performed to date have not
demonstrated any significant adverse effect of
androgen replacement therapy upon the pros -
tates of older men. However, there may be possi-
bilities that androgens play a role in promoting
prostatic growth and, therefore, the treatment of
the aging male with exogenous androgens remains
a concern vis a vis the development of BPH and
prostate cancer. The presence of a clinical prosta -
tic carcinoma is an aboslute contraindication for
androgen supplementation and should be exclu -
ded by rectal examination and PSA measure -
ment, eventually complemented by rectal echo -
graphy.
While there are two studies in the literature that
demonstrate an increase in PSA with androgen
therapy [164,190], there are about a dozen or so
studies that do not demonstrate any increase in
PSA. However, caution must be exercised in the
aging male and a baseline elevation in PSA or
elevation in PSA following therapy may indicate
an underlying malignancy that needs to be eva -
luated [191,192].
5. HEPATOTOXICITY
Liver damage and occasionally hepatomas have
been associated with the use of oral 17 alpha-
alkylated androgens but not parenteral or transder-
mal preparations [193]. The main effect on hepatic
function occurs at the site of the transport of meta-
bolites from the hepatocyte to the bile. Under-
lying hepatic disease may reduce the metabolism
of estrogens formed from parenteral androgens
and lead to gynecomastia. The elevation in the
liver enzymes are reversible once the androgens
are stopped [194].
6. GYNECOMASTIA
While common in children after testosterone sup-
plementation, gynecomastia is rare in adults unless
extremely large doses of testosterone are adminis -
229
tered. Since estrogens are formed from testostero-
ne peripherally in the adipose tissue, it is metabo-
lized in the liver. A normally functioning liver is
capable of metabolizing the estrogen unless there
is preexisting liver damage. Therefore, the pre-
sence of gynecomastia in an adult following tes-
tosterone supplementation may be an indicator of
underlying hepatic disease [195].
7. ACNE
The development of acne with exogenous testoste-
rone therapy is reversible once the testosterone
injections are stopped [194].
V. CLINICAL RECOMMENDATIONS
FOR TESTOSTERONE
SUPPLEMENTATION
The discussion will focuses mainly on hypogona -
dism in aging male as guidelines for impotent
patients are similar to those of aging male.
1. PROPOSED CANDIDATE FOR
SUPPLEMENTATION
It is evident that men with subnormal or borderli-
ne normal testosterone levels are candidates for
androgen substitution. Among the clinical signs,
decrease in muscle mass and strength, decrease in
bone mass and increased abdominal fat mass are
most easily identified, whereas clinical symptoms
such as decrease in libido, memory loss or decrea-
se in general well being are more difficult to
objectivate.
The final decision whether to treat or not will
depend upon the balance between expected bene-
fits and possible serious side effects. If testostero-
ne therapy is clearly indicated, it can be given to
enhance the quality of life of patients, even if they
are of advanced age [141].
2. EXPECTED OUTCOME
Recent studies have shown that testosterone sup-
plementation in aging men provides beneficial
effects on bone density and bone turnover, muscle
mass and strength, and body composition, as well
as possibly enhancing their sense of well being,
energy level, sexual function and libido [51,196].
Even though older men may have successful erec-
tions, their sexual desire, mood and general beha-
vior may be impaired, and these aspects of sexual
function can be expected to improve with testoste-
rone supplementation. Furthermore, the intensity
of orgasms and ejaculations might also be expec-
ted to improve [165].
3. GOAL OF TESTOSTERONE SUPPLEMENTA-
TION
The goal of testosterone supplementation in the
aging male is less well defined, but may be sum-
marized as follows:
• Elderly men should benefit from the disappea-
rance of symptoms related to hypogonadism
with hormonal supplementation.
• Serum levels of testosterone and its metabo-
lites, such as DHT and estradiol, should increa-
se with exogenous testosterone supplementa-
tion. There is some debate over the target level
of testosterone during supplementation. Weks-
ler [197] advocates a serum level of between
240 and 460 ng/dl as a reasonable target, whe-
reas others [198] have suggested the desired
level is between 400 and 900 ng/dl.
• The hormonal deficiency in the aging male is
partial, and most men maintain their secretory
capacity to some extent. Ideal supplementation
with exogenous testosterone will maintain pre-
existing testosterone secretion, and not sup-
press the hypothalamic-pituitary-gonadal axis.
In the case of secondary hypogonadism caused
by hypothalamic or pituitary dysfunction, the
underlying disease should be treated before ini-
tiating hormonal supplementation.
4. ASSESSMENT AND DIAGNOSTIC TESTS
a) Medical history, physical examination and
blood tests
A full medical history looking for the presence of
diabetes mellitus, hypertension, smoking, endocrine
disorders, heart disease, sleep-related apnea, and
other medications should be undertaken when tes-
tosterone supplementation is considered. The physi-
cal examination and tests conducted prior to initia-
ting testosterone therapy should include measure-
ment of body weight, pulse rate, blood pressure,
complete blood cell count, urine analysis, and blood
chemistry analysis. The physical manifestations
related androgen deficiency also should be assessed.
230
b) Plasma hormone determinations
Total testosterone has been regarded as accepted
single determinant of serum hormonal level. When
patients are found to have a testosterone level
which is low or at the lower borderline of normal
range, repeat testosterone measurement is general-
ly recommended. At this time measurement of bio-
available fraction of serum testosterone, LH, and
prolactin can be done to clarify the level of scree-
ning testosterone.
In secondary hypogonadism where the serum LH
level is low or normal with concomitant low level
of serum testosterone, further the evaluation for
identifying a cause of hypogonadism is required.
c) Prostate evaluation
It is generally accepted that the most effective
method for early detection of prostatic cancer is
the combination of prostate-specific antigen
(PSA) determination and digital rectal examina-
tion (DRE) [199]. However, in a study in which
ultrasound-guided prostate needle biopsy was per-
formed in 77 patients with low total or free testos-
terone levels but normal PSA levels (4 ng/ml or
less) and DRE results, prostatic cancer was identi-
fied in 14% of the entire group and 29% of those
older than 60 years [200]. Thus, the possible pre-
sence of prostatic cancer should still be borne in
mind despite normal PSA and DRE findings. Fur-
thermore, there is a possibility that exogenous
androgen administration may aggravate the pre-
existing prostate cancer. Therefore, it has been
recommended that TRUS (with or without biopsy
of the prostate) is performed before starting hor-
monal therapy in the men over the age of 60. Since
screening TRUS is unreliable, and random biopsy
unproven, this practice cannot be enthusiastically
embraced. Further information on prostatic assess-
ment and hormonal treatment of men with low tes-
tosterone levels is required
d) Other recommended tests
Questionnaires are available for evaluating subjec-
tive symptom score for hypogonadism, the patient’s
sense of well-being and sexual function in the aging
male. In addition, physicians may measure the
waist-hip ratio for the evaluation of body composi-
tion. Lipid profile including triglyceride, high den-
sity lipoprotein cholesterol (HDL-C), total choleste-
rol and liver function tests could be recommended
to monitor risk to patients.
5. F OLLOW-UP
Periodic follow-up during supplementation is
mandatory to detect adverse reaction related to
treatment as early as possible. However, the inter-
val of appropriate follow-up is not well defined. In
his paper describing 10 years’ experience with
administration of oral testosterone undecanoate,
Gooren [201] followed his patients at 3-monthly
intervals during the first year of treatment. After
that, follow-up was performed every 6 months for
the following 3 years. Other protocols[165] inclu-
de a follow-up interval of 6 months for the first 2
years after initiating treatment.
The first follow-up should take place within 3
months after initiating treatment, to evaluate whe-
ther the testosterone level is rising to the desired
level, whether the patient has developed any adver-
se effects (e.g. elevation of PSAand acne), how the
patient feels about testosterone supplementation,
and how symptoms have improved with supple-
mentation. At this time, physicians can measure
serum PSA and testosterone levels, perform a phy-
sical examination including DRE, and ask the
patient to fill out questionnaires, if required.
Subsequent follow up will take place every 6
months for next 2 years to continuous monitoring
of clinical symptoms and adverse effects of treat-
ment. Laboratory tests consist of urinalysis and
complete blood cell counts, as well as DRE and
PSA for prostate evaluation. In addition, physi-
cians may assess the patient’s liver function, blood
glucose level and serum lipid profile.
It is suggested that at least for 1. 5 to 2 years moni-
toring is needed to assess PSA Velocity (PSAV), a
highly specific marker for the presence of prostate
cancer, and that three PSA measurements might
be optimal during this period to minimize short-
term within-individual variability between measu-
rement[202]. Considering that occult prostate can-
cer can be missed in men with normal DRE fin-
dings and normal PSA levels, physicians should
do everything possible to detect preclinical carci-
noma of prostate. In this regard, measurement of
PSAmust be recommended at 6 months interval of
treatment, especially in men over the age of 40.
After this period, annual follow up is recommen-
ded. When supplementation ceases less than 6
months after initiation of testosterone treatment,
measurement of PSA is recommended even after
231
discontinuation of treatment. Any increase of PSA
with more than 0.75 ng/ml in two consecutive
controls requires further exploration, whereas an
increase of the hematocrite over 50 % or unfavo-
rable changes in the lipid profile requires a reduc-
tion of the substitutive dose or discontinuation of
treatment. It is evident that androgen substitution
should be continued lifelong, unless side effects
appear or the patient is no longer concerned by the
signs and symptoms of hypogonadism
VI. RECOMMENDATIONS
I. PATHOPHYSIOLOGY OF HYPOGONADISM
The association between hypogonadism and
erectile dysfunction is not clearly defined.
There is a direct relationship between serum
androgen levels and libido, but the association
of androgens and erectile function is more com-
plex. Nocturnal erections have been related to
testosterone levels in several studies. On the
other hand, erections induced by visual stimuli
or fantasies, are only partly androgen-depen-
dant. In addition to libido and erectile function,
testosterone increases the ejaculate volume.
The threshold value of serum testosterone in
relation to sexual activity appears to be rather
low. It is generally believed that the effects of
testosterone on sexual function are adequate at
the lower limits of the normal adult range.
Serum testosterone levels decline with age.
Similarly, prevalence of erectile dysfunction
increases with age. Only those aged men with
hypogonadism will potentially benefit from tes-
tosterone therapy.
Metabolic conditions such as diabetes mellitus,
hypercholesterolemia, obesity, renal and thy-
roid disease, and hyperprolactinemia may be
prominent factors in sexual dysfunction.
II. SYMPTOMS OF HYPOGONADISM
Clinical menifestations of hypogonadism differ
according to the time of onset in life. Common
symptoms and signs of hypogonadism include:
asthenia,decrease of libido, sexual activity,
reduced ejaculate volume, decrease in muscle
mass and strength, osteopenia, decrease of
cognitive functions, decrease of the feeling of
general well-being.
III. DIAGNOSIS OF HYPOGONADISM
The most widely used biochemical parameter
for the diagnosis of hypogonadism is a single
morning total serum testosterone. However,
there increasing evidence that androgen defi-
ciency can be better demonstrated by measu-
ring bioavailable testosterone, i.e. free and
albumin-bound fractions of circulating testos-
terone. Therefore, it is essential that diagnostic
criteria for bioavailable testosterone be establi-
shed to improve the accuracy of the diagnosis of
hypogonadism especially in the aging male.
A morning baseline total testosterone should be
measured. When the level of total serum testos-
terone is low or borderline, repeat measure-
ment of total testosterone should be performed
with assessment of bioavailable testosterone.
SHBG, LH, and prolactin levels are determined
to evaluate bioavailable testosterone, and status
of hypothalamic-pituitary-gonadal axis.
Criteria for routine measurement of prolactin
are less well defined.
IV. TREATMENT
Patients with either low or borderline normal
levels are candidates for the testosterone repla-
cement therapy as plasma level of testosterone
does not necessarily reflect the intensity of
androgenic effects in target tissues in men and
patients with borderline testosterone values
may benefit from this intervention.
While many other etiologies of erectile dysfunc-
tion may play a role in the older patient, when
erectile dysfunction, is accompanied by hypo-
gonadism, testosterone replacement therapy is
indicated. Androgens, also, have considerable
effects not only on sexual function, but also on
bone mass, muscle mass and strength and cer-
tain cognitive brain functions in men.
Testosterone replacement therapy is contraindi-
cated in men with prostate cancer, breast cancer,
polycythemia, and severe cardiac insufficiency.
Patients with the following conditions can be
treated with testosterone replacement therapy
and careful monitoring: sleep apnea, low urina-
ry tract smyptoms (LUTS), hyperlipidemia,
unsatisfactorily treated hyperprolactinemia.
Parenteral testosterone esters, oral undecanoa-
te form of testosterone, and transdermal testos-
232
terone preparations are available. Testosterone
replacement therapy should restore serum tes-
tosterone levels to normal.
Close monitoring during the treatment should
be mandatory to avoid potential complications
of testosterone treatment. Monitoring should
include: regular digital rectal examination,
PSA, and Hb/Hct determinations especially in
older man.
APPENDIX
PRACTICAL CLINICAL
RECOMMENDATIONS ON TESTOS-
TERONE SUPPLEMENTATION
I. EVALUATION OF PATIENTS
1. Only men with low or borderline normal
serum testosterone are suitable candidates
for testosterone supplementation.
2. Careful history and physical examination
should be performed before beginning tes-
tosterone replacement therapy.
3. The etiology of hypogonadism should be
determined in all patients.
4. The patients following conditions are
contraindicated from testosterone supple-
mentation:
a) Breast cancer and prostate cancer
b) Polycythemia
c) Severe cardiac insufficiency
5. Patients with the following conditions can
be treated with testosterone replacement
therapy and careful monitoring: Sleep
apnea, low urinary tract symptoms
(LUTS), hyperlipidemia, unsatisfactorily
treated hyperprolactinemia.
6. A morning baseline total testosterone
should be measured. When the level of
total serum testosterone is low or borderli-
ne, repeat measurement of total testostero-
ne should be performed with bioavailable
testosterone. SHBG, LH, and prolactin
 levels are determined to evaluate bioavai-
lable testosterone and for status of hypo-
thalamic-pituitary-gonadal axis.
7. Regular monitoring of patients with testos-
terone replacement therapy should include:
digital rectal examination, PSA, Hb/Hct
especially in older men.
II. TESTOSTERONE
PREPARATIONS
1. Parenteral testosterone esters, oral undeca-
noate form of testosterone, and transdermal
testosterone preparations are available.
2. Testosterone replacement therapy should
restore serum testosterone levels.
III. RECOMMENDED FOLLOW-UP
PROTOCOL
1. FIRST 1-3 MONTHS
The first follow-up should evaluate the tes-
tosterone level, and whether any adverse
effects, as well as the hypogonadal symptoms.
At this time, physicians can measure serum
testosterone levels, PSA and perform DRE.
2. SUBSEQUENT FOLLOW UP (EVERY 6
MONTHS FOR 2 YEARS THEN ANNUALLY)
Continuous monitoring of clinical symptoms
and adverse effects of medication. Laboratory
tests consist of urinalysis and complete blood
cell counts, as well as DRE and PSA for pros-
tate evaluation.
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__________________
 Committee 8

Oral Non-Endocrine Treatment

Chairman
R. KRANE

Members
G. BROCK,
I. EARDLEY,
J. FOURCROY,
F. GIULIANO,
A. H UTTER,
C. TELOKEN,
M. VICKERS

241
 CONTENTS

A. CENTRALLY ACTING NO DONORS

DRUGS

I. APOMORPHINE L-ARGININE/YOHIMBINE

II. MELANOTAN II
D. POTENTIAL
COMBINATION THERAPIES
B. CENTRALLY AND/OR
PERIPHERALLY ACTING
DRUGS
E. CONCLUSION
I. TRAZODONE

II. PHENTOLAMINE REFERENCES

III. YOHIMBINE
ANNEX I

C. PERIPHERALLY
ACTING DRUGS ANNEX II

PDE INHIBITORS
ANNEX III
I. SILDENAFIL

ANNEX IV
II. IC 351

242
 Oral Non-Endocrine Treatment
R. KRANE,
G. BROCK, I. E ARDLEY, J. F OURCROY, F. GIULIANO, A. H UTTER, C. T ELOKEN,
M. V ICKERS
INTRODUCTION
Although many oral remedies have been utilized
for the treatment of erectile dysfunction, the
approval by the U.S. Food and Drug Administra-
tion of sildenafil (Viagra®) marked the beginning
of a new and exciting era in the treatment of this
disorder. From the moment that sildenafil became
commercially available, it became clear that not
only would ED treatment be forever changed but
also society’s ability to discuss sexual matters and
disorders would never be the same. Almost daily
in a newspaper, magazine or on television Viagra
made news. Who would have thought that a Repu-
blican nominee for the Presidency of the United
States would become a spokesman for erectile
dysfunction?
In addition to its cultural effects, Sildenafil has
changed the way ED is treated. Clearly it has
become the first line of therapy for ED. It has also
for the most part, changed the focus of the prima-
ry ED doctor from the urologist to the primary
care physician. It has also brought into question
the role of the psychologist/sex therapist. If a
patient fails Sildenafil treatment should he have a
diagnostic evaluation or should he simply be
considered to have an organic etiology and move
on to the next therapy available? These and other
related issues must be answered as a new thera-
peutic algorithm develops.
In addition, unlike previous oral agents for ED,
Sildenafil’s development is directly related to the
243
rapid growth in basic scientific investigation rela-
ted to the pathophysiology of erectile dysfunction
that began in the early 1980’s and led to the fin-
ding that NO is the primary neurotransmitter
required for the initiation of an erection. A review
of our present knowledge of erectile physiology
appears elsewhere in the text. Sildenafil and the
other drugs reviewed in this chapter are products
of this knowledge. A variety of neurotransmitters
(both central and peripheral) have been elucidated
and include VIP, NO, dopamine, serotonin (5-HT),
oxytocin, ATP, norepinephrine and acetylcholine
to name a few. Substances that can enhance or
block these neurotransmitters may promote erecti-
le initiation centrally or corporal smooth muscle
relaxation peripherally. Centrally apomorphine,
trazodone and melanotan-II have been used and
studied in the treatment of ED. Peripherally silde-
nafil and other PDE-5 inhibitors, trazodone, phen-
tolamine, yohimbine and arginine have also been
shown to have erectogenic capabilities. These and
other newer and more recently introduced drugs
will be critically reviewed. We have chosen to dis-
cuss melanotan II in this chapter even though it
has to date been administered subcutaneously for
the treatment of ED. The reader should be aware
that most of the placebo-controlled studies of oral
agents have used the results of questionnaires (e.g.
the IIEF) as the means of determining outcomes
and benefits of the agent being tested. An impro-
vement in one’s erection may not always translate
to reproducible ability to perform sexual relations
with an adequately rigid erection.

A. CENTRALLY ACTING
DRUGS
I. APOMORPHINE
1. INTRODUCTION
Apomorphine is an aporphine (not an opiate) that
acts as a dopaminergic agonist. Although synthesi-
zed from morphine, there is little pharmacological
similarity with morphine, and apomorphine has
not been shown to result in narcotic addiction [1].
2. PHARMACOLOGY
Apomorphine was the first dopamine receptor
agonist to be synthesized and has the most com-
plete pharmacological profile compared with other
dopamine agonists. Apomorphine has a high affi-
nity for D2, D3, and D4 receptors and is unique in
its affinity for D1 receptors [2]. It elicits effects
similar to those of levodopa. Apomorphine was
first synthesized via acid-catalyzed skeletal rear-
rangement of morphine, with the levo-rotating
product, (-)apomorphine, retaining little structural
similarity to the narcotic analgesic. Throughout
the latter 19th century, concurrent clinical and ani-
mal studies led to further use of apomorphine as an
antispasmodic and for the treatment of specific
movement disorders and epilepsy. In the 19th cen-
tury it was used for its behavioral effects in
domestic animals and was approved in veterinary
medicine for induction of vomiting. In the first
half of the 20th century, apomorphine was used as
a sedative for psychiatric disturbances and as
behavior-altering agent for alcoholics and addicts.
In the 1960s, it was established that apomorphine
is structurally similar to dopamine and it was
found to be a useful drug in the management of
refractory on-off oscillations in Parkinson’s disea-
se. Since then it has been documented to have
potent activity at D1 and D2 dopamine receptor
sites. It is not known to share the addictive poten-
tial of morphine. Its actions are thought to be
mediated post-synaptically.
Apomorphine has been demonstrated to produce
an arousal response manifested by yawning and
penile erection in animals and man [3, 4, 5].
244
Apomorphine can be administered via mucosal
membranes and other possible routes are intrana-
sal, sublingual, and rectal. Intranasal administra-
tion is quite effective, but the dose needed to
achieve the same effect can be up to 10 times that
of subcutaneous apomorphine. The latency of
onset was substantially longer.
Unmodified parenteral administration of apomor-
phine has disadvantages in human use for erectile
dysfunction when compared with its application in
the management of Parkinson’s disease. Unmodi-
fied apomorphine given orally or sublingually
may be effective in producing erections, but is
associated with unacceptable side effects.
Apomorphine has now been specifically formula-
ted in a tablet for sublingual administration that
has been demonstrated to maintain its erectogenic
effects while minimizing the side effects associa-
ted with other routes of administration.
Apomorphine sublingual is the first drug for ED
that acts as a central initiator. It is effective cen-
trally at nanogram concentrations.
Since apomorphine acts in the brain, the signals
generated follow the natural pathways and genera-
te an erection indistinguishable from a physiologi-
cal erection. The action on the cerebral nuclei is
highly specific and sensitive, and there is little dis-
cernible direct action on cells outside the central
nervous system at the doses used.
3. ANIMAL STUDIES
Central dopaminergic transmission is involved in
the control of penile erection. The incerto-hypo-
thalamic dopaminergic pathway reaches the
medial preoptic area (MPoA) and the paraventri-
cular nucleus (PVN) of the hypothalamus. The
proerectile role of these two nuclei has been deter-
mined in animal models [6]. Therefore there exists
a strong link between central dopaminergic trans-
mission, the PVN and penile erection. Animal data
strongly suggest that dopaminergic mechanisms
are involved with the erectile responses. and these
have been associated with activity on nuclei in the
supraoptic region of the hypothalamus. The cha-
racteristics of apomorphine activity as an erecto-
genic agent have been well defined in animal
models. In rats it causes a stereotypical behavior
of erections in concert with yawning.
In rats, apomorphine administered intraperitoneal-
ly causes episodes of penile erection. Following
subcutaneous apomorphine in rats, erections are
accompanied by intracavernosal pressure in-
creases, occurring as a plateau of 47.9 ± 3.9
mmHg, lasting 34.0 ± 4.0s, with 11.2 ±1.5 peaks
lasting 0.20 ± 0.03s and reaching 194.5 ± 22.4
mmHg [3].
Episodes of penile erection are also elicited by
micro-injection of apomorphine to the paraventri-
cular nucleus of the hypothalamus in the rat [4].
In monkeys, in a placebo-controlled study, apo-
morphine facilitated erections in males in the pre-
sence of receptive females, but did not facilitate
erections in the absence of females.
Experimental results provide neuroanatomical evi-
dence that apomorphine, at a dose which selecti-
vely induces erections, causes specific and selecti-
ve expression of c-fos in several brain structures
which are recognized to play a crucial role in the
integration of autonomic, vascular and endocrine
regulation of penile erection [7]
4. HUMAN STUDIES
a) Injected apomorphine
Lal et al [5] showed, in a placebo-controlled,
double-blind study on healthy volunteers that apo-
morphine, injected subcutaneously (0.25-0.75
mg), was able to induce erection. This was confir-
med by Danjou et al [8], showing that apomorphi-
ne induced erection and potentiated the erection
induced by visual erotic stimulation. There was no
increase in libido, which was in agreement with
previous observations.
In 28 patients with impotence, Lal found that 17
responded with erection after subcutaneous apo-
morphine [9]. Segraves et al. [10] also administe-
red apomorphine subcutaneously (0.25-1.0 mg) to
12 men (eight with psychogenic impotence) in a
double-blind and placebo-controlled study. They
found a dose-related increase in maximal penile
circumference. An erection was obtained in 11 of
the 12 patients, while 8 of the 12 developed nau-
sea as a side effect.
The therapeutic potential of apomorphine, howe-
ver, seems to be limited due to frequently occur-
ring side-effects. High doses (up to 5-6 mg in adult
245
patients) may cause respiratory depression and, in
the low-dose range (0.25-0.75 mg), where effects
on penile erection can be demonstrated, emesis,
yawning, drowsiness, transient nausea, lacrima-
tion, flushing, and dizziness may occur [11].
b) Oral apomorphine
Apomorphine has poor bio-availability in oral
form (approximately 10% of the subcutaneous
dose) but has been shown to be absorbed through
mucous membranes. Apomorphine is rapidly clea-
red because of its high lipid solubility, large volu-
me of distribution, and rapid metabolism.
Heaton et al. [12] described a study in which apo-
morphine was formulated in a proprietary slow-
release tablet form. It was hoped that the slow
release form (onset of action was 30 minutes)
would provide an erectile response without the
previously described side effects, especially nau-
sea and drowsiness. It was administered sublin-
gually to a selected population of patients with no
documentable organic causes of erectile dysfunc-
tion, but with proven erectile potential (psychoge-
nic ED). Initially it was felt that since the drug
worked centrally it required normal peripheral
neurovascular integrity if it were to be erectoge-
nic, hence the initial trial on patients with psycho-
genic ED. Twelve patients were given either pla-
cebo, 3 mg or 4 mg of apomorphine sublingually
and underwent real-time Rigiscan measurements
in a single-blind dose escalation study. Eight of the
12 patients (67%) had durable erections without
side effects at a dose of 3 and 4 mg. Erectile acti-
vity was seen during both sexually neutral and ero-
tic visual stimulation to a significantly greater
extent than with placebo. About 70-80% of the
erection obtained while watching erotic stimula-
tion could be obtained while watching sexually
neutral videos. There were no side effects seen
during the trial. An on demand home trial was
continued by 7 of the 8 responders and found to be
successful.
The efficacy of Apomorphine SL tablets for the
treatment of male erectile dysfunction was deter-
mined by Rigiscan testing. The mean value of
every Rigiscan parameter (tip rigidity and tumes-
cence and base rigidity and tumescence) was
higher for both the 6 mg and the 4 mg doses of
apomorphine than for placebo [12]. All differences
were statistically significant for the 6 mg dose,
with mean values vs. placebo of 52.5% vs. 40.1%
for maximum base rigidity (p=.013), 43.1% vs.
26.7% for maximum tip rigidity (p=.004), 10.9
cm vs. 10.3 cm for maximum base tumescence
(p=.018), 9.4 cm vs. 8.7 cm for maximum tip
tumescence (p=.001), and 4.8 minutes vs. 1.7
minutes for duration above 55 % base rigidity
(p=.014). Differences for the 4 mg dose vs. pla-
cebo were significant for both maximum base
rigidity (50.7% vs. 41.0%, p=.037) and maxi-
mum tip rigidity (45.8 % vs. 32.3% p=.024) [12].
In the first Phase III study using the sublingual
preparation 457 [13] men with ED and no major
organic component were randomized into 3 arms
each being a separate crossover comparing either
2 mg, 4 mg or 6 mg of apomorphine to placebo.
The primary endpoint was the number of
attempts resulting in an erection firm enough for
sexual intercourse.
The percentage of attempts that resulted in a firm
enough erection for each group was: 45.8% for 2
mg vs. 32.2% for placebo (p<0.001); 52% for 4
mg vs. 35% for placebo (p<0.001) and 59.6% for
6 mg vs. 34.2% for placebo (p<0.001) (Figure 1).
Mostly mild to moderate nausea (only 2.7% of
the 6mg group had severe nausea) was the most
common adverse event seen in 39%, 19.5%, and
2.1% in the 6mg, 4mg and 2mg groups, respecti-
vely (up to 4.9% in the placebo group) [13].
Padma-Nathan et al. randomized 520 patients
with ED (median age 54) into four arms each
being a separate crossover arm comparing either
2 mg, 4 mg, 5 mg or 6 mg of apomorphine sub-
lingually to placebo [14]. The primary endpoint
for the study was the percentage of attempts that
resulted in an erection firm enough for intercour-
se. Secondary endpoints included successful
intercourse rate (according to patient and part-
ner), time to erection and IIEF responses.
The percentage of attempts resulting in an erec-
tion firm enough for intercourse was significant-
ly higher for each of the four apomorphine SL
dose than for placebo:
44.1% for 2 mg vs. 38.0% for placebo (p=0.013);
58.1% for 4 mg vs. 36.6% for placebo (p<.001);
52.8% for 5mg vs. 28.9% for placebo (p<0.001)
246
and 60.9% for 6mg vs. 29.3% for placebo
(p<0.001) (Figure 2).
The commonest adverse event was nausea (most-
ly mild to moderate) seen in 2.9%, 21.4%, 32.8%
and 34.5% of patients taking 2, 4, 5 and 6 mg,
respectively. Only 2.6% of the 6 mg group and
0.8 % of the 5 mg group experienced severe nau-
sea (no severe nausea at lower doses).
Vasovagal episodes have been reported in less
than 1% of patients apparently in relation to age
or presence of hypertension. The median time to
erection for all dosing regimens ranged from 15-
22 minutes. [14] (Table 1).
The efficacy and safety of apomorphine in
patients with hypertension and ED has been stu-
died. A review of two multicenter, double-blind
studies involving 977 patients randomized to
2mg, 4mg, 5mg and 6mg of apomorphine vs. pla-
cebo revealed that 236 (24 %) were hypertensive.
The primary endpoint for these studies was the
percentage of attempts resulting in an erection
firm enough for intercourse.
For the patients with hypertension, the percenta-
ge of attempts resulting in erections firm enough
for intercourse was significantly higher for apo-
morphine SL dosing than for placebo: 42.0% vs.
32.4% for 2 mg compared to placebo (p=.013),
51.2% vs. 27.8% for 4 mg compared to placebo
(p<.001), 46.4% vs. 30.0% for 5 mg compared to
placebo (p=.017), and 63.2% vs. 33.1% for 6 mg
compared to placebo (p<.001) (Figure 3).
The commonest adverse event reported for these
patients was nausea with 15.0%, 20.0%, and
29.4% of patients reporting related nausea when
taking 4, 5, and 6 mg apomorphine SL, respecti-
vely, versus up to 1.6% while on placebo (no
nausea was seen with 2 mg dosing) [15].
c) Conclusion
Apomorphine will act as an erectogenic agent
when absorbed through the oral mucosa.
The preparation of apomorphine in a sublingual
form is effective in inducing erections under
laboratory conditions and is also effective in
home use. The commonest adverse effect is nau-
sea and is dose-dependent [16].
Table 1: Average percentage* of administrations resulting in adverse events

2 MG GROUP 4 MG GROUP 5 MG GROUP 6 MG GROUP

ADVERSE EVENT APO SL PBO APO SL PBO APO SL PBO APO SL PBO
N=127 N=130 N=117 N=117 N=128 N=118 N=116 N=106
Nausea 0.5 0.1 11.7 0.8 16.0 1.0 16.6 0.3
Dizziness 0.3 1.0 7.5 0.2 6.8 0.6 6.7 0.2
Sweating 0.2 0 5.7 0 6.0 0 7.4 0.1
Somnolence 0.3 0.9 5.9 0.3 5.6 0.2 6.0 0.9
Yawning 0.3 0 3.4 0.1 5.8 0.2 4.7 0
Vomiting 0.1 0 2.6 0 5.0 0 2.4 0
Hot flushes 0.9 0.3 0.7 0.1 2.3 0.5 3.0 0.1
Asthenia 0.3 0 1.3 0 2.1 0.2 4.8 0

Padma-Nathan H. et al J.Urol, 161: 214S, 1999 [14]

Padma-Nathan H. et al
J. Urol, 159: 214S, 1998 [13]

Figure 1: Attempts resulting in an erection firm enough for intercourse

Padma-Nathan H. et al
J. Urol, 161: 214S, 1999 [14]

Figure 2: Attempts resulting in an erection firm enough for intercourse

247
Lewis. R et al
J. Urol, 161:214s, 1999 [15]
Figure 3: Attempts resulting in an erection firm enough for intercourse
II. MELANOTAN II
1. BACKGROUND
Melanotan II is a non-selective melanocortin recep-
tor agonist. Melanotan II is a synthetic cyclic hep-
tapeptide, which contains the 4-10 melanocortin
receptor binding region common to Alpha-MSH
and ACTH, but with a lactam bridge and several
amino acid substitutions. This cyclic peptide was
synthesized by solid phase chemistry [1].
The injection of ACTH or MSH peptides into the
cerebrospinal fluid of mammals induces a dramatic
change in behavior, characterized mainly by repea-
ted stretching and yawning movements (stretching
yawning syndrome (SYS)) and by recurrent epi-
sodes of erection and ejaculation [2]. Sexual res-
ponse to ACTH and alpha MSH has been observed
in rats, rabbits, cats, dogs and in squirrel monkeys.
Antagonists to both oxytocin and dopamine do not
block this reaction to ACTH and alpha MSH, nor
does pretreatment with MSG, which depletes
ACTH and MSH from the hypothalamus. It is like-
ly that dopamine, oxytocin and ACTH act in the
hypothalamus in a sequence to induce sexual beha-
vioral responses [3]. The exact area in which ACTH
and alpha MSH act is not known, but it is felt to be
downstream from the paraventricular nucleus
where dopamine agonists such as apomorphine
work [3].
248
The SYS is usually seen 15-60 minutes after injec-
tion of ACTH or MSH into the lateral ventricle and
lasts with erections for 2-5 hours. Copulatory
movements and usually ejaculation accompany
these erections. Castrated animals will not show
any sexual effect from these injections.
Melanotan II is an analog of alpha MSH. In 1992 it
initially underwent a phase I pilot study with the
intention of developing this drug to increase skin
pigmentation without being exposed to ultraviolet
light, because of its direct effect on melanocytes. In
1996, a phase I single-blind placebo-controlled
study administered subcutaneous injections to nor-
mal males daily for two weeks to study its effect on
erectile dysfunction [4].
In addition to increased pigmentation in 2 of the 3
males, all males showed the stretch yawning syn-
drome combined with spontaneous intermittent
erections, which lasted 1-5 hours, and increased as
the dose of melanotan II increased. Melanotan II
has been known to darken the skin color of animals
for several months until the color returns to normal.
As mentioned before the spontaneous erections that
occurred were dose-dependent. This marked the
first time that this type of drug caused erections
when not given directly into the CNS. It is still felt
that this effect is mediated through receptors in the
brain, as melanotan II does cross the blood brain
barrier.
2. C HEMICAL PROPERTIES
MT-II is a cyclic heptapeptide synthetically mode-
led from melanotropin derivatives. The drug (a
white powder) is reconstituted in 0.9% NaCl solu-
tion for injection and concentrations of 5 mg per
ml.
• Chemical name: Ac-Nle-c Asp-His-D-Phe-Arg-
Trp-Lys -NH2
• Molecular formula:C50H69N15O9
• Molecular weight:1024.2
Appearance: white powder
Administered subcutaneously
3. PRECLINICAL STUDIES
a) Toxicology studies
MT-II has been shown to be relatively non-toxic.
Mice tolerated a high dose of 56 mg/kg by subcu-
taneous injection with no toxicity or mortality
during a 90-day observation period. Rats treated
with 0.5 mg/kg/day of MT-II orally or subcuta-
neously for 30 days showed no change in mortali-
ty, food intake, weight gain or behavior. There
were no serum chemistry changes and, except for
a lower platelet count in female rats, there were no
hematological abnormalities. MT-II did not
demonstrate any mutagenic potential. In the repea-
ted dose study, all rats were sacrificed after 30
days and organs were analyzed for gross or histo-
pathologic changes which were not evident.
b) Pharmacokinetics
The oral bio-availability of MT-II is unknown. It is
apparently cleared by the kidney. The estimated
half-life for the initial phase is 8 hours.
c) Clinical studies
In 1996 a double-blind placebo-controlled phase I
study was conducted in three subjects to evaluate
the ability of this drug to cause skin tanning which
was in fact observed in the MT-II group [4]. Sub-
cutaneous injections of MT-II or saline were admi-
nistered daily for 2 weeks for a total of 10 injec-
tions per subject. The starting dose of MT-II was
0.01 mg/kg and the increments of escalation were
0.005 mg/kg. Two subjects were escalated to 0.03
mg/kg and 1 subject was escalated to 0.025 mg/kg.
All subjects developed intermittent spontaneous
erections at 1-5 hours after dosing. Two of the sub-
jects showed increased skin pigmentation.
249
A randomized double-blind placebo-controlled
crossover study in 10 patients with psychogenic
erectile dysfunction was performed [5]. Patients
were determined to have psychogenic erectile dys-
function on history, physical exam and NPT moni-
toring.
Patients were required to have at least one noctur-
nal erection for at least 10 consecutive minutes
with 70% tip rigidity. Patients with known causes
of organic erectile dysfunction or vascular risk
factors were excluded from the study. Patients
received 4 injections of MT-II (0.025-0.157
mg/kg) or saline placebo subcutaneously with 24-
hour washout periods between injections. Rigis-
can data were obtained for six hours following
injection. The patients were followed for one hour
for acute toxic responses and then sent home on
Rigiscan monitoring for the additional five hours
which was to be free of any sexual stimulation. At
home during the five hours of Rigiscan study, a
questionnaire was completed which recorded sub-
jectively the number and duration of erectile
events as well as penile pain and other side effects.
Following placebo injection, erectile activity as
well as rigidity were minimal to non-existent. At
the 0.025 mg/kg dose, there was an increase in
both circumferential change as well as penile rigi-
dity, which increased even further when 0.133
mg/kg was injected subcutaneously. Of 10 men in
the study 8 reported subjective erections during
the 6-hour period, which were confirmed by Rigis-
can study.
There was no episode of ejaculation or painful
erection. The time to erectile onset in the 8 respon-
dents ranged from 15-270 minutes (mean 127.5
minutes). There was a marked statistical differen-
ce between the injected group and the placebo
group in terms of total duration of erectile activity,
tip rigidity duration, tip tumescence activity, base
rigidity duration and base tumescence activity.
Transient side effects were reported in all patients
and in 5 of 10 placebo-treated patients. Adverse
events largely involved nausea, yawning and
decreased appetite. Fourteen of the twenty injec-
tions of MT-II produced stretching and yawning.
In 1998 a similar study using MT-II was perfor-
med in men with organic erectile dysfunction [6].
Ten subjects based on history, physical exam, and
NPT testing were felt to have organic dysfunction
and were entered into the study. The pre-trial NPT
revealed a mean of 0.5 erectile events per night
lasting a mean of 6 minutes (0-18) with a mean
maximum rigidity of 36%. Pre-treatment mean
values for questions 3 and 4 of the IIEF were 0.77
and 0.22 respectively.
A double-blind placebo-controlled crossover study
design was used. MT-II and the dosage of 0.025
mg/kg and a vehicle were administered twice by
subcutaneous injection. Injections were separated
by at least 48 hours. Rigiscan monitoring, a ques-
tionnaire and visual analog score of penile rigidity
were used to quantify erectile responses.
The results showed that 9 of 10 subjects reported
Rigiscan and subjective evidence of erections with
MT-II versus only 1 patient in the placebo group.
The mean values for rigidity were 4.37 in the MT-
II group versus 0.47 in the placebo group. The
subjective reported duration of erection in the MT-
II group was 64.1 minutes.
There was a statistical difference in the level of
sexual desire between the groups with a higher
score in the MT-II group. Nausea, stretching and
yawning and flushing occurred more frequently in
the MT-II group with 4 of 19 injections resulting
in severe nausea and 1 subject vomited.
d) Conclusion
This drug, which mimics the activity of ACTH and
alpha MSH when injected into the lateral ven-
tricle, appears to be able to cause spontaneous
erectile activity after subcutaneous injection in
patients with psychogenic as well as organic erec-
tile dysfunction. At present, our knowledge is
based on clinical data involving studies of very
few patients. The drug must now be tested in a lar-
ger group of patients who are older (both previous
studies were done in relatively young patients)
with both organic and psychogenic erectile dys-
function.
The outcome for this next study should be the abi-
lity to perform sexually with an adequate erection.
It should also be remembered that some of these
patients would have an increase in skin pigmenta-
tion, which they may not desire.
If this drug is consistently effective in patients
with organic dysfunction, further studies would be
necessary to determine its exact site of activity.
250
B. CENTRALLY AND/OR
PERIPHERALLY ACTING
DRUGS
I. TRAZODONE
1. INTRODUCTION
Trazodone hydrochloride was introduced as an
antidepressant in 1982. Soon after its launch,
anecdotal reports of associated priapism began to
appear in the literature [1,2] and these were soon
followed by occasional cases of successful use of
trazodone in men with erectile dysfunction [3,4].
2. BASIC SCIENCE
a) Pharmacology
Trazodone is a triazolopyridine derived oral anti-
depressant agent. It has a number of pharmacolo-
gical actions including alpha-adrenoceptor bloc-
king actions, 5-HT receptor blocking actions and
dopaminergic blocking actions [5]. One of its
major metabolites, mCPP ((-)-m-Chlorophenyl-
piperazine), is a central 5-HT agonist [6] and an
alpha-adrenoceptor blocking agent.
b) Mode of action
There are two main theories concerning the mode
of action of trazodone.
• Peripheral -adrenoceptor antagonist
Trazodone is an α-adrenoceptor antagonist. In
vitro studies [7] demonstrated an ability to impair
cavernosal contractions induced by noradrenaline
suggesting a local action for the drug within the
penis. However, in another study, intracavernosal
injection of trazodone only produced tumescence
rather than a full erection [8], suggesting that other
mechanisms were also active.
c) Central actions on the serotonin (5-HT)
system
Trazodone is a central blocker of 5-HT receptors,
with a preferential affinity for 5-HT2 over 5-HT1
receptors. It has been demonstrated in animal
experiments that 5-HT is intimately involved in
sexual activity [9], and it has been suggested that
trazodone produces its effects on sexual function
by anti-5HT mechanisms; m-CPP may also have a
role in this respect. In animals mCPP, which sti- Table 1: Results of a randomized trial comparing Trazado -
mulates 5-HT-2C receptors, increased giving in ne, Ketanserin, Mianserin and Placebo in the treatment of
psychogenic ED [12];
the cavernous nerve and elicits use in intracaver-
nous pressure through the activation of the spinal TRAZODONE KETANSERIN MIANSERIN PLACEBO
sacral parasympathetic outflow to the penis [10]. N=23 N=21 N=19 N-22
mCPP is still active in spinalized rats suggesting Response 15 4 6 3
an action at the spinal cord. 5-HT-2C receptors rate (65.2%) (19.1%) (31.6%) (13.6%)
have recently been described on spinal neurons
controlling penile erection in the rat [11]. Further- Table 2: Results of a controlled trial comparing Trazodone,
more evidence for a specific role of mCPP on 5- Testosterone and hypnosis in the treatment of psychogenic
HT-2C in the proerectile responses of conscious ED [13]
rats has been provided [10]. TRAZODONE TESTOSTERONE HYPNOSIS CONTROL
N=21 N=20 N=20 N=18
d) Laboratory data and animal studies
Cure 8 8 12 0
Trazodone has been shown to have a relaxant
Moderate
effect upon cavernous smooth muscle [7] while response 6 4 4 1
intracavernosal injection of either trazodone or No response 7 8 4 11
mCPP produces penile tumescence in rabbits [8].
In normal men who were administered trazodone
nocturnal penile tumescence studies demonstrated There was no statistical advantage for any of the
increased erectile activity compared with trimipri- treatments.
mine and placebo [7].
Meinhardt et al. enrolled 69 men with both psy-
3. CLINICAL DATA
chogenic and organic ED [14]. Patients were ran-
a) Efficacy domized to receive either 150mg trazodone per
Anecdotal reports initially suggested that trazodo- day or placebo for 4 weeks after a 2-week run-in
ne might be effective in men with erectile dys- period. The mean age was 54-55 years and 11
function [3,4]. patients failed to complete the study. The main end
In the first published placebo-controlled trial, 100 point was a global question concerning the
men with psychogenic ED, all of whom responded patient’s opinion of whether the medication had
to intracavernosal 60mg Papaverine were rando- worked well. Only 4/26 of the trazodone group felt
mized into 4 groups taking either trazodone 50mg that the medication worked well, compared with
tid, ketanserin 20mg bid (5-HT2 antagonist), 5/32 of the placebo group.
mianserin 10mg tid (anti 5HT1 and 5HT2) or pla-
cebo for 30 days [12]. The mean age of the A more recent double-blind placebo-controlled
patients was 47 years. Success was defined as 3 or crossover study randomized 51 patients to either
more successful intercourses within the 30 days. 50 mg of trazodone or placebo at bedtime for 3
15 men were ultimately excluded from the analy- months and then, after a washout period, patients
sis for varying reasons. Positive responders are crossed over to the other group. There were no sta-
enumerated in Table 1. tistically significant differences in respect to
A subsequent trial randomized 79 men with psy- improved erections or improved sex drive between
chogenic ED to receive either 120mg testosterone any of the groups [15].
undecanoate daily (n=20) or 150mg trazodone b) Safety
daily (n=21) or to undergo hypnosis (n=20) [13].
The final 18 men acted as controls. The mean ages A number of adverse events have been reported
of the patient groups were 34-40 years. Cure was including priapism, sedation, xerostomia, blurred
defined as a man who was happy and who had no vision [9], sedation [13], dizziness, drowsiness,
sexual problems on questioning, while a moderate headache and nausea [14]. The numbers in the
result was considered to be a man who was impro- trials were too small to allow definitive assess-
ved but who still had some failures. The results are ments of the frequency of these side effects,
shown in Table 2. although sedation seems to be the commonest.

251
c) Indications
1. DOSING
The usual dosage is 150mg per day in divided
doses.
2. P OTENTIAL SYNERGIES
One trial explored the value of combination thera-
py with yohimbine [16]. In a placebo-controlled
crossover study, 63 men with psychogenic ED
received placebo or 15mg yohimbine per day and
50mg trazodone per day. Each treatment period
lasted 8 weeks. The trial demonstrated an advanta-
ge for combination treatment with 39 men (62%)
achieving a good response (p<0.01), which was
subsequently sustained for up to 6 months in 31
men.
d) Conclusion
The clinical trials have failed to consistently
demonstrate efficacy for this medication in the
treatment of men with ED. Available data are lack-
ing concerning the use of this drug for ED
II. PHENTOLAMINE
1. INTRODUCTION
Phentolamine has been used as an adrenoceptor
antagonist for around 40 years. Outside the realm
of andrology, its chief use is in the treatment of
pheochromocytoma-induced hypertension. Since
the 1980s it has been used as an intracavernosal
agent, usually in combination with Papaverine and
prostaglandin El [1,2]. When injected alone it has
usually shown less than modest erectile responses.
Following a number of pilot studies with oral for-
mulations of the drug [3,4] for the treatment of
erectile dysfunction it has recently entered Phase
II/III clinical trials for this condition [5,6,7,8].
2. BASIC SCIENCE
a) Pharmacology
Phentolamine is an α1 and α2 adrenoceptor bloc -
king agent [9]. It also has other actions including
blockade of 5HT receptors and blockade of potas-
sium channels.
b) Mechanism of action
Phentolamine currently thought to act via three
main mechanisms.
252
c) Intracavernosal -adrenoceptor blockade
Both α1 and α2 receptors are found within both
the cavernosal smooth muscle and on the arterio-
lar smooth muscle of the penis [10]. Noradrener-
gic stimulation leads to contraction of both sets of
smooth muscles and α1/α2 adrenoceptor blockade
results in cavernosal smooth muscle relaxation
and arteriolar dilatation [11]. It has been demons-
trated that phentolamine displaces α1 and α2 ago-
nists from cavernosal smooth muscle in both man
and in rabbits, and in vitro organ bath experiments
have confirmed that it inhibits both α1 and α2
mediated cavernosal contraction [12].
d) Direct intracavernosal relaxant effects
A second local effect of phentolamine within the
penis has been proposed [12]. Phentolamine was
found to decrease the endothelin and potassium
induced contraction of cavernous smooth muscle.
Since these agents cause contraction by non-adre-
nergic mechanisms, it has been postulated that
phentolamine has other actions in addition to its a-
adrenoceptor blocking actions. Since the effect of
phentolamine on cavernosal relaxation was reduced
by a nitric oxide synthase (NOS) inhibitor (L-
NAME) and since it was also reduced by de-epithe-
lialisation, it has been postulated that this additional
mechanism of action is exerted via α receptor on
the endothelium which leads to activation of NOS.
e) Central -adrenoceptor blockade
It is interesting that intracavernosal injection of
phentolamine alone does not lead to a full and
rigid erection [13]. This might suggest that phen-
tolamine has extra-cavernosal actions. It is also
known that centrally acting α2 adrenoceptor bloc-
king agents such as yohimbine have some benefit
in erectile dysfunction [14]. Since it seems likely
that phentolamine crosses the blood-brain barrier,
it is therefore possible that phentolamine has addi-
tional central α2 adrenoceptor antagonistic
actions, which are valuable in the treatment of
erectile dysfunction.
There exist both morphological and pharmacolo-
gical evidence to support a role for noradrenaline
in the neural control of penile erection at the brain
and spinal cord level [15]. Nevertheless, the α-
adrenoceptor subtypes mediating this regulation
remain essentially unknown. From available phar-
macological data, the general view is that central
activation of α1 adrenoceptors and inhibition of
α2 adrenoceptors facilitates sexual functions.
More studies are mandatory to define the exact
mechanism of action of phentolamine within the
central nervous system.
f) Laboratory data and animal studies
There are no reported or published data relating to
animal studies with this formulation. Organ bath
and other in vitro data relating to the compound
are discussed above.
g) Pharmacokinetic data
The Cmax, Tmax and T1/2 following an oral dose
of phentolamine mesylate are shown in Table 3.
If a level of 10ng/ml is considered adequate for a
pharmacological effect in the penis, then the onset
of clinical activity would be less then 20 minutes
and would last for just under 2 hours.
3. CLINICAL DATA
a) Pilot studies
An initial placebo-controlled crossover trial in 16
men with ED suggested a modest benefit for oral
phentolamine 50mg over placebo, with 11/16
responding to phentolamine and 3/16 responding
to placebo [3]. This formulation of the drug was
subsequently withdrawn. A further pilot study
using phentolamine mesylate 50mg in 3 centers
suggested that there was a 42.3% rate of full spon-
taneous erections in men with ED [4].
Phase II studies in Germany were reported in 1996
[5,6]. In one large placebo-controlled multicentre
study, using phentolamine mesylate, 230 men with
organic ED were recruited [5]. The age of the
patients was not stated. All were given 3 doses of
placebo and any man who obtained an erection
with any of the doses was excluded from the sub-
sequent trial. 177 men who entered the second
phase were randomized to receive 3 doses of phen-
tolamine (20mg, 40mg, 60mg) or placebo. Success
was defined as at least one successful attempt at
sexual intercourse. The results are outlined in
Table 4.
There was no statistically significant advantage
for phentolamine over placebo.
In a smaller, single center study, 44 men with
recent onset (less than 3 years) ED and a probable
organic etiology were randomized to receive phen-
tolamine mesylate (20mg, 40mg, 60mg) or place-
253
Table 3: Pharmacokinetic data for orally administered Phen -
tolamine
ORAL 40 MG
PHENTOLAMINE
Area under the curve 33.3 ng/hr/ml
Cmax(peak concentration) 19.3 ng/ml
T 1/2 (Half-life) 2.14 hr
Tmax (time to peak concentration) 0.69 hr
bo [6]. Following a single-blind placebo phase, 4
men reported successful erections and were exclu-
ded. Success was defined as an erection adequate
to achieve vaginal penetration. The success rates
are shown in Table 5.
Again, the results for phentolamine were not signi-
ficantly better than those achieved with placebo.
b) Phase III trials
The largest reported trials to date have been under-
taken in men with mild to moderate erectile dys-
function [7,8].
Two protocols were used. In one, 459 men were
randomized to receive phentolamine 40mg, 80mg
or placebo and were asked to attempt sexual inter-
course at least 4 times in 4 weeks [7]. 424 men
completed the study. Mean ages of the patient
groups were 57-59 years. End points included the
change in the IIEF, the ability to achieve vaginal
penetration and the ability to achieve erection suf-
ficient for penetration and ejaculation in at least
75% of attempts. The results are outlined in Table
6.
An analysis of the individual domain scores of the
IIEF again demonstrated an advantage for phento-
lamine over placebo (Table 7).
All changes were statistically significant other
than those noted in the table as NS.
The other protocol randomized 312 men to recei-
ve both placebo and 40mg phentolamine in a cros-
sover fashion [8]. Again the mean ages were 58-59
years. The results of the trial are shown in Table 8.
The latter 2 parameters (shaded) are quoted in the
abstract but are not fully defined.
c) Safety data
Only limited safety data are currently available for
this formulation of the drug. The basic side effects
profile, from the parallel group and cross-over stu-
dies outlined above [7,8], is shown in Table 9.
Table 4: Phase II studies of oral Phentolamine in 177 men with ED [5]
PLACEBO 20 MG 40 MG 60 MG
PHENTOLAMINE PHENTOLAMINE PHENTOLAMINE

Success rate in men <50 yr. 42% 36% 27% 50%

Success rate in men > 50 yr. 28% 17% 50% 40%

Table 5: A single centre placebo-controlled study of oral phentolamine in men with organic ED [6].
PLACEBO 20 MG 40 MG 60 MG
PHENTOLAMINE PHENTOLAMINE PHENTOLAMINE
N=10 N=10 N=10 N=10

Successful patients 2 3 5 4
Successful doses 13.4% 20% 30% 36.7%

Table 6: Phase III trial of oral Phentolamine in the treatment of men with mild to moderate ED [7]. Men were randomized to
receive either placebo or phentolamine 40 mg or 80 mg
PLACEBO PHENTOLAMINE PHENTOLAMINE
40 MG 80 MG
N=139 N=139 N=146

Mean change in IIEF from baseline + 2.39 + 5.65 + 6.66

p<0.0001 p<0.0001
Shift in domain score of IIEF 15% 40% 53%
p<0.0001 p>0.001
Ability to achieve penetration in 38% 51% 53%
at least 75% of cases p=0.012 p=0.005
Ability to achieve ejaculation in 16% 29% 29%
at least 75% of cases p=0.005 p=0.006
Overall satisfaction 10% 33% 40%

Table 7: Phase III trials of oral Phentolamine in the treatment of men with mild to moderate ED [7]. Results of the indivi -
dual domain scores of the IIEF.
PLACEBO PHENTOLAMINE PHENTOLAMINE
40 MG 80 MG

Frequency of penetration - 0.3 NS 0.3 0.6

Frequency of maintaining erections -0.2 NS 0.4 0.8
Orgasmic function -0.1 NS 0.8 1.0
Sexual desire 0.1 NS 0.3 NS 0.3 NS
Intercourse satisfaction -0.4 NS 0.8 1.2
Overall satisfaction 0.2 NS 1.3 1.5

Table 8 : A phase III placebo-controlled crossover trial of phentolamine and placebo in men with mild to moderate ED [8]
PLACEBO PHENTOLAMINE 40 MG
Ability to achieve penetration in at 48% 55% p=0.004
least 75% of attempts
Ability to achieve ejaculation 26% 37% p<0.001
in at least 75% of attempts
Improved erectile function 26% 36% p=0.0149
Overall responders 24% 35% p=0.0013

254
Table 9 : Side effects of oral Phentolamine [7, 8 ]

PLACEBO PHENTOLAMINE PHENTOLAMINE

40 MG 80 MG

Rhinitis 3.8% 7.7% 20.9%

Headache 1.7% 3.1% 4.5%
Dizziness 0.2% 2.0% 7.0%
Tachycardia 0.6% 1.5% 7.0%
Nausea 0% 0.7% 3.5%
Hypotension 0% 0.2% 2.0%
Hypertension 0.2% 0% 2.0%

It seems that most side effects are dose-related, 4. CONCLUSION

and that the drug is generally well tolerated at
these doses with this formulation.
Phentolamine is a mixed alpha-l and alpha-2
receptor antagonist, which is used clinically to
treat hypertension caused by pheochromocytoma.
It is therefore theoretically capable of inducing
hypotension. In the clinical trials outlined above, a
number of patients were taking concomitant medi-
cations including antihypertensive agents (place-
bo: 32%, phentolamine 40mg: 25%, phentolamine
80mg: 28% in the parallel group study), but there
were no reported interactions.
d) Indications
Presented or published phase II clinical trial data
only relate to mild or moderate ED, and further
data are awaited in men with more severe ED.
e) Dosing and storage
Phentolamine mesylate is a white dry odorless,
crystalline powder. At present it seems likely that
the tablet will be available in 40mg and 80mg
doses.
f) Potential synergies
Because of the differing mechanisms of action, it
seems possible that phentolamine will be useful in
combination with a wide range of other treatments
for ED, including sildenafil, apomorphine, intrau-
rethral therapy and intracavernosal therapy. At
present this is largely hypothetical with few stu-
dies exploring combination therapy.
However, one recent study has, suggested that an
adrenoceptor blockade might potentiate intraca-
vernosal therapy, although on this occasion doxa-
zosin, an alpha-l adrenoceptor blocking agent, was
used [15].
Phentolamine is an alpha-adrenergic blocking
agent with both central and peripheral activity. In
placebo-controlled studies, it has been found to
have modest efficacy in patients with mild to
moderate ED.
Adverse events profile dizziness, nasal stuffiness
and tachycardia which is generally well tolerated
at the 40 mg dose.
III. YOHIMBINE
1. PHARMACOLOGY
Yohimbine is an indolalquinolonic alkaloid found
in the bark of the Pausinstalia yohimbe tree and
the root of Rauwolfia. It is a selective competitive
antagonist for α2 adrenergic receptors [1].
2. ANIMAL STUDIES
a) Mode of Action
1. DIRECT
Yohimbine partially antagonized norepinephrine-
induced contractions in bull retractor penis,
although its action is 1000 times weaker than that
of phenoxybenzamine [2]. The injection of yohim-
bine into the penis of dogs did not induce tumes-
cence or rigidity [3].
2. INDIRECT
The medial preoptic area has been implicated in the
control of sexual arousal in males [4]. The medial
preoptic area receives noradrenergic innervation
from the α1 and α2 cell groups of the brain-stem
[5]. α2 receptors have been identified in the medial
preoptic area and other hypothalamic areas [6].
Yohimbine facilitates norepinephrine release from
the rat hypothalami in vitro [7,8,9]. Yohimbine

255
increases 3-methoxy-4-hydroxyphenylethylenegly-
col sulphate norepinephrine metabolite [10].
There was no statistically significant difference in
mean norepinephrine content between control and
yohimbine treated rabbit corpus cavernosum, and
control and yohimbine treated corpus cavernosum
human [11].
Strips of the rabbit main pulmonary artery, pre-
contracted with noradrenaline, were exposed to
yohimbine, which enhanced the smooth muscle
contraction induced by transmural sympathetic
nerve stimulation [12].
b) Animal evidence for positive effect of yohimbi -
ne on sexual function
In male rats, yohimbine induced copulatory activity
in sexually inactive males and increased mounting
after penile desensitization, a test which specifical-
ly measures sexual motivation [13]. Yohimbine
induced copulatory activity in sexually inactive
male rats up to 91 days after castration [14]. Yohim-
bine improved age-related deficits in sexual beha-
vior of rats [15]. In male rats, yohimbine drastical-
ly decreased the ejaculation latency and the interco-
pulatory and post-ejaculatory intervals [16].
Yohimbine increased sexual motivation in rats
with lithium chloride-induced inhibition of copu-
latory behavior [17]. The study of Lang demons-
trated differences in the behavioral effects of
yohimbine in several species. Yohimbine was
excitatory when given to dogs and rats. In contrast,
it produced behavioral depression in cats [18] and
did not increase sexual motivation in primates.
Early maternal and social deprivation markedly
affects the behavioral response of adult nonhuman
primates (macaque monkeys) to oral yohimbine
[19].
3. H UMAN STUDIES
a) Mode of Action
1. DIRECT
Tolazoline (α2 adrenergic antagonist) inhibited
noradrenaline-induced contraction of human cor-
pora cavernosa smooth muscle cells [20]. Yohim-
bine partially antagonized norepinephrine-induced
contractions of human CC in an in vitro muscle
bath [11]. The inhibition of norepinephrine-indu-
ced contractions of strips from human corpus
cavernosum by phentolamine is more intense than
256
that induced by moxisylyte, which in turn is more
intense than that induced by yohimbine [21].
2. INDIRECT ACTION VIA NOREPINEPHRINE OR NORE-
PINEPHRINE METABOLITES
Yohimbine increases the levels of norepinephrine
in cerebrospinal fluid [22]. In addition, Yohimbi-
ne, when compared to placebo, caused a signifi-
cant increase in plasma MHPG concentrations (3-
methoxy-4-hydroxyphenylethyleneglycol) an
index of brain norepinephrine turnover, 2, 3 and 4
hours following administration [23].
Yohimbine causes dose-dependent increases in
plasma NE due to an increased rate of appearance
of NE in plasma and not reduced clearance from
plasma [24]. Yohimbine has an absorption half-life
of 0.17 h ± 0.1 1 h and an elimination half-life of
0.60 ± 0.26 h. It does not have a distinct second
compartment [25]. Hypertensive patients who
were given 22 mg of oral yohimbine experienced
a mean BP increase of 5 mm Hg, a 66% increase
in plasma norepinephrine and a 25% increase in
plasma dihydroxyphenylglyco1 (neuronal metabo-
lite of NE) [26]. However, patients who received
Yohimbine (l2 mg po qd) did not have any signifi-
cant change in plasma noradrenaline after 15 days
of treatment [27].
b) Physiological effects of yohimbine in humans
Yohimbine 0.30 mg/kg iv did not modify penile
diameter (without stimulation) and did not affect
the physiological response to erotic stimuli [28].
Furthermore, there was no change in the penile
brachial index with yohimbine during a double-
blind clinical trial [3]. Vogt et al. found no signifi-
cant difference in NPT recordings with yohimbine
during a double-blind clinical trial [29]. In addi-
tion, yohimbine (0.30 mg kg iv) did not induce
erection and did not potentiate erection induced by
visual stimulation [28].
Cherney et al. reported no change in sexual drive
or sexual function with the administration of
yohimbine 30 mg po [23].
In another study, there were no statistically signi-
ficant changes in subjective response (sexual desi-
re, best erection during sexual contacts, frequency
of sexual contacts, sexual satisfaction) during the
administration of yohimbine 30 mg po. In fact the
values of the latter three parameters were identical
in the yohimbine and placebo groups [29].
c) Clinical Trials
For close to 75 years, yohimbine has been consi-
dered to be an aphrodisiac. As seen above, some
animal experiments demonstrated yohimbine to
increase arousal and sexual motivation in rats.
Early clinical investigators reported in uncontrol-
led studies up to 75-80% good to excellent results
in the treatment of impotent patients [30]. More
recent controlled studies have not been very pro-
mising regardless of the subset of the impotent
population studied. Yohimbine is usually prescri-
bed at a dose of 5.4 mg tid. A review of the rele-
vant clinical trials in various etiological categories
follows.
1. PSYCHOGENIC ERECTILE DYSFUNCTION
Two [31,32] of the three clinical trials with
patients with psychogenic erectile dysfunction
demonstrated a statistically significant difference
in complete recovery of erectile function between
yohimbine and placebo.
However, the Reid trial [31] used methodology
(partial crossover) which biased the study toward
yohimbine. Additionally, the group of patients
who crossed over from placebo to yohimbine did
not show a significant change in response to thera-
py after the changeover. Only 21% of the crosso-
ver group reported some improvement in sexual
functioning over pretreatment levels. 16 % of this
group had responded favorably to placebo in the
first phase of this study. The Turchi trial [32]
demonstrated a significant difference in successes
only in the group of patients with mild complaints
such as inconsistently incomplete erections or loss
of erections during intercourse. It is not clear how
many of the successes had complete recovery with
yohimbine or placebo. Additionally, we are not
informed of the methods used to analyze the data.
The third trial [33] found no significant difference
in response between yohimbine and placebo based
on the daily logs, NPT, VSS and Global Assess-
ment.
• Summary Statement:
The efficacy of yohimbine to restore normal erec-
257
tile function in patients with psychogenic ED has
not been demonstrated.
2. NO OBVIOUS CAUSE ED
Vogt [29] studied patients in this group. His study
combined questionable methodology with unac-
ceptable statistical methods. The group included
86 men who were selected out of 309 men with
ED. Outcomes were based on improvement, not
on functional rigidity. Statistical significance was
achieved by a secondary exploration of a combi-
nation of two negative initial statistical analyses.
3. MIXED (ORGANIC AND PSYCHOGENIC) ED
In two [3, 34] of the four studies of patients with
mixed ED, there was no significant difference
between yohimbine and placebo. A third study
[35], found a significant difference between
yohimbine and placebo only for patients with
psychogenic ED. This appeared to be a very
small clinical effect. We are not informed as to
how many patients had erections, which were
good enough for intercourse, after taking the pla-
cebo or yohimbine. In the fourth study [36],
yohimbine increased the number of men repor-
ting good erections. There was a statistically
significant difference between the favorable res-
ponse to placebo and yohimbine. Missing data
points after 12 weeks however seriously compro-
mised the study. It is probable that these data
would have had a negative impact on the yohim-
bine response rate.
• Summary statement:
The majority of studies have failed to demonstra-
te that yohimbine facilitates functional penile
rigidify in patients with mixed ED. The one study
which suggests this possibility has flaws in
methodology.
4. O RGANIC ED
Three studies [37,38,39] did not demonstrate a
significant difference between the effect of
yohimbine and placebo on the erectile capacity of
patients with organic ED (Table 10).
Table 10 : Yohimbine trials - randomized, double-blind, placebo-controlled trials

STUDY-YEAR NUMBER OF ETIOLOGY STUDY DOSE COURSE QUESTIONNAIRE OBJECTIVE STATISTICAL

PATIENTS DESIGN TEST TEST ANALYSIS

Rowland-1997 11 psych crossover 15 mg 2 weeks NS NS ANOVA

30mg 2 weeks
Turchi-1992 19 psych crossover 1 gm 30 days Significant1 NA Biostatistics
software
Reid-1987 48 psych partial 18 mg 10 weeks Significant 2 NA Chi-square test
crossover
Vogt-1997 83 no obvious no 30 mg 8 weeks NS3 NS Fisher’s Exact
cause crossover
Kunelius-1997 27 mixed crossover 36 mg 25 days NS NS Mann-Whitney
Riley-1989 61 mixed crossover 16.2 mg 8 weeks Significant4 NA Chi-square test
with Yates
correction
Sonda-1990 33 mixed crossover 16.2 mg 4 weeks NS NS Chi-square test
Mann-1996 30 mixed no crossover 15 mg 7 weeks Significant5 NS ANCOVA
Teloken-1998 22 organic sequential 100 mg 30 days NS NA Chi-square test
with Yates
correction
Susset-1989 74 organic partial 22-42 mg 30 days ?6 NA t test
crossover
Morales-1987 100 organic partial 18 mg 10 weeks NSD NA Chi-square test
crossover
1. A significant difference was only noted in patients with mild complaints, such as inconsistently incomplete erections or loss of erections during
coitus. 2. This partial cross-over has a bias toward yohimbine. The small size (<5) of some of the cells makes the statistical analysis questio-
nable. 3. Significance is achieved in only one area of analysis and only through questionable methodology. 4. The data is incomplete after 12
weeks and it is possible that the missing data would significantly alter the statistical analysis. 5. Yohimbine had a very small and not therapeuti -
cally significant effect in patients with psychogenic ED. 6. The difference in response to yohimbine and placebo is unclear.

Central to our current theories of the physiology of

C. PERIPHERALLY ACTING
DRUGS
PDE INHIBITORS
I. SILDENAFIL
1. REVIEW OF SILDENAFIL
Viagra® (sildenafil citrate), a selective inhibitor of
cyclic guanosine monophosphate (cGMP)-specific
phosphodiesterase type 5 (PDE5), initially designa-
ted as compound UK 92,480 by Pfizer research,
was studied in the late 1980s as an anti-anginal
drug. An unexpected side-effect of the early clinical
investigations was improved erectile function
among the men studied. This serendipitous finding
has transformed the field of erectile dysfunction
(ED) therapy.
erection is the role played by nitric oxide (NO). As
shown in Figure 1 a, in the normally functioning
man, NO released from cavernous nerves and from
the endothelial surfaces within the penis during per-
iods of sexual excitement activates the enzyme gua-
nylate cyclase causing an increase in cGMP levels.
Through subsequent activation of ion channels, ele-
vated levels of cGMP induce calcium efflux and
smooth muscle relaxation that results in increased
penile blood flow and tumescence.
The surrounding non-elastic tunica albuginea stret-
ched by the increased penile blood volume limits
the length and girth enhancement producing a rigid
fully erect phallus. cGMP levels remain elevated
only briefly as catalysis by PDE5 rapidly leads to
degradation of cGMP within the penis. In disease
states, such as diabetes, renal failure, or spinal cord
injury, impaired NO stimulated cGMP induced
Ca++ efflux is seen, resulting in reduced penile rigi-
dity.

258
In brief, sildenafil potentiates the physiological
erectile response through inhibition of PDE5, allo-
wing higher local concentrations of cGMP within
the corpus cavernosum. Although sildenafil has no
direct action on the corpus cavernosum smooth
muscle it enhances the biologic response to sexual
stimulation of the cGMP pathway second messen-
ger system through inhibition of PDE5 enzyme
activity (Figure 1 a and b) [1-3].
On March 27, 1998, the Food and Drug Adminis-
tration approved sildenafil, the first oral pill to treat
ED, a dysfunction that affects millions of men
worldwide. Unlike previously approved treatments
for impotence, sildenafil does not directly cause
penile erections, but affects the response to sexual
stimulation. The submission for approval included
21 clinical trials and over 40 pharmacokinetic and
metabolism studies [4].
a) Basic science data
Sildenafil is a member of a class of PDE inhibitors
(Table 1). It is a highly selective inhibitor of
Sildenafil citrate - Viagra , UK-92,480
Viagra is manufactured by Pfizer Pharmaceu-
ticals, New York, NY.
Structural formula
1-[3-(6,7-dihydro-1-methy]-7-oxo-3-propyl-
1 H - p y r a z o l [ 4 . 3 - d ] p y r i m i d i n - 5 - y l ) - 4 - e t h o x y-
phenyl] sulfonyl]-4-methylpiperazine citrate
- molecular weight of 666.7
- a white to off-white crystalline power with a
solubility of 3.5 mg/ml in water
- formulated as a blue, film-coated rounded-
diamond-shaped tablet of 25 mg, 50 mg and
100 mg
cGMP-specific PDE5. Investigations have recent-
ly revealed that isozymes of cyclic-3’,5’-nucleoti-
de PDE are a critically important component of the
cyclic-3’,5’-adenosine monophosphate (cAMP)
and to the cGMP signalling pathways. This super-
family of cyclic-3’,5’-PDE isozymes consists of at
least 11 gene families (types): PDE1 to PDE11.
Many PDE families are diverse and can consist of
several subtypes and isoform-splice variants. PDE
isozymes differ in molecular structure, catalytic
properties, intracellular regulation, location, and
sensitivity to selective inhibitors. They have selec-
tive sensitivities to cAMP and cGMP [5-7].
b) Other selective cGMP PDE inhibitors:
Zaprinast, developed as an anti-allergy agent, was
one of the first type 5 PDE inhibitors to be repor-
ted. It is a weak antagonist and poorly selective
[8]. Excitement over sildenafil has led other phar-
maceutical companies to investigate similar com-
pounds.
c) Potency
Sildenafil is an orally active inhibitor of type 5
cGMP-specific phosphodiesterase and is a more
potent phosphodiesterase type 5 inhibitor than
other known inhibitors with the following selecti-
vities over the other PDE enzymes (>80 fold for
PDE1, >1,0000 fold for PDE 2, PDE 3, and
PDE4). Sildenafil is only about 10-fold as potent
for PDE5 compared to the PDE6 isozyme found in
the retina.
d) Metabolism (Figure 2)
There are 5 primary metabolic pathways of silde-
nafil that include
1) demethylation at the N-methyl piperazine,
2) N-methyl pyrazole moieties,
3) oxidation of the piperazine ring,
4) loss of a two carbon piperazine ring and
5) aliphatic hydroxylation. The major circulating
metabolite results from N-desmethylation of silde-
nafil; this compound is itself further metabolized.
This metabolite has approximately 50% of the
potency of the parent drug with plasma concentra-
tions of approximately 40% of those seen for sil-
denafil. The metabolites account for about 20% of
the pharmacologic effects of sildenafil.

259
Table 1: Families of Phosphodiesterase Inhibitors

SUBSTRATE SUBTYPES OF PHOSPHODIESTERASE (PDE INHIBITORS)

SPECIFICITY TYPE OF TISSUE SPECIFICITY COMPARATIVE ACTIVITY#
PDE 1 cAMP+ cGMP Cardiac ventricle cells 80
calcium/calmodulin-dependent
PDE 2 cAMP+ cGMP Human corpora cavernosa 55,000
PDE 3 cAMP Smooth muscle, platelets
and cardiac tissue 30,000
(milrinone inhibits)
PDE 4 cAMP Human skeletal muscle 15,000
brain and lung lymphocytes
(rolipram inhibits)
PDE 5 cGMP Predominant enzyme of
human corpus cavernosum 1
PDE 6 cGMP Rod specific cGMPis a key
enzyme of the phototransduction 10
cascade.

# adapted from Boolell et al 1996

The P450 system, and in particular CYP3A4 and
CYP2C9, is responsible for the metabolism of sil-
denafil. Sildenafil is cleared predominantly by the
CYP3A4 (major) and CYP2C9 (minor) hepatic
microsomal isoenzymes. Drugs that can cause an
increase in sildenafil serum concentrations by
inhibiting the CYP3A4 system include protease
inhibitors (ritonavir, indinavir, saquinavir), cimeti-
dine, erythromycin, and ketoconazole (Table 2). A
list of drugs that inhibit CYP3A4 is included in the
ACC/AHA Expert Consensus Document, 1999
[8]. However sildenafil itself has no inhibitory
effects on the P450 system and hence does not
interfere with the metabolism of drugs that rely on
this system for their catabolism.
The terminal half-life of both sildenafil and its
metabolites is 4 hours. Maximum observed plasma
concentrations are reached within 30 to 120
minutes with a median of 60 minutes following
oral dosing in the fasted state. This absorption is
reduced after a high fat meal. There is no signifi-
cant interaction with alcohol.
e) Mechanism of action
Penile erection is dependent on NO and its second
messenger cGMP. cGMP is the ubiquitous second
messenger for G-protein coupled receptors activa-
ted by endogenous substances such as NO and
atrial natriuretic peptide (Figure 2 b). Intracellular
levels of cGMP are controlled by activation of
nucleotide cyclases and breakdown by PDEs.
Neuronal NO is believed to be the main pathway
Table 2: P450 Hepatic metabolism
INHIBITORS
CYP3A4 Erythromycin
Ketoconazole
Itraconazole
Cimetidine
Ritonavir
Saquinavir
CYP2C9 Tolbutamide
Warfarin*
*no evidence that this inhibition alters sildenafil concen -
trations
for penile smooth muscle relaxation and erection.
Stimulation of penile autonomic innervation
releases NO which activates guanylate cylase and
enhances levels of cGMP. Elevated levels of
cGMP in penile smooth muscle are normally
hydrolyzed by PDE5. Inhibiting the cGMP break-
down catalyzed by PDE5 amplifies the neuronal
NO/cGMP pathway essential for relaxation of
human corpus cavernosum. The final erection
results from relaxation of smooth muscle control-
ling inflow of blood to the corpus cavernosum.
PDE5 has no direct effect on cavernosal tissue
(Figure 2 b).
The guanylate cyclase system affects vascular
dilatation which may be associated with lowering
of blood pressure. In addition, the guanylate cycla-
se system is involved in controlling platelet aggre-
gation; in vitro PDE5 inhibition with sildenafil has

260
Figure 1 a: Physiology of penile erection

Figure 1 b: The mechanism of action of sildenafil in penile erection

261
Figure 2a: Metabolism of sildenafil

Figure 2 b: Second messenger cGMP pathway

262
been shown to result in inhibition of platelet
aggregation in the presence of the NO donor
sodium nitroprusside; however sildenafil shows
no direct effects on bleeding time when taken
either alone or with aspirin [4].
f) Recommended doses:
Sildenafil is available in 25, 50, and 100 mg doses.
For most patients the recommended starting dose
is 50 mg to be taken as needed approximately
1 hour before planned sexual activity.
g) Review of animal experimentation carcinoge -
nesis, mutagenesis, and effects on fertility
Sildenafil was not carcinogenic when administe-
red to rats for 24 months, at a dose resulting in
total systemic drug exposure to unbound sildenafil
and major metabolite corresponding to 29 and 42
times, for male and female rats, respectively, the
exposures observed in human males given the
maximum recommended human dose of 100 mg.
Sildenafil was not carcinogenic when administe-
red to mice for 18 to 21 months at dosages up to
the total maximum tolerated dose of 10
mg/kg/day. Sildenafil was negative in the in vitro
bacterial and Chinese hamster ovary cell assay to
detect mutagenicity and in vitro human lympho-
cytes and in vivo mouse micronucleus assays to
detect clastogenicity.
There was no impairment of fertility in rats given
sildenafil up to 60 mg/kg/day for 36 days to
females and 102 days to males, a dose correspon-
ding to more than 25 times the human male dose.
Table 3: Subjects in clinical trials.
SILDENAFIL
PHASE II/III ONLY
Single Dose 98
PRN 2600
Multiple-daily 305
Table 4: Subjects in placebo-controlled and open-label controlled studies
Age (years)
18-28 28-38 38-48 48-58
PBO 10 124 351 930
OL 2 33 154 545
263
There was no effect on sperm motility or morpho-
logy after single 100 mg oral doses of sildenafil in
healthy volunteers [4] No effects of sildenafil on
spermatogenesis have been demonstrated [4].
2. CLINICAL DATA
The clinical data for submission to FDA included
several thousand men. Over 1000 subjects partici-
pated in fixed-dose, placebo-controlled studies for
6 months. Placebo-controlled titration studies of 1
to 6 months involved another 1500 subjects.
Open-label studies contributed around 1000 sub-
ject-years of exposure to sildenafil.
The men in the clinical trials, including both the
dose-response and dose-escalation studies, ranged
from 20 to 87 years of age with a mean between 57
and 60 (Tables 3, 4). Ninty-four percent of the sub-
jects in the clinical studies were Caucasian.
Sildenafil was evaluated primarily at doses of 25
mg, 50 mg, and 100 mg in 21 randomized, double-
blind placebo-controlled trials of up to 6 months in
duration. Efficacy trial results were analyzed in
terms of entry criteria, objective and subjective
means of efficacy assessment, adverse reactions
and complications.
In 8 double-blind, placebo-controlled crossover
studies of patients with either organic or psycho-
genic ED, sildenafil resulted in improved erections
as assessed by an objective measurement of hard-
ness and duration of erections using RigiScan®.
Most studies assessed the efficacy of sildenafil
approximately 60 minutes post-dose.
PLACEBO TOTAL
- 98
769 3369
- 305
Total
58-68 68-78 78-88 88+
1373 993 152 2 3935
790 595 79 1 2199
The inclusion criteria were men age >18 with ED
of more than 6 months duration and in a hetero-
sexual relationship for >6 months.
The exclusion criteria included those with blood
pressure outside the 90/50 to 170/100 mm Hg
range. Patients could be entered once their blood
pressure was controlled. There was a 4-week,
treatment-free run-in period during which baseline
sexual performance data were collected.
The primary measurement of efficacy was a scien-
tifically developed and validated sexual function
questionnaire, the International Index of Erectile
Function (IIEF), administered during a 4-week
treatment-free run-in period, at baseline, at follow-
up visits and at the end of double-blind, placebo-
controlled at home treatment [10].
The IIEF was developed as a simple scale to be
used in the multi-national assessment of erectile
function. The IIEF is a 15-item self-report ques-
tionnaire that received initial testing for feasibility
and face validity in a clinical population and has
been translated and linguistically validated into
most major languages and dialects. The entire
IIEF is included in Annex II.
Two of the IIEF questions served as primary
study endpoints
Question 3: Over the past 4 weeks when you
attempted sexual intercourse, how often were you
able to penetrate (enter) your partner?
Question 4: Over the past 4 weeks during sexual
intercourse, how often were you able to maintain
your erection after you had penetrated (entered)
your partner.
The categorical responses for all 15 questions
were
(0) - no attempted intercourse
(1) - never or almost never
(2) - a few times
(3) - sometimes
(4) - most times
(5) - almost always or always
Improvement in erections in hypertensive patients
and diabetic patients are noted in Figures 3 and 4
[11-13].
264
Other measurements included in the clinical trials
were latency, rigidity, frequency, and duration of
erections with RigiScan monitoring.
Partner satisfaction was not evaluated in all stu-
dies, but when it was evaluated it looked at part-
ner’s satisfaction with treatment, and overrall
satisfaction with treatment; partners were also
asked to evaluate the quality of the erection.
In the clinical trials, men were included with the
following concomitant conditions: hypertension,
ischemic heart disease, hyperlipidemia, history of
radical prostatectomy, spinal cord injury, and dia-
betes mellitus.
a) Efficacy in diabetic men:
A specific diabetic-only protocol reported by Ren-
dell et al [13] entered 268 patients who were eva-
luated for safety and efficacy.
Subgroup analysis from these trials lasting bet-
ween 6 and 26 months demonstrated improved
erectile function in 59% of patients on active drug
compared with 15% receiving placebo. Approxi-
mately 20% of the men were type 1 and 80% type
2 diabetics.
Doses between 25 and 100 mg of sildenafil were
tested. After 12 weeks of study (n=136) IIEF ques-
tion 3 and 4 scores were 3.2 vs 2.0 and 2.9 vs 1.6
for sildenafil versus placebo, respectively.
The global efficacy question demonstrated an
improvement in 57% of diabetic men receiving
sildenafil compared with 10% of those receiving
placebo (Figure 3) [13,14].
Figure 3: Improvement in erections in diabetic patients.
b) Efficacy in psychogenic ed or men without
identifiable organic causes:
These studies were performed early in the clinical
trial program and resulted in a clear dose-response
relationship of sildenafil to erectile function
improvement. At doses between 10 and 100 mg,
65-93% of patients reported improved quality of
erections. In these early trials, 87% of patients had
doses titrated up to 50 or 100 mg of sildenafil.
With active drug, patients described having erec-
tions firm enough for penetration 1.52 times per
week compared to 0.64 for placebo [15].
c) Efficacy in spinal cord injured men:
An early pilot study evaluated 12 men over a brief
4-week period. Patients were selected based on
reporting some residual erectile function after
traumatic spinal cord injury. In this cohort of men
with incomplete injuries, 9 of 12 reported that 50
mg of sildenafil improved their erections compa-
red to 1 of 14 on placebo. Interestingly, 16 of 25
men without evidence of residual erectile function
Figure 4: Improvement in erections post radical prostatectomy - Viagra product monograph.
265
pretreatment reported improved function with sil-
denafil [16]. In the largest sildenafil study on spi-
nal cord injured men, 111 of 143 (78%) reported
improvement in erections at doses between 25 and
100 mg over a 6-week study period [17]. This
study also reported improvements in quality of life
in both SCI men and their partners [18].
d) Efficacy in post-radical prostatectomy men:
Men post-radical prostatecomy were included
across trials and had a reported 43% improvement
versus 15% (Figure 4) [19,20].
In summary, treatment with sildenafil was well
tolerated and the studies demonstrated statistically
and clinically significant improvement in erec-
tions when compared to placebo in all clinical
trials. Studies in special populations, e.g., hyper-
tension, depression, diabetes mellitus, spinal cord
injuries and post radical prostatectomy patients
also demonstrated significant improvement in
erections.
3. SPECIAL CONSIDERATIONS Concomitant medical conditions in men with ED
a) Cardiovascular disease: are important to consider because of the possible
adverse effects involved in sexual activity [see
In the clinical studies there were no relevant ECG
Appendix I]. Tables 5 a and b show the associated
changes noted in normal male volunteers. There
were transient decreases in blood pressure with factors and medications applying to the men with
sildenafil that were not associated with mean ED involved in the sildenafil trials.
changes in heart rate. Although such effects are of A subgroup analysis of men on antihypertensive
little consequence to most patients, caution is agents were compared to men not on antihyper-
advised in patients who may not be able to tolera- tensive drugs. The hypertension-treated group
te such changes (e.g. patients with aortic stenosis, reported sildenafil response at 70% compared to
hypertrophic obstructive cardiomyopathy, and the age-matched group without hypertension treat-
patients with severely impaired autonomic dys- ment at 72%. Placebo-controlled reported respon-
function). In healthy volunteers with single oral se rates were 21% and 27%, respectively (Figure
administered doses of 100 mg there was a mean 5) [11]. Conti et al. [21] noted that patients with
maximum decrease of 8.5 mm Hg for systolic and erectile dysfunction and ischemic heart disease
5.5 mm Hg for diastolic blood pressure (see silde- who were not taking nitrate therapy tolerated sil-
nafil label annex IV). The decreases in blood pres-
denafil.
sure were most notable approximately 1 to 2 hours
after dosing and returned to normal within 8 See also Jackson et al, 1999 [22] for further dis-
hours. These blood pressure changes were not cussion of hemodynamic changes in men with
considered to be dose or plasma level related. stable ischemic heart disease.
Table 5 a: Predisposing factors for ED in clinical trial Table 5 b: Concomitant medications in clinical trial patients.
patients
ACE inhibitors 283 10%
Hypertension 656 24% Ca Channel Blockers 266 10%
Diabetes mellitus 432 16% Beta Blockers 123 5%
Cardiovascular disease 376 14% Diuretics 112 4%
Insulin 137 5%
Hyperlipidemia 389 14%
Oral anti-diabetic drugs 260 10%
Spinal cord injury 175 6%
Analgesics 490 18%
Depression 132 5% Drugs for hyperlipidemia 249 9%
Radical prostatectomy 1 10 4% Ulcer-healing drugs 140 5%
Antidepressant drugs 104 4%
Regulatory submission database, placebo-controlled studies
SILDENAFILN=2722, PLACEBO N=1552 Regulatory submission data base, placebo-controlled studies
SILDENAFIL N=2722, PLACEBO N=1552

Figure 5: Improvement in erections in hypertensive patients

266
b) Effects on Color Discrimination : Table 6: Treatment-related adverse events and discontinua -
tion from treatment.
There may be a transient dose-related impairment
PLACEBO SILDENAFIL
of blue/green color discrimination. This is repor-
50mg 100mg 200mg
ted in less than 3% of patients and the effects on (N=181) (N=189) (N=190) (N=191)
blue-green color discrimination have been shown
N % N % N % N %
to occur usually 1 to 2 hours post-dosing during
Headache 7 (4) 34 (18) 58 (31) 63 (33)
peak plasma levels of the drug [4]. These pharma-
Flushing 7 (4) 37 (20) 37 (20) 33 (17)
cological changes are consistent with the inhibi-
Dyspepsia 2 (1) 11 (6) 38 (20) 35 (18)
tion of PDE6 which is involved in retinal photo-
transduction and is the reason for the FAA recom- Abnormal vision 0 (0) 3 (2) 28 (15) 80 (42)
mending that pilots should not fly within 6 hours Discontinued
treatment 9 (5) 5 (3) 4 (2) 9 (5)
of using sildenafil. Sildenafil has no effects on
visual acuity or intraocular pressure [4]. Adapted from Morales [23] – Amsterdam meeting presentation
1998
c) Use in Special Populations
• Geriatric population A clinical study demonstra- dicated to use sildenafil because of the risk of deve-
ted that men older than 65 years had a significant- loping potentially life-threatening hypotension. As
ly reduced apparent clearance of sildenafil after a a PDE5 inhibitor sildenafil potentiates the hypoten-
single 50 mg dose. There was a 4% decrease in sive effects of cGMP generated by nitrates. The
drug clearance for each age decade increase. combination of sildenafil with organic nitrates can
produce profound hypotension.
• Hepatic impairment Clinical trials demonstrated
that chronic stable hepatic cirrhosis altered the Data describing a safe interval between sildenafil
pharmacokinetics of sildenafil. In cirrhotic and nitrates is not available, however patients
patients there was a 46% lower drug clearance lea- should be warned prior to use of any nitroglycerin
ding to an 85% increase in drug exposure. product that a 24-hour minimal time interval is
likely required to allow for complete elimination of
• Renal impairment Men with severe renal sildenafil in most men [9].
impairment, i.e. creatinine clearance <30mL/min,
had significantly altered metabolism of sildenafil. b) Precautions
The increased exposure to the active drug was The labeled warnings which imply caution is requi-
attributed to a reduction in oral clearance. Men red when sildenafil is administered to patients who
with lesser degrees of renal impairment metaboli- were not studied in clinical trials at the time of
zed the drug normally. review and approval.
Since higher plasma concentrations may increase - patients who have suffered a myocardial infarc-
both the efficacy and incidence of adverse effects, tion, stroke, or life-threatening arrhythmia
consideration should be given to starting patients within the last 6 months
who are older than 65 years, or with hepatic or - patients with resting hypotension (BP<90/50) or
severe renal impairment at a dose of 25 mg and hypertension (BP>170/110)
increasing the dose as indicated [4].
- patients with cardiac failure or coronary artery
4. SAFETY PROFILE disease causing unstable angina
The safety profile of sildenafil is illustrated by both - patients with retinitis pigmentosa (a few of these
Table 6 and the sildenafil label (Annex IV). It patients have genetic disorders of retinal PDEs).
should be noted that few patients discontinued treat- Patients requiring a complicated antihypertensive
ment; the discontinuation rate was not significantly regime may also need to be cautioned when using
different from placebo in clinical trials (2.5% vs sildenafil, as clinical data confirming safety in this
2.3%) [4]. population is limited [9].
a) Contraindications c) Post-Approval Safety Surveillance and Sponta -
neous Cardiac Reports
Patients undergoing any short or long-acting nitra -
te drug therapy or nitric oxide donors are contrain- Almost immediately following the FDAapproval of

267
sildenafil in the United States, reports of treatment
associated cardiovascular adverse events began to
appear in the lay press and were subsequently pos-
ted on an FDA website. The reports of sildenafil-
linked cardiovascular events generated great
concern among patients and physicians, however
their clinical significance remain undetermined.
While some of the cases listed were clearly unrela-
ted to drug intake (drowning and homicide) or
based on heresay and unsupported statements
alone, other reports were concerning about a pos-
sible increased cardiovascular risk among sildenafil
users. The last update on this website was perfor-
med in November 1998. An initial revised label for
sildenafil in November 1998 added the exclusion
criteria from the phase 3 studies and reports of pria-
pism in most marketing experience, not seen among
the preapproval studies. A more recent labeling
change occurred in November 1999 and included
information on protease inhibitors and recent hemo-
dynamic data (See label Table) [22]. For more
detailed information the reader is referred to the
product monograph (Annex IV).
In the interval since approval (March 1998), a vast
clinical experience has been achieved which permits
a more refined evaluation of the issue of cardiovas-
cular impact and safety associated with sexual acti-
vity as its relates specifically to sildenafil use.
Recently, pooled data from 53 studies (30 double-
blind and 23 placebo-controlled) trials involving an
exposure of 6884 patient years for sildenafil was
compared to those patients receiving placebo (543
patient years) has been reported (Table 7). Incidence
rates of myocardial infarction and death per 100
patient years demonstrated no increase in the treat-
ment arms compared to placebo [23].
Table 7: Incidence of serious adverse events
Myocardial Infarction*
As for all drugs, the manufacturer the FDA and
regulators wolrldwide continue to monitor all spon-
taneous adverse reports in order to maintain the safe
use.
5. SUMMARY
Since the approval of sildenafil the clinical safety
and efficacy of sildenafil has been studied in
numerous trials that have includ patients with ED
due to organic, non-organic, and mixed etiologies.
Over the past 4 years sildenafil has undergone
numerous multicenter placebo-controlled trials
demonstrating efficacy, as shown in Table 8.
Recently, individual center experiences with silde-
nafil from general urology practices have been
published [34,35] that support the efficacy and
safety data from the pre-approval submission.
Improvement in ability to achieve and maintain a
rigid erection (Questions 3 and 4 of the IIEF) show
significant improvement. A 65-85% positive res-
ponse is seen in most studies describing general
improvement in quality of erections.
Sildenafil appears to be an effective and well tole-
rated oral therapy for the treatment of ED across a
broad spectrum of etiologies. The clinical data bank
upon which this PDE type 5 inhibitor has achieved
approval in 101 countries world-wide is impressive
in scope and consistency. The interaction with nitro-
glycerin compounds and safety in subpopulations
with ischemic heart disease, angina, and those who
wish to use other erectogenic agents in a concomi-
tant fashion remains to be elucidated in future stu-
dies. The use of this first oral therapy should not
preclude the appropriate evaluation of the causes of
sexual dysfunction. Satisfactory sexual function is
an important part of a couple’s healthy relationship
and ongoing quality of life.
Death*

Placebo (543) 1.11 (0.41-2.40) 0.74 (0.20-1.89)

Sildenafil DB (964) 1.45 (0.79-2.44) 0.83 (0.36-1.64)
Sildenafil OL (5920) 0.69 (0.50-0.94) 0.35 (0.22-0.54)
Sildenafil Total (6884) 0.80 (0.60-1.04) 0.42 (0.28-0.61)

*Data are mean incidence per 100 patient years (95% confidence interval)
Adapted from Mittleman MM, Glasser DB, Orazem J, Collins M: Incidence of Myocardial infarction and death in 53 clinical
trials of Viagra® (sildenafil citrate). J Am Col Cardiol 35(Suppl.A):302,2000.

268
Table 8: Table of sildenafil in clinical trials

SILDENAFILIN ERECTILE DYSFUNCTION

TREATMENT SIL DOSE NUMBER PATIENT/POPULATION RESULTS

REFERENCE PERIOD IN WEEKS OFPATIENTS STUDIED DOSAGE %

Cuzin,1997 [25] 24 25 - 100 mg 205 organic - 29% SIL 79

non organic - 32% PL 27
mixed - 36%
Derry,1998 [16] 4 50 mg 27 organic - 100% SIL 75
spinal cord injury PL 7
Eardley,1996 [26] 4 25 - 75 mg 42 non organic --100% SIL 92
PL 27
Goldstein,1998 [27] 24 25 - 100 mg 532 organic - 78% 25 mg 56
non organic - 9% 50 mg 77
mixed - 13% 100 mg 84
PL 25
Hodges,1997 [28] 12 25 - 100 mg 111 organic - 40% SIL - 81
non organic - 39% PL 18
mixed - 8%
Holmgren,1998 [17] 6 50, 100 mg 178 organic-100 % spinal SIL 76
- cord injury PL NR
Lue,1997 [29] 8 5 - 100 mg 416 organic - 73% 5 mg 48
non organic - 9% 25 mg 61
mixed - 25% 50 mg 73
100 mg 78
PL 28
Morales,1998 [30] 12 50 - 200 mg 497 organic - 58% 50 mg 72
non organic - 17% 100 mg 80
mixed - 25 200 mg 79
PL 21
Morales,1998 [30] 12 50 - 200 mg 254 organic - 49% 50 mg 72
non organic - 7% 100 mg 80
mixed - 44 200 mg 79
PL 21
Montorsi, 1999 [31] 12 25, 50, 100mg 515 organic -29% SIL 84
non organic - 24% PL 24
mixed - 46%
Montorsi,1998 [32] 12 25 - 100 mg 514 organic - 43% 25 mg 67
non organic - 32% 50 mg 78
mixed - 25% 100 mg 86
PL 24
Olsson,1996 [33] 4 10 - 50 mg 351 non organic - 58% 10 mg 65
mixed - 42% 25 mg 79
50 mg 88
PL 39
Padma-Nathan, 44 25 - 100 mg 329 organic - 59% SIL 74
1998 [34] non organic - 15% PL 19
mixed - 26%
Rendell,1998 [12] 12 50. 100 mg 268 organic-96% diabetic SIL 57
mixed - 4% PL 10

Legends: SIL: sildenafil; PL: Placebo; NR: dose not recorded

269

II. IC-351
1. INTRODUCTION
IC-351 is a selective orally available PDE-5 inhi-
bitor. As discussed in the section on Sildenafil,
phosphodiesterases (PDE’s) facilitate the hydroly-
sis of secondary messengers (c-AMPand c-GMP).
Therefore PDE inhibitors would block cyclic
nucleotides thereby increasing normal cellular
signals by increasing secondary messenger
concentrations.
PDE inhibitors will only work after appropriate
stimulation has been forthcoming. To date 10
types of human cyclic nucleotide PDE’s have been
identified. PDE-5 is the PDE specific for both c-
GMP and the human corpus cavernosum.
2. FEATURES IC-351
IC-351 is a longer acting PDE-5 inhibitor than sil-
denafil and therefore may be effective over a much
longer period of time. This property may be both a
positive and negative element. Obviously if IC-351
remains active over many hours it preserves the abi-
lity to be spontaneous to a greater degree than a
shorter acting PDE-5 inhibitor. However prolonged
PDE-5 inhibition may cause more and prolonged
side effects not seen with shorter acting agents.
Another potential specific improvement over silde-
nafil is the relatively poor inhibitory properties of
IC-351 towards PDE-6 (found in the retina) in
contrast with sildenafil. While sildenafil is only 10
times more potent against PDE-5 than PDE-6, IC-
351 is approximately 800 times more potent. Thus
one would expect little in the way of visual adverse
events with the use of IC-351 (see Table 1).
Table 1: IC351 Selectivity
PDE IC50 (nM)
Human PDE 5 0.9 ± 0.12
Human PDE 6 730 ± 120
Data provided by ICOS/Lilly
270
3. CLINICAL STUDIES
The effect on erectile function of IC-351 has been
assessed in a Phase II study measuring Rigiscan res-
ponse to visual sexual stimulation [1].
44 patients with mild to moderate erectile dysfunc-
tion for at least 6 months duration, ages 21-60 were
entered into a double-blind, placebo-controlled,
single crossover study. Each patient therefore
underwent 2 sessions, one with placebo and one
with 100 mg of IC-351 given prior to Rigiscan
monitoring of response to VSS. In addition the
patient evaluated the best erection by a 5-point
scale. Response to IC-351 was reported as the dif-
ference in Rigiscan values obtained during a pre-
vious placebo run-in phase. The increase in > 55%
rigidity at the penile base was 1.43 ± 6.34 minutes
for placebo and 9.43 ± 12.66 minutes for IC-351
(p<0.001).
The mean increased area under the Rigiscan curve at
the base was 179 +/- 558.7 for placebo and 723.8 ±
830 for IC351 (p<0.001). Similar effects were seen
at the penile tip. The patient’s change in his erectile
assessment was 0.5 for placebo and 1.6 for IC-351
(p<0.001). There were no significant adverse events,
EKG or vital sign changes during the study.
The most common side effects were headache, back
pain and dyspepsia.
Two other larger placebo-controlled, double-blind
multicenter safety and efficacy studies in mild to
moderate ED have been performed to date with IC-
351. 300 patients at 19 sites undergoing a daily dose
study were randomized to either 4 different doses of
IC351 or placebo (5 groups) daily for 3 weeks.
The study endpoints were change in IIEF res-
ponses (especially questions 3 and 4) as well as
personal diaries. In another study, 175 patients
underwent an on-demand study and were rando-
mized to the same 5 groups. Patients were permit-
ted to take up to 14 pills in a 21-day period.
The endpoints in this study were similar to those
of the daily dose study. Unfortunately the results
of these studies are not yet available for analysis.

NO DONORS
L-ARGININE/YOHIMBINE
1. INTRODUCTION AND COMBINATION RATIO-
NALE
The combination of drugs that can produce direct
smooth muscle relaxation along with blocking a-
adrenergic contraction has proven beneficial in
treating erectile dysfunction in man. Alpha bloc-
king agents have been shown clinically to poten-
tiate the effects of direct vasodilators in the area of
intracorporal pharmacotherapy with the combina-
tion of Papaverine and/or prostaglandin E-1 (both
smooth muscle relaxants) with phentolamine. It
has recently been shown that the ability of yohim -
bine to relax endothelin contracted corporal
muscle strips was significantly enhanced by nitro-
sylated yohimbine [1].
This action was further potentiated by Zaprinast, a
selective PDE-5 inhibitor. There was also a
concentration-dependent increase of tissue c-GMP
seen with nitrosylated yohimbine but not with
yohimbine alone. These observations demonstrate
that nitosylated a-blockers act as NO donors as
well as an alpha blocking agents. In addition it has
been shown that intracavernosal injections in the
rabbit of nitrosylated yohimbine produced higher
intracavernosal pressures for longer duration than
the injection of yohimbine alone.
The enhancement of yohimbine corporal smooth
muscle relaxation by nitrosylation formed the
rationale for combining yohimbine with L-argini-
ne, a NO precursor, for the treatment of erectile
dysfunction.
2. P HARMACOLOGY
Yohimbine has previously been presented in this
chapter. Arginine is an endogenous amino acid,
which plays an essential role in protein synthesis.
In addition it is a precursor of NO in the equation:
arginine + O2 = NO + citrulline in the presence of
NOS. Arginine is available in the United States as
a non-prescription food supplement sold in 700
mg tablets. It is also available in liquid nutritional
271
supplements in concentrations of 13.2 g/L and
23.2 g/L. Patients have taken 10 g of arginine per
day over prolonged periods without adverse
effects. Arginine is absorbed in the gut and reaches
peak levels in about 2 hours. Radio-labelled L-
arginine studies have shown that approximately
1% of dietary L-arginine is excreted as labeled
nitrate in the urine.
3. CLINICAL STUDIES: L-ARGININE ALONE
Intravenous arginine infusion (30 g over 60
minutes) has been successfully used to produce
NO-dependent vasodilatation in cases of severe
limb ischemia [2]. Femoral artery blood flow was
significantly improved by 8%, while urine levels
of NO3- and c-GMP increased by 39.5% and
84.9%, respectively. These effects were not seen
with infusion of placebo.
In another study, patients with congestive heart
failure were treated with oral arginine, 5.6-12.6
grams or placebo daily for 6 weeks [3]. L-arginine
significantly improved forearm blood flow in res-
ponse to exercise, increased distances achieved
during a 6-minute walk, improved arterial com-
pliance and decreased circulating endothelin
levels as compared to placebo in these patients.
In 1994 Zorgniotti [4] treated 20 impotent men
with 2800 mg of L-arginine vs. a placebo daily for
2 weeks. The placebo was given first. Patients
older than 65 years or with significant vascular
risk factors were excluded. Six of the 15 patients
who completed the study responded positively to
L-arginine treatment. None of the placebo group
responded. The responders were younger and had
better penile arterial pressures than the non-
responders.
In 1999 Chen et al. randomized 50 patients with
organic ED to 5 g of L-arginine per day and pla-
cebo. Patients responded to the O’Leary sexual
questionnaire, recorded sexual diaries and under-
went penile duplex ultrasonography. In addition,
serum levels of nitrites and nitrates were determi-
ned pre- and post-therapy. 31% of the treated
group and 11% of the placebo group reported sub-
jective improvement of their erections. There was
no difference between these groups or between
responders and non-responders in terms of objec-
tive results of duplex ultrasonography (i.e. peak
systolic velocity, end-diastolic velocity or resistive
index). Urinary and serum nitrate and nitrite levels
were statistically increased in the L-arginine trea-
ted group. Initial levels of these metabolites were
significantly lower in responders than in non-
responders. No side effects were noted [5]
4. CLINICAL STUDIES: L-ARGININE AND
YOHIMBINE
Recently, two studies in men with mild to modera-
te erectile dysfunction have been performed using
the combination of L-arginine and yohimbine.
Padma-Nathan [6] performed a double-blind, cros-
sover study between L-arginine (6 g) and yohim-
bine (6 g) (A/Y) vs. Yohimbine and placebo (Y/P)
on 20 patients. Initially patients were tested with
placebo/placebo (P/P) in a single-blind fashion
prior to randomization. Doppler ultrasound of the
cavernosal arteries was performed in intervals bet-
ween 60 and 105 minutes following the 3 combi-
nations in 3 separate visits. Mean peak systolic
velocities at 60 minutes were 13.47, 10.6 and 6.44
for A/Y, Y/P and P/P, respectively.
The results seen with the drug combination (A/Y)
were statistically significant compared to placebo
(P/P). This was not true for yohimbine alone (Y/P
vs. P/P) In another study, Barre [7] et al used the
same three groups (A/Y, Y/P, P/P) to treat 48
patients with ED on demand in the home setting.
Efficacy was assessed by the IIEF.
In this study, the erectile function domain respon-
se statistically improved in men in the A/Y group
as compared to the P/P group (p=0.004) and sho-
wed a trend to improvement as compared to the
Y/P group (p=0.096). The global sexual satisfac-
tion score was statistically improved in the A/Y
group as compared to the Y/Pgroup (p=0.047) and
P/P group (p=0.022).
5. CONCLUSION
It should be noted that in many countries both
Yohimbine and L-arginine are available as over
the counter drugs (i.e. no prescription needed).
The adverse effects of this combination were mini-
mal. It would appear that larger Phase III studies
are required to determine the efficacy of these
drugs for the treatment of milder forms of ED.
272
E. POTENTIAL COMBINATION
THERAPIES
ERECTILE INITIATORS
- apomorphine
- melanotan II
PERIPHERAL SMOOTH MUSCLE RELAXANTS:
- PDE-5 inhibitors
- alpha blocking agents
- NO precursors
Combination therapy may involve any number of
agents until a desired effect is obtained or side
effects become intolerable. It would seem plau-
sible that the erectile response of an initiator
should be enhanced by the addition of a periphe-
rally acting corporal smooth muscle relaxant.
Drugs that act on the CNS would be expected to
ultimately stimulate NO release in an enhanced
manner by facilitating sacral parasympathetic
nerves. They presumably work by delivering more
NO than the normal physiological response. The-
refore patients who fail peripherally acting agents
should theoretically have increased corporal
smooth muscle relaxation by combining a per-
ipherally with a centrally acting drug.
Two recent papers addressed this issue of central
and peripheral synergy. Heaton studied the impact
of severe stress induced by adrenergic stimulation
on erections induced by apomorphine alone, silde-
nafil alone or a combination. Andersson et al. [1]
recorded intracavernosal pressures in the awake
rat after subcutaneous apomorphine injection. The
intracavernosal pressure increases following apo-
morphine injection was prolonged (from 37 to 62
s) and increased (area under the curve: from 67 to
142) by an intravenous injection of sildenafil.
Brien et al. [2] demonstrated that in the rat the rate
of apomorphine induced erections in the presence
of hyperadrenergic “stress” (produced by ip.
methoxamine) was improved after intraperitoneal
administration of sildenafil.
As with combination therapy used for intracaver-
nosal pharmacotherapy, synergies exist between
peripherally acting agents. Thus combined therapy
with two or three of the peripheral agents would
seem likely to successfully treat a larger percenta-
ge of ED patients than using one agent alone. As
the addition of phentolamine (blocks smooth
muscle contraction) enhanced the results of Papa-
verine (promotes smooth muscle relaxation) intra-
cavernosal injections alone, so may the addition of
oral phentolamine add to the performance of a
PDE-5 inhibitor. Combination therapy with
yohimbine and L-arginine attempts clinically to
prove this principle.
FUTURE COMBINATION THERAPIES
ORAL DRUGS: SITE OFACTION
Apomorphine and sildenafil central and peripheral
Apomorphine and phentolamine central andperipheral
Apomorphine, sildenafil and
phentolamine central and peripheral
Sildenafil and phentolamine central and peripheral
In the future newer drugs will assuredly be develo-
ped to treat ED. An endothelin antagonist and a pro-
tein G inhibitor are just beginning clinical trials.
More specific and longer acting PDE-5 inhibitors
are also undergoing clinical trials.
Within several years it would be expected that 3 or
4 drugs will be FDA approved and clinically avai-
lable for ED treatment. Basic science investigations
have shown that the natural history in most age-
related (vasculogenic) ED begins with mild arterial
insufficiency and progresses to more severe arterial
damage and secondary corporal collagen replace-
ment and venous leak. It would be interesting if oral
treatment (which as mentioned above will begin at
the stage of mild arterial disease) will be able to
alter the natural history of the disease by promoting
erections and thereby bringing oxygen rich blood to
the corporal muscle. This may forestall collagen
replacement of the corporal smooth muscle despite
progressive worsening of the arterial insufficiency
and allow oral agents to work for a longer period of
the patient’s life.
F. CONCLUSION
This chapter has attempted to critically review the
oral agents (with the addition of melanotan II) pre-
sently available for the treatment of ED. These
drugs can be classified with respect to their phar-
macologic action in several ways. They can be
273
expected in many cases to act synergistically as
their modes of action usually differ. With the
expected FDA approval of more of these agents,
we can therefore expect a wide array of potential
combination therapies.
If this becomes the case one can expect that the
primary care physician will continue to orchestra-
te ED treatment with a wider array of therapeutic
possibilities. The urologist who had been the pri-
mary physician for the treatment of ED prior to
successful oral drug therapy will most likely in the
future see less and less early ED and more and
more organic disease. The questions raised in the
introduction of this chapter regarding the role of
the psychologist and the new diagnostic algorithm
will certainly need to be addressed. Another
byproduct of better and improved medicines and
combination therapies may well be patients see-
king treatment with earlier disease.
This will be much the same as the experience with
the advent of oral agents for benign prostatic
hyperplasia when patients with mild symptoms
who would not have sought treatment when only
surgical therapy was available began taking oral
agents. This may initially increase the number of
new patients for ED therapy but eventually a stea-
dy state will be reached with a larger proportion of
patients with earlier vascular disease which will be
more amenable to oral medicines.
Again the urologist will be seeing patients with
more advanced ED who have failed oral drugs.
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_________________________
 ANNEXES I - IV

ANNEX I
RISK FACTORS FOR CARDIOVASCULAR DISEASE
MEDICAL CONDITIONS ASSOCIATED WITH ED

ANNEX II
INTERNATIONAL INDEX OF ERECTILE FUNCTION QUESTIONNAIRE

ANNEX III
USE OF SILDENAFIL (VIAGRA) IN PATIENTS WITH CARDIOVASCULAR
DISEASE (ACC/AHA CONSENSUS)

ANNEX IV
VIAGRA® (SIDENAFIL CITRATE) LABEL (Revised June 1999)

279
 ANNEX I

Risk Factors for Cardiovascular Disease

Family history of CHD <55 years old
Current smoking
Hypertension >140/90 mmHg or on antihypertensive
medication
HDLCholesterol <35 mg/dL
Diabetes mellitus
Lack of exercise

Adapted from:Wilson PWF, Culleton BF: Epidemiology of

cardiovascular disease in the United States. Am J Kidney Dis,
32, S56-S65, 1998.

Medical conditions associated with ED

CANADA FRANCE GERMANY ITALY SPAIN UK

Heart disease 52% 45% 32% 39% 36% 19%
High blood pressure 33% 33% 62% 24% 21% 30%
Diabetes 36% 13% 20% 20% 20% 6%
Depression 13% 15% 13% 23% 10% 13%
Severe stress 17% 20% 13% 11% 10% 13%

Adapted from: Truica T, Sweeney M: Concomitant medical conditions in men with erectile dysfunction from six
countries:results of the men’s health survey. Abstract of the First World congress on the Aging Male, 1998.

280
 ANNEX II

INTERNATIONAL INDEX OF ERECTILE FUNCTION QUESTIONNAIRE

Please answer the following questions as honestly and clearly as possible.

In answering these questions the following definitions apply:
❑ Sexual activity included intercourse, caressing, foreplay and masturbation.
❑ Sexual intercourse is defined as vaginal penetration of the partner (you entered your partner)
❑ Sexual stimulation includes situations like foreplay with a partner, looking at erotic pictures, etc
❑ Ejaculation is defined as the ejection of semen from the penis (or the feeling of this)
Please answer the following questions for the past -------weeks by checking one box per question.

1. HOW OFTEN WERE YOU ABLE TO GET AN ERECTION DURING SEXUALACTIVITY ?

❑ No sexual activity
❑ Almost never/never
❑ A few times (much less than half the time)
❑ Sometimes (about half the time)
❑ Most times (much more than half the time)
❑ Almost always/always

2. WHEN YOU HAD ERECTIONS WITH SEXUAL STIMULATION, HOW OFTEN WERE YOUR ERECTIONS HARD
ENOUGH FOR PENETRATION?

❑ No sexual activity
❑ Almost never/never
❑ A few times (much less than half the time)
❑ Sometimes (about half the time)
❑ Most times (much more than half the time)
❑ Almost always/always

3. WHEN YOU ATTEMPTED SEXUAL INTERCOURSE, HOW OFTEN WERE YOU ABLE TO PENETRATE (ENTER)
YOUR PARTNER?

❑ Did not attempt intercourse

❑ Almost never/never
❑ A few times (much less than half the time)
❑ Sometimes (about half the time)
❑ Most times (much more than half the time)
❑ Almost always/always

281
4. D URING SEXUAL INTERCOURSE, HOW OFTEN WERE YOU ABLE TO MAINTAIN YOUR ERECTION AFTER YOU
HAD PENETRATED ( ENTERED) YOUR PARTNER?

❑ Did not attempt intercourse

❑ Almost never/never
❑ A few times (much less than half the time)
❑ Sometimes (about half the time)
❑ Most times (much more than half the time)
❑ Almost always/always

5. DURING SEXUAL INTERCOURSE, HOW DIFFICULT WAS IT TO MAINTAIN YOUR ERECTION TO COMPLETION
OF INTERCOURSE?

❑ Did not attempt intercourse

❑ Extremely difficult
❑ Very difficult
❑ Difficult
❑ Slightly difficult
❑ Not difficult

6. HOW MANY TIMES HAVE YOU ATTEMPTED SEXUAL INTERCOURSE?

❑ No attempts
❑ One to two attempts
❑ Three to four attempts
❑ Five to six attempts
❑ Seven to ten attempts
❑ Eleven + attempts

7. WHEN YOU ATTEMPTED SEXUAL INTERCOURSE, HOW OFTEN WAS IT SATISFACTORY FOR YOU?
❑ Did not attempt intercourse
❑ Almost never/never
❑ A few times (much less than half the time)
❑ Sometimes (about half the time)
❑ Most times (much more than half the time)
❑ Almost always/always

8. HOW MUCH HAVE YOU ENJOYED SEXUAL INTERCOURSE?

❑ No intercourse
❑ No enjoyment
❑ Not very enjoyable

282
❑ Fairly enjoyable
❑ Highly enjoyable
❑ Very highly enjoyable

9. WHEN YOU HAD STIMULATION OR INTERCOURSE, HOW OFTEN DID YOU EJACULATE?
❑ No sexual stimulation/intercourse
❑ Almost never/never
❑ A few times (much less than half the time)
❑ Sometimes (about half the time )
❑ Most times (much more than half the time)
❑ Almost always/always

10. WHEN YOU HAD SEXUAL STIMULATION OR INTERCOURSE, HOW OFTEN DID YOU HAVE THE FEELING OF
ORGASM OR CLIMAX?

❑ No sexual stimulation/intercourse
❑ Almost never/never
❑ A few times (much less than half the time)
❑ Sometimes (about half the time)
❑ Most times (much more than half the time)
❑ Almost always/always
The next two questions ask about sexual desire. Let’s define sexual desire as a feeling that may include
wanting to have a sexual experience (for example, masturbation or intercourse), thinking about having
sex, or feeling frustrated due to lack of sex.

11. HOW OFTEN HAVE YOU FELT SEXUAL DESIRE?

❑ Almost never/never
❑ A few times (much less than half the time)
❑ Sometimes (about half the time)
❑ Most times (much more than half the time)
❑ Almost always/always

12. HOW WOULD YOU RATE YOUR LEVEL OF SEXUAL DESIRE?

❑ Very low/none at all
❑ Low
❑ Moderate
❑ High
❑ Very high

283
13. HOW SATISFIED ARE YOU WITH YOUR OVERALL SEX LIFE?

❑ Dissatisfied
❑ About equally satisfied and dissatisfied
❑ Very dissatisfied
❑ Moderately satisfied
❑ Very satisfied

14. H OW SATISFIED HAVE YOU BEEN WITH YOUR SEXUAL RELATIONSHIP WITH YOUR PARTNER?
❑ Dissatisfied
❑ About equally satisfied and dissatisfied
❑ Very dissatisfied
❑ Moderately satisfied
❑ Very satisfied

15. H OW DO YOU RATE YOUR CONFIDENCE THAT YOU COULD GET AND KEEPAN ERECTION?

❑ Very low
❑ Low
❑ Moderate
❑ High
❑ Very high
REPRODUCED WITH PERMISSION OF THE AUTHOR.

284
 ANNEX III

USE OF SILDENAFIL (VIAGRA) IN PATIENTS WITH CARDIOVASCULAR

DISEASE (ACC/AHA CONSENSUS)

The American College of Cardiology and Ameri-
can Heart Association convened an Expert
Consensus Panel to evaluate the use of Sildenafil
in patients at risk for cardiovascular side effects.
The full report has been published. The Writing
Group reviewed the published data available on
Viagra and also the unpublished data provided by
the manufacturer of Viagra, Pfizer, Inc. The docu-
ment was subjected to external review and appro-
ved by both the ACC and AHA.
We wish to emphasize that most patients with car-
diovascular disease can safely take Viagra. On the
other hand, Viagra is absolutely contraindicated in
patients taking nitrate therapy in any form.
Nitrates should not be taken for twenty-four hours
before or after the use of Viagra.
Other groups of patients were identified where
individual clinical evaluation should be made
before prescribing Viagra. The first group is those
with coronary artery disease and possible active
ischemia. If these patients have not be evaluated
for some time, a repeat exercise test might be indi-
cated to rule out active ischemia which might be
precipitated by resumption of intercourse. The
second group of patients would be those with
congestive heart failure and borderline low blood
pressure and borderline low volume status. These
patients might be unusually sensitive to the hypo-
tensive effects of Viagra. It is recommended that
these patients be started at a very low dose to be
sure that hypotension does not occur. The Viagra
dose can then be titrated up without resumption of
intercourse to be sure that the normal dose of 50 to
100 mg is well tolerated. If so, the patient could
then be advised to resume sexual activity. A third
group would be those patients on complicated
multi-drug antihypertensive programs. Most of
these patients should be able to take Viagra safely
and indeed there is now more experience indica-
ting that that is true. Nevertheless, it would be rea-
sonable to be sure that the normal dose of Viagra
does not cause and unusual drop in blood pressure
in the individual patient before resuming sexual
activity.
It should be emphasized that sexual activity car-
ries with it its own emotional and physical
stresses. Thus, the cardiac patient resuming sexual
activity should be advised to do so with relative
equanimity.

285
ANNEX IV

286
287
288
289
290
291
292
293
294
295
 ANNEX IV

VIAGRA® (SIDENAFIL CITRATE) LABEL (Revised June 1999)

296
297
298
299
300
301
302
303
304
 Committee 9

Local Pharmacological Treatment

Modalities

Chairman
R.VIRAG

Members
E. BECHER,
S. CARRIER,
F. GOVIER,
K. M C VARY,
H.C. MCMAHON,
H. PORST

305
 CONTENTS

A. INTRODUCTION AND D. CLINICAL STUDIES

HISTORICAL FEATURES
I. COMPARATIVE EFFICACY OF
B. STATE OF THE ART INTRACAVERNOUS
INTERNATIONAL OVERVIEW MEDICATIONS

I. STUDY DESIGN AND II. COMPARATIVE EFFICACY OF

METHODOLOGY INTRACAVERNOUS AND
INTRAURETHRAL THERAPY

II. MEDICATIONS IN USE III. COMPARATIVE EFFICACY OF

ORALAND INTRACAVERNOUS
THERAPY
III. TECHNIQUES

IV. LONG-TERM FOLLOW-UP

IV. COMPLICATIONS

V. DROP-OUT RATE (TABLE 5) E. GUIDELINES FOR LPT

C. SPECIFIC MODALITIES I. GENERAL OVERVIEW OF

PRACTICE

I. GENERAL COMMENTS
II. INJECTION TOOLS AND
II. INTRACAVERNOUS TECHNIQUES
MONOTHERAPY
III. BEHAVIOR TOWARDS
III. INTRACAVERNOUS THE PARTNER
BI THERAPY

IV. INTRACAVERNOUS TRIPLE F. THE FUTURE OF TOPICAL

AND MULTIPLE COMBINATION THERAPY
THERAPY

V. TRANSURETHRAL DRUG
THERAPY
G. CONCLUSIONS
VI. TOPICAL THERAPY FOR
ERECTILE DYSFUNCTION

306
 Local Pharmacological Treatment
Modalities
R.VIRAG
E. BECHER, S. C ARRIER, F. GOVIER, K. M C VARY, H.C. M C MAHON, H. P ORST

never been fully explained. The present review is

A. INTRODUCTION AND an attempt to clarify the possibilities, results and
HISTORICAL FEATURES main guidelines of the available local pharmacolo-
gical treatment modalities (LPTM).
The concept of local pharmacological treatments
of erectile dysfunction (ED) is found far back in
history in the Arabian, Greek and Roman worlds B. STATE OF THE ART
when all sorts of ointments, herbs and medications INTERNATIONAL OVERVIEW
were applied locally to the genitals to enhance
“vigor”. The modern era started with the develop-
ment of artificial erection as a tool for the diagno-
I. STUDY DESIGN AND
sis of ED: Michal and Virag [1] separately repor-
METHODOLOGY
ted improvements after sessions of provoked erec-
tions with saline in patients with arterial impoten-
ce. Then came the first reports of pharmacologi- Each committee member was given a questionnai-
cally induced erections with papaverine [2] and re (Figure 1), which he had to distribute to as
phenoxybenzamine [3]. The initial therapeutic use many colleagues as possible. We received 277
of injections was the use of artificial erection of answers concerning about 100,000 patients.
mixed saline and vasoactive agents (papaverine
These results represent a trend which does not pre-
and saline) to enhance natural erections. Then
tend to be a multicentre evaluation according to
emerged the concept of self-injection therapy [4].
accepted standards.
In the beginning, the main concern was priapism,
followed by concerns about possible local modifi - • Geographical origin: 60% of Centers are loca -
cations which limited the long-term use of treat- ted in North America, 20% in Europe, 13% in
ment but strongly stimulated research for impro- Latin America, and 1.2% in Asia and Africa.
ved methods of treatments such as topical, intrau-
• Main speciality of each center: 83% are uro-
rethral, or oral modalities. Nevertheless, the effi-
logists and 4.4% are andrologists; while 11%
cacy of local therapy was never challenged, and
are cardiovascular specialists; all but one from
continuously improved. PGE1 was introduced in
Europe.
1986. Several drug combinations have increased
the overall efficacy rate of injection therapy to as • Number of patients/center: the average num-
high as 90% of the ED population. Automatic ber of patients followed is 175/center with great
injection improved the acceptance of the tech- discrepancies from less than 50 to 5,000
nique. The use of α adrenergic agents to reduce the
• Duration of follow-up: 80% of centers started
risk of priapism and a better knowledge of the
their programs at least 5 years ago; and 64%
medications and their dosage have made the tech-
have a ten-year experience of injection therapy.
nique safer and more effective [5]. Finally, until
the recent appearance of oral therapy, intracaver- • How are patients monitored ? Mostly by
nous injections (ICI) were the most frequently visits only (80%). Controls are performed
used treatment for ED. Its long-term use is chal- twice-yearly for the majority of centers (58%)
lenged by a high drop-out rate whose reasons have or yearly for 36%.

307

II. MEDICATIONS IN USE
Two sorts of information are available: which
medications are used and in what proportion.
(Figure 2). Alprostadil is the leader and is used by
68% of the centers, as “first line” intracavernous
medication in 47% of cases. Triple and multi-
combination therapy is used by more then 50% of
centers, but only 14% use it as their most frequent
medication.
III. TECHNIQUES (FIGURE 3)
1. HOW DO PATIENTS INJECT ?
62% manually, 31% with an automatic injector
and 7% with both techniques. Some comments
mention that many patients start with the automa -
tic injector because they fear to inject manually
but subsequently give up the automatic tool, to
simplify treatment.
2. HOW ARE MEDICATIONS AND DOSES
DETERMINED ?
A majority (58%) uses multidisciplinary evalua-
tion, including pharmacological testing; 42%
associate it with home trials. One third of the ans-
wers mention home trials as the usual way to titra-
te treatment. In one study, it appears that the drop-
out rate is much higher when patients were treated
without any evaluation.
3. FREQUENCY OF INJECTIONS:
84% of patients use the injection once (34%) to
twice (35%) per week. Frequent users (2.5 times
and more) are less than 5%.
4. DURATION OF ERECTION (average per injec-
tion per center): the majority (62%) reports dura-
tions between 60 and 90 minutes; in 4% the avera-
ge duration exceeds 90 minutes, and in 6% it is
less than half an hour.
5. TIME ALLOTTED BEFORE PRIAPISM TREAT-
MENT:
60% of centers allow four hours and more, 33%
limit it to three hours and 7% are restrictive giving
a two-hour delay. There is a higher percentage of
drop-out in those centers allowing a longer time
308
before considering treatment for priapism.
Patients might be concerned by excessively pro -
longed erection and anxiety concerning priapism.
6. DEPENDENCY ON THERAPY:
35% of patients use treatment for each sexual
attempt; 35% use it 50 to 75% of the time. Almost
25% report intermittent use of the medication;
mainly when they feel the need for it.
7. PREVENTION AND TREATMENT OF
PRIAPISM:
In 33% of centers, oral α blockers are prescribed,
9% use self-administered intracavernous α bloc-
kers, 40% use cold and exercise. Those centers
using a preventive self injection technique did not
observe any cases of priapism. (see below V. Gui -
delines for LPTM)
8. ADDITIONAL TREATMENTS:
75% of centers mention at least one additional
treatment or regimen; stop smoking (69%) and
anti fat treatment (47%) are much more common
than sexual counseling (34%) and relaxation
(22.5%)
IV. COMPLICATIONS
Each center was asked about general and local
complications and duration of erection (Figure 4)
• general complications: no cerebral, 17 cardiac
events (with one death) and 19 episodes of
hypotension without consequences.
• local complications: about 70% of centers
mention nodules and fibrosis, and 57% Peyro -
nie’s like plaques. Nevertheless, they are pre-
sent in less than 20% of patients and are res-
ponsible for drop-out in less than 10%. Pria -
pism is mentioned by 36% of centers, but in less
than 10% of patients.
V. DROP-OUT RATE (FIGURE 5)
The average drop-out rate for all centers is 40%;
for one third of centers, the rate is less than 30%.
In addition reasons for stopping treatment are not
all related to the technique: stopping any sexual
activity is mentioned by 56% of centers for about
 Figure 1: Local pharmacological
treatment modalities, internatio-
nal survey

Figure 2: International question-

naire data, medications in use in
the different centers

Figure 3: International question-

naire data, practical design of self
injection

309
Figure 4: International questionnaire data: duration of erection

Figure 5: International questionnaire data, indications of LPTM since the availability of oral therapy (n=46,000)

310
20% of the patients stopping treatment. So-called
“cured” (i.e. patients who no longer need the
treatment) is present in 57% of the reports for 5 to
20% of the drop-out rate. Thus, the average drop-
out rate linked to the technique is close to 20%:
it concerns decreased efficacy (mentioned in
66%), partner’s hostility (43%), cost (45%) and
local side effects (67%), and switch to another
treatment (see below and Figure 5).
1. C HANGE IN LPTM SINCE ORAL
THERAPY (FIGURE 5):
• Switch to oral therapy: it concerns 60% of the
centers; they announce between 10 to 50% switch
to oral therapy. Nevertheless, the switch rate
seems to have decreased during the last months of
the study. Several centers reported variable num-
ber of returns to injection therapy.
• Indications (Figure 5): In 37% of centers, oral
therapy is proposed to all patients (these are most-
ly American centers); 22.5% rely on pharmacolo-
gical testing to make a decision; 36% offer the
choice to the patient, and 19% still consider LPTM
as first-line treatment. Finally, 50% of the propo-
sed local treatments were actually started.
C. SPECIFIC MODALITIES
I. GENERAL COMMENTS
Numerous agents have been used as monotherapy,
dual therapy or combination therapy since the ini-
tial use of papaverine by Virag [2] and phenoxy-
benzamine by Brindley [3]. Many of these agents
had been marketed for other indications and were
tried by clinicians in prospective trials without
double-blind control. When monotherapy failed,
dual or combination therapy was proposed as an
alternative. In addition, economic concerns were
raised when specific medications were developed
by manufacturers and proved to be much more
expensive than previous medications (see guide-
lines below). Basic and clinical research conduc-
ted following the development of ICI therapy gave
support to the use of these compounds initially tes-
ted only on a clinical basis. Furthermore, and
311
because of the fear of injections, other local admi-
nistration techniques were tested. Intraurethral
therapy with alprostadil was approved in 1997 and
topical administration still seeks its efficacy and
development. All these aspects are discussed in
this chapter.
II. INTRACAVERNOUS
MONOTHERAPY
1. PAPAVERINE
The first published data on the use of papaverine in
impotence, relates its injection into an epigastric
artery bypassed into the corpus cavernosum of an
impotent man (Michal I operation) which gave a 2-
hour injection, under anesthesia with clamping of
the grafted epigastric artery Virag [1].
a) Chemistry and penile pharmacodynamics
Discovered by Merck in 1848 in the "papaverum
somniferum", papaverine is a benzylquinoline
synthesized from tyrosine. Known as a spasmoly-
tic medication and used to activate cerebral circu-
lation, the drug was well known by vascular sur-
geons for its capacity to strongly relax spasm in
any artery. By non-specific inhibition of the phos-
phodiesterases which normally inactivate cGMP,
papaverine is able to relax the erectile smooth
muscle independently any sexual stimulation. The
efficacy and duration of the "erectile blockade" is
dose-dependent in functioning erectile tissue.
Whether papaverine is able to act on the venous
return remains controversial: studies by Wespes
[6] and more recently by Virag and Sussman [7]
show differences in the capacity to block the
venous outflow, independently of intracavernous
pressure, suggesting an active mechanism. Clini-
cal experience using large doses (up to 80mg) of
papaverine also suggests an active mechanism, as
reversible prolonged erection (priapism) was
achieved in 25% of cases. Mikhailidis and Jeremy
[8] hypothesized that this might be the consequen-
ce of an increased production of prostacyclin by
the penile endothelium. In any case, papaverine is
the most powerful medication, used in isolation, to
induce and maintain an erection. When injected in
the penis at a low dosage (8mg), it cannot induce
erection, by itself, but the effect of papaverine is
enhanced by sexual stimulation Virag [9]. Finally,
it is the agent most frequently used in dual and
combination therapy (see below). When injected
in the systemic circulation, 90% of the medication
is metabolized by the liver. Papaverine should the-
refore be avoided in patients suffering from liver
disease. In a retrospective literature review (see
below Porst Table 1), elevated liver enzymes were
present in 1.6% of cases. Liver function should be
monitored once a year in patients treated with
papaverine.
b) Clinical use
The recommended formulation is papaverine
hydrochloride in 30 (North America) to 40 mg/ml
(Europe) vials. The solution is acidic and respon-
sible for burning when injected. Some authors the-
refore recommend dilution in 10 ml saline vials to
avoid burning and scarring. The relationships bet-
ween scarring, penile fibrosis and papaverine are
controversial. An experimental study (Lue [10]) in
monkeys demonstrated an increased rate of fibrosis.
Ageneral review (see below) showed a 5.7% rate of
penile fibrosis with papaverine in 1056 cases. The
role of papaverine in this effect is unclear. The
injection technique, the volume injected, and the
frequency seem to play a role as well. A retrospec-
tive study (Virag) of 1327 cases with a minimum 5
years follow-up, found a dose of papaverine over
40mg and volume injected over 1 ml to be the main
factors responsible for fibrosis. In addition, perso-
nal susceptibility could also be part of the problem,
as most of the fibrosis cases occur early in the cour-
se of treatment. Lastly, fibrosis rate is higher with
papaverine phentolamine mixture than with papa-
verine alone (see below). This complication can be
observed with alprostadil. The average efficacy of
papaverine is 60% with dosages between 20 to 110
mg.
c) Papaverine today
In a very long-term study, Virag [10] on 2352
patients treated by ICI, 25% still use papaverine, at
a dosage below 40mg/ml. Efficacy, low cost and
available local treatment to reverse priapism (see
below Prevention and management of complica-
tions) make papaverine still suitable for intraca-
vernous therapy. Recommendations will be to use
it at a dose not exceeding 40mg and at a maximum
volume of 1 ml.
312
2. ALPROSTADIL (PROSTAGLANDIN E1)
a) History of alprostadil (PGE1)
The name prostaglandin is derived from the disco-
very of U.S. Euler in 1935, who found a blood
pressure lowering substance in considerable
concentrations in seminal and prostatic secretions.
The detailed chemical structure of PGE1 was des-
cribed by Bergström et al [12] in 1963. Since
1973, PGE1 has been increasingly used for the
treatment of peripheral arterial occlusive disease
and was officially approved in 1984 in Germany
for the parenteral treatment of Fontaine’s stage III
and IV disease of the lower limbs. In 1983 PGE1
was also officially approved in the United States to
maintain patency of the ductus arteriosus in so-
called blue babies.
First reports on the beneficial effects of PGE1 in
self-injection therapy in erectile dysfunction were
presented by Akaikan et al [11] and Ishii et al
[19]1986 at the Second World Meeting on Impo-
tence in Prague. The promising preliminary results
were confirmed by further studies by Stackl et al
[36] and Porst [28] both publishing high efficacy
and low side-effect rates. These first uncontrolled
studies were the basis for the development of two
different Alprostadil preparations: Alprostadil-
Alfadex and Alprostadil Sterile Powder which are
now officially approved for self-injection therapy
in many countries.
b) Biological effects of PGE 1 in general
Due to the fact that prostaglandins are distributed
in many tissues especially in the cardiovascular
system these compounds and especially PGE1
have been the subject of many investigational stu-
dies in various diseases. The most important bio-
logical effects of PGE1are summarized in the
review article. The rationale for prostaglandin E1
in erectile failure is as follows:
Relaxation of arterioles and precapillary sphinc-
ters resulting in increasing blood flow. Contractile
effects on the venous system especially in the
capacity veins. Inhibition of cholesterol biosyn-
thesis and low-density lipoprotein receptor activi-
ty thus preventing cholesterol deposition into the
arterial wall. This effect together with its inhibi-
tion of platelet function contributes to the anti-
atherosclerotic effects of PGE1.
Positive impact on the cellular nutritive metabo-
lism of ischemic tissue by lowering the lactate/
pyruvate ratio resulting in an improvement of the
hypoxic state.
Positive effects on red cell deformity and inhibito-
ry effects on platelet aggregation with consecuti-
vely improved viscosity and blood flow.
c) Special effects of PGE 1 on cavernous tissue
(Figure 6)
The family of E-prostaglandins, particularly PGE1,
stimulates the membrane bound enzyme adenylcy-
clase leading to an intracellular increase of 3´5´-
cAMP (cyclic-adenosine monophosphate) [27].
This second messenger cAMP leads, via various
biological activities, to a decrease of the intracellu-
lar Ca++ concentration and subsequently to smooth
muscle relaxation. In this context, Hedlund and
Andersson [17] showed in in-vitro studies that
among all prostanoids investigated PGE1 shows the
strongest relaxant power on the cavernous smooth
musculature. PGE1 also inhibits the negative
influence of the sympathetic tone on erection by
modulation of noradrenaline release at alpha1-adre-
noceptors in the cavernous tissue [23].
Collagen synthesis, stimulated by TGF-ß1 (trans-
forming growth factor), is decreased by PGE1 in a
dose-dependent fashion [26].
In addition, it is proven that PGE1 inhibits angio-
tensin II secretion by endothelial cells, which lie
underneath cavernous smooth muscle cells. In this
way PGE1 counteracts the contractile and therefore
erection preventing effects of Angiotensin II [20].
Finally Zhang et al [39] provided evidence that
PGE1 is able to directly activate the Maxi-K+-chan-
nels resulting in hyperpolarization and relaxation of
smooth muscle cells. Although all the aforementio-
ned effects mainly occur at the level of the caver-
nous tissue, PGE1 is also supposed to increase the
activity of various cerebral neurons according to the
experiments of Moltz [24]. For example, numerous
PGE1 receptors were found in the hypothalamus
and medial preoptic area, both regions well-known
to be important for the control of erectile and ejacu-
latory behavior. All the cited biological and bioche-
mical functions provide the basis for the marked
efficacy of PGE1 observed in the treatment of erec-
tile dysfunction.
313
d) Pharmacokinetics and metabolism of PGE1
(Figure 7)
The original compound from which all prostaglan-
dins are derived is dihomo-gamma-linolenic acid,
an analogue of arachidonic acid. The final com-
pound PGE1 is generated via various enzyme acti-
vities. The plasma half-life of PGE1 is less than 1
minute due to its rapid pulmonary clearance of up
to 65 to 80% during the first lung passage. The
cleavage of PGE1 is generally accomplished by
two different pathways originating from the 15-
Keto PGE0 metabolite (Fig. 2). Although all the
subsequent metabolites of the one pathway are
biologically inactive, the PGE0 metabolite from
the other pathway has proven biological activities,
which may also be responsible for some of the sys-
temic effects of PGE 1 [30].
With regard to the cavernosal activities, Roy et al
[32,33] provided evidence that the corpora caver-
nosa were able to both generate and metabolize E-
prostaglandins. In view of these findings it can be
calculated that intracavernously injected PGE1 will
be at least partially be metabolized within the
cavernous tissue. On the other hand, Cawello et al
[13] showed in 24 volounteers, in whom the per-
ipheral plasma levels of PGE1 and its biological
active metabolite PGE0 were measured after intra-
cavernous injection of PGE1, that within 2 minutes
after application the peripheral levels of PGE1 and
PGE1 were elevated 15-20 fold and returned to
baseline levels after 2 hours. Interestingly the
levels of the biologically active metabolite PGE0
were considerably higher in non-responders to
PGE1 who were suspected to suffer from veno-
occlusive dysfunction.
1. R ESULTS OF PGE1 IN THE DIAGNOSIS AND
THERAPY OF ERECTILE DYSFUNCTION
a) Diagnosis
Due to its superior efficacy and tolerable side
effects, PGE1 was recommended as first drug
choice in self-injection-therapy by the USA clini-
cal guidelines panel on erectile dysfunction [25].
In a diagnostic dose-escalation study, von Heyden
et al [18] showed a dose-dependent increase of the
efficacy curve for dosages between 2.5 – 20 µg.
Dosages higher than 20 µg levelled up to a plateau
and only 20% of failures to 20 µg PGE 1 profited
from a dosage increase up to 40 µg. The same
Figure 6: The impact of PGE1 (Alprostadil) on erectile function

Figure 7: Biosynthesis and metabolism of prostaglandin E1

314
observation was made by Porst [30] in a similar
diagnostic trial: in 91 (20%) of 450 patients, not
responding with sufficiently rigid erections to 20
µg of PGE 1, rigid erections could be provoked by
a dosage increase up to 40 µg. Acomparison of the
literature as well as comprehensive personal expe-
rience with several vasoactive drugs provided evi-
dence that PGE1 is 5-10% more effective than the
combination of papaverine/phentolamine (Table 1).
Nevertheless, several publications and personal
experience have both shown that small subsets of
impotent males only react to either papaverine/
phentolamine or PGE1 [14,16,34] (Table 2). There-
fore, if a patient opts for self-injection therapy at
home and does not respond to PGE1 alone, a trial
with the papaverine/phentolamine combination,
with or without PGE1, seems worthwhile. The pre-
vailing advantage of PGE1 compared to papaverine
or the combination of papaverine/phentolamine
especially for diagnosis is the significantly lower
risk of priapism (Table 3).
b) Therapy
A literature review of the relevant publications on
self-injection therapy considering efficacy and
side-effects of the aforementioned vasoactive
drugs was also in favor of PGE1 especially concer-
ning the occurrence of local fibrotic alterations
(Table 3). But all the cited studies were conducted
in a retrospective fashion with all the shortco-
mings inherent to retrospective trials. In the
meanwhile several prospective trials with both
PGE1-preparations i.e. Alprostadil-Alfadex and
Alprostadil Sterile Powder were conducted world-
wide and the final results of these long-term trials
are available and published [21,22,31]. The most
important findings of these prospective US and
European trials are summarized in Tables 4-9.
Indicative for all trials was the impressive high
efficacy-rate in home-use with success-rates (suc-
cessful coitus per attempt) between 90 and 95%
with both Alprostadil-injectables (Table 4). These
success-rates were considerably higher than those
yielded with transurethral Alprostadil (IUA) in the
European trial. Priapisms > 6 hours were encoun-
tered in about 1% and all these priapisms occurred
within the first weeks of treatment when the dose-
finding was not yet finalized and the optimal dosa-
ge not yet found.
A special issue in self-injection therapy with
Alprostadil is the occurrence of intrapenile painful
sensations in the course of the PGE1-induced erec-
315
tion. These painful sensations were reported in up
to 52% but are usually minimal or moderate. Only
2-4% of all patients complained of severe pain
interfering with enjoyment of sexual activities and
causing early drop-outs in a few cases.
A further problem in long-term self-injection the-
rapy with vasoactive drugs, irrespective of the
drug used, is the manifestation of so-called penile
fibrosis. The term “penile fibrosis” covers a varie-
ty of different fibrotic changes such as nodules or
plaques in the tunica albuginea or septum penis,
respectively, as well as fibrotic alterations of the
cavernous tissue itself. In addition a part of these
fibrotic alterations are accompanied by penile
deviations which may interfere with vaginal pene-
tration. In the long-term trials, penile fibroses
were observed in 4 to 12% of cases and showed a
clear dependence on the number of injections
and/or the follow-up (Table 5-7). Fortunately in
the majority of cases these fibroses were usually
minimal or moderate consisting of small nodules
or plaques and did not prevent the patients from
enjoying sexual activities (Table 7). In two studies,
namely in the European 4-year trial and the US
trial with Alprostadil-Sterile Powder, the outcome
of these penile fibroses was thoroughly followed-
up by reinvestigation of the affected patients.
These reevaluations of the patients some time after
first onset of the fibrosis revealed that 33 – 47% of
all these alterations healed spontaneously without
any detrimental sequelae on penile shape or func-
tion (Table 8). In some cases, spontaneous recove-
ry from the fibrotic changes was supported by
temporary discontinuation of treatment and, after
resumption of self-injection therapy, by more care-
ful instruction of the patient concerning the correct
self-injection technique. To date there are no
convincing data to suggest that some special
patient-groups are at higher risk for the develop-
ment of such fibroses or whether needle size (27
gauge to 30 gauge) or injection-technique
(manual, semiautomatic or autoinjector) may be
contributory factors to such fibroses. Both accor-
ding to personal experience and some cases obser-
ved within the European trials, insulin-dependent
diabetics seem to be especially more likely to
develop penile fibrotic changes related to self-
injection therapy.
Concerning penile fibroses, Chen et al. [15] were
also not able to find obvious risk profiles for peni-
le fibrosis in a retrospective study with 92 patients.
Table 1: Efficacy and complications in the diagnostic use of vasoactive drugs in erectile failure
DRUG DOSAGE NO.PTS. RESPONDERS PRIAPISM PAIN
(COMPLETE > 6 HOURS
ERECTION)
Papaverine
Literature review 30-110 mg 2161 61% 6.8% Not stated
(987/16l6) (144/2108)
Personal series 12.5-50 mg 950 39% 5.3% Not stated
(370/950) (50/950)
Papaverine/Phentol.
Literature review 15mg/1.25mg 3016 68.5% 6% Not stated
60mg/2mg (2065/3016) (73/1210)
Personal series 12mg/1mg 249 60.6% 5.2% Not stated
50mg/2mg (151 /249) (13/249)
PGE1(Alprostadil)
Literature review 5-40 µg 10353 72.6% 0.25% 11.5%
(7519/10353) (26/10353) (881/7637)
Personal series 5-20 µg 4577 70% 0.26% 9.2%
(3206/4577) (12/4577) (422/4577)

Source: Porst,H. J Urol 1996

Table 2: Intraindividual comparative trial on the efficacy of papaverine, papaverine/phentolamine and PGE1 (alprostadil)

316
Table 3: Complications and drop-out rates in self -injection therapy: literature-review of retrospective studies with various
vasoactive Drugs

DRUG NO. PRIAPISM FIBROTIC LIVER PAIN DROP-OUT

PUBL. > 6 HOURS ALTERATIONS ENZYMES ↑

Papaverine 15 7.1% 5.7% 1.6% 4% 4.6%

(92/1300) (60/1056) (5/314) (18/452) (417/895)

Pap./Phentol. 22 7.8% 12.4% 5.4% 1.6% 45%

(122/1561) (288/1843) (43/799) (141/1215) (903/2005)

PGE1 10 0.36% 0.8% 0% 7.2% 37%

(10/2745) (18/2180) (40/558) 608/1641)

Source: Porst, H. J Urol 1996

Table 4: Home success-rates of the prospective European trials with alprostadil (PGE1) in In-Office responders

DRUG NO.PTS. SUCCESS-RATES FOLLOW-UP

(COITUS/ATTEMPTS)

Alprostadil-Alfadex 162 93.1% 48 months

(Viridal®,Edex®) (15713/16886)

Alprostadil St. Powder 848 88% 1-6 months

(Caverject®) (16233/1848 l )

Transurethral Alprostadil 249 50% 1-3 months

(MUSE®) (4966/9866)
78%
(3238/4177) 4-15 months

Table 5: Complications of Alprostadil Sterile Powder as a function of follow-up - results of the US studies

MONTHS 0-6 7-18 19-30 31-62

No. Pts. 683 386 257 214

Pain 52% 47% 5% 1%

(352) (181) (14) (2)

Fibrosis 2% 10% 4% 3%
(15) (39) (9) (7)

Priapism < 1% (5) 0 0 0

Source: Linet,O. Int J lmpotence Res 1998

317
Table 6: Adverse events in the European long-term trial with alprostadil-alfadex
TOTAL 0-12 23-24 25-36 37-48 MONTHS
No.Pts 162 162 81 68 58
Pain 29% 27% 12% 7% 12%
(47) (43) (10) (5) (7)
Fibrotic changes 12% 7% 2% 7% 2%
(19) (11) (2) (5) (1)
Priapism> 6 h 1% 1% 0 0 0
(2) (2)
Hematoma 33% 30% 23% 10% 12%
(54) (48) (19) (7) (7)
Source: Porst,H. Int J Impotence Res 1998

Table 7: Severity of penile fibrotic alterations in long-term self-injection trials with alprostadil (PGE1)
NO.PTS. FOLLOW-UP FIBROSES NODULES DEVIATIONS CAVERN.
(MONTHS) TOTAL PLAQUES FIBROSES

Alprostadil-Alfadex 162 48 19 (11.7%) 10 6 3

European Trial
Alprostadil St. Powder 848 6 34 (4%) Not published
European Trial 511 7-18 26 (5.1%)
Alprostadil St.Powder 683 18 51 (7.5%) 22 8 21

In addition, no increase of these fibroses could be
observed during the course of Alprostadil-self-
injection therapy in patients with preexisting
fibrotic changes due to self-injection therapy with
papaverine/phentolamine or due to genuine Peyro-
nie’s disease[15].
As we have seen in all the retrospective trials with
various vasoactive drugs (Table 3), the prospecti-
ve studies with Alprostadil were also characterized
by relatively high drop-out rates (Table 4). For
example, in the European Alprostadil-Alfadex
trial, the drop-out rates after 12, 24 and 48 months
were 28%, 54% and 67% and, in the European
Alprostadil-Sterile Powder trial, the drop-out rate
after 18 months was 55%. In the US trial with ori-
ginally 643 patients involved, the completer-rate
after 5 years was 22%. Main reasons for prematu-
re discontinuation of self-injection therapy were
adverse events, not necessarily due to the drug,
partner problems, or dissatisfaction with the thera-
py itself. Recurrence of spontaneous erections
making self-injection therapy unnecessary
accounted for only 6 – 10% of cases of premature
discontinuation. Comparable to the cited trials
Sharlip [35] came to the same conclusion after a
thorough review of the literature with 2817
patients involved in 15 publications dealing with
self-injection therapy: In only 9.2% of all evalua-
ted patients, self-injection therapy improved the
natural erectile capacity so that these patients
could rely on their natural erecions and no longer
required self-injection therapy.
Although the self-injection trials were associated
with considerable drop-out rates, these rates were
higher in the European IUA trial with only 25%
completers after 15 months (Table 9).
Despite the relatively high discontinuation rates, all
the worldwide prospective Alprostadil trials provi-
ded convincing evidence that self-injection therapy
with PGE1 represents a reliable and satisfactory
therapeutic option for many couples confronted
with male impotence. For example, more than 90%
of both affected males and confronted females were
satisfied with PGE1-therapy once they have deci-
ded to continue treatment (Table 9). In addition, in
both the European and US trials, more than 80-90%
of males and females reported that the possibility
engaging in satisfactory sexual relationships by
means of Alprostadil (PGE1) had a considerable
positive impact on self-esteem and personality as
well as partnership [31,37,38].
None of these trials demonstrated any differences
between Alprostadil powder and Alprostadil-Alfa-
dex in terms of efficacy and side-effects as well as
positive influences on personality and partnership
(Table 10).

318
Table 8: Outcome of penile fibrotic alterations in self-injection therapy with alprostadil PGE1

NO.PTS. TIME TO ONSET SPONTANEOUS

NO. I NJECTION FOLLOW-UP HEALING-RATE

Alprostadil-Alfadex 11.7% 62 12months 47%

(19/162) (16-132) (4-48) (9/19)
European Trial
Alprostadil St.Powder 7.5% Not published 33%
(51/683) (17/51)

Table 9: Satisfaction rates of completers in the various European trials with alprostadil (PGE1)

DRUG FOLLOW-UP COMPLETERS SATISFACTION-RATE

Alprostadil-Alfadex 48 months 54/162 90 - 92%

(33%)

Alprostadil St. Powder 18 months 348/848 92 - 95%

(Caverjec®) (41%)

Transurethral Alprostadil 15 months 62/249 67 - 71%

(25%)

Table 10: Pharmacological profile of alprostadil (PGE1) in erectile dysfunction

History: 1986 first reports on PGE1 in self-injection therapy (Adaikan, Ishii)

Influence on Erection: Stimulation of adenylcyclase → 3 5 -cAMP-accumulation
Inhibition of noradrenaline-release on alpha1-adrenoceptors → antiadrenergic effect
Inhibition of Angiotensin II-secretion → anticontractile effect
Stimulation of Maxi-K+-channels → Hyperpolarisation
Dosage/Pharmacokinetics: 2.5 - 40 µg, (mean dosages 10 - 20 µg)
Half-life 30 - 60 sec.
Biological active metabolite: PGE 0
Efficacy: 70 - 80% of unselected ED patients
Side-effects: 10 - 20% painful sensations
5 -10% fibrotic alterations
< 1% priapism
No systemic side-effects at common dosages
Trade Names: Alprostadil-Alfadex (Viridal® or Edex® Schwarz Pharma)
Alprostadil-Sterile Powder (Caverject® - Pharmacia & Upjohn)

319

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155, 138-140, 1996.
16. EARLE C.M., KEOGH E.J., WISNIEWSKI Z.S. et al:
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18. VON HEYDEN B., DONATUCCI C.F., MARSHALL
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20. KIFOR J.,WILLIAMS G.H.,VICKERS M.A. et al: Tis-
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Angiotensin peptide content, secretion and effects in the
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21. LINETO.J., OGRINC F.G.: Efficacy and safety of intra-
cavernosal Alprostadil in men with erectile dysfunction.
N Eng J Med 334, 873-877,1996.
22. LINET O.J.: Long-term safety of CaverjectTM (Alpros-
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28. PORST H.: Stellenwert von Prostaglandin E1 (PGE) in
der Diagnostik der erektilen Dysfunktion (ED) im Ver-
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Urologe A 28, 94-98, 1989.
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ty of human corpora cavernosa muscle to generate pros-
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glandin 15-hydroxydehydrogenase activity in human
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glandin mediated penile erection. Br J Urol 64,180-
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37. WILKE R.J., GLICK H.A., MCCARRON T.J. et al:
Quality of life effects of Alprostadil therapy for erectile
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38. WILKE R.J., HASS S.L., BORG G.: Intracavernous
Alprostadil therapy for diabetics: quality of life results
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3. M OXISYLYTE
Moxisylyte is a competitive α-receptor antagonist
which act preferentially on post-synaptic α-1 adre-
noceptors. It was introduced more than thirty years
ago for the treatment of cerebrovascular disorders
and was recently shown to modulate urethral pres-
sure and constitute a potential treatment for ED.
In the treatment of impotence, intracavernous
injection of moxisylyte at 10, 20 or 30 mg can
induce an erection adequate for intercourse in
most patients. Initial interest in moxisylyte was
prompted by its role as a facilitator of erection
with a lower rate of adverse effects compared to
inducing agents such as papaverine and alprosta-
dil. However, controlled clinical studies on effica-
cy and safety are limited, as moxisylyte is appro-
ved for treatment of ED only in Europe.
Moxisylyte is a prodrug which is rapidly degraded
into an active plasma metabolite, deacetylmoxisy -
lyte (DAM). This active metabolite is further
degraded by N-demethylation, sulpho- and glucu-
ro-conjugation and is excreted in the urine [1]. In
vitro, moxisylyte produced a concentration-depen-
321
dent relaxation of a norepinephrine-induced
contraction of human corpus cavernosum strips
[2]. Pretreatment with moxisylyte competitively
reduced the norepinephrine-induced contraction.
In 1989, Buvat first reported that moxisylyte,
although less efficacious than papaverine, resulted
in erection suitable for intercourse within 2 hours
of in office injection in 42 of 91 patients with ED
[3]. Of 37 patients instructed in moxisylyte self-
injection, 92% achieved successful results without
any significant side effect. In a dose-ranging pla-
cebo-controlled double-blind study of 73 men
with psychogenic and neurogenic ED, Costa et al.
reported a significantly higher response rate than
with placebo, with 62 patients achieving either
partial or complete rigidity sufficient for sexual
intercourse [4]. The superiority of moxisylyte to
placebo was confirmed by both Hermabessiere et
al. and Navratil et al. in further placebo-controlled
double-blind studies [5,6]. In a multicentre study
of 307 patients, Hermabessiere et al. reported that
48% of patients responded to an office intracorpo-
ral injection with an erection suitable for inter-
course. Furthermore, 62% of home administered
injections resulted in sexual intercourse and 95%
of these injections were free from adverse effects.
More recently, Costa et al., in a placebo-controlled
dose-ranging study, reported a dose-dependent
response of tumescence sufficient for intercourse
in 34.9% to 45.9% of patients for moxisylyte
administered in the clinic [7]. At home, 54% to
71% of moxisylyte injections resulted in sexual
intercourse.
Arvis et al. reported an extensive series of 143
patients with a total of 7,509 home injections of
moxisylyte [8]. A total of 1,041 adverse effects
were reported by 90 patients which were predomi-
nantly local adverse effects such as injection pain,
hematomas and ecchymoses. No severe adverse
effects were reported.
Moxisylyte appears less effective that alprostadil.
In a retrospective study of 130 patients, Buvat et
al. reported that alprostadil was significantly more
effective than moxisylyte with 71% of patients
using alprostadil at home reporting rigid erections
as opposed to 50% with moxisylyte [9]. Although
alprostadil induced pain and prolonged erections
in significantly more patients, including 2 pria-
pisms, moxisylyte was associated with a higher
discontinuation rate. The authors suggested that
moxisylyte is mainly indicated in patients with a
history of priapism and significant pain following
alprostadil. In a recent comparative study of 156
men with organic, psychogenic and mixed ED,
Buvat et al. reported that 81% of patients achieved
at least 1 rigid erection after intracorporal alpros-
tadil α-cyclodextrin (Edex™, Schwatz Pharma)
administered at home compared to 61% after
moxisylyte [10]. Local injection related adverse
effects occurred with the same frequency, but
moxisylyte resulted in more systemic side effects
and alprostadil resulted in more painful and pro-
longed erections. They concluded that alprostadil
α-cyclodextrin is significantly more effective than
moxisylyte in producing full penile rigidity.
Although moxisylyte is less potent than alprostadil
or papaverine, and may produce an insufficient
response with an office challenge injection, Buvat
et al. suggested that it be used as a first-line treat-
ment for ED before resorting to alprostadil or
papaverine, due to its favourable adverse effect
profile [11]. Buvat reported a reduced rate of pro-
longed erections (1.3%) compared to papaverine
(8.8%) and less corporal fibrosis (1.3% versus
32% with papaverine). Although alprostadil indu-
ced penile pain and prolonged erections occur in
significantly more patients, moxisylyte was asso-
ciated with a higher discontinuation rate [9]. This
suggests that many patients choose treatment effi-
cacy over a superior adverse effect profile.
However, moxisylyte appears to have a role in the
treatment of ED in patients with a history of pria-
pism related to other agents and significant pain
following alprostadil.
REFERENCES
1. COSTAP, BRESSOLLE F, SARRAZIN B, MOSSER J,
NAVRATIL H, GALTIER M. Moxisylyte plasma kine -
tics in humans after intracavernous administration. Bio-
pharm Drug Dispos 13(9):671-9, 1992
2. IMAGAWA A, KIMURA K, KAWANISHI Y, TAMU-
RA M. Effect of moxisylyte hydrochloride on isolated
human penile corpus cavernosum tissue. Life Sci;44
(9):619-23, 1989
322
3. BUVATJ, LEMAIRE A, BUVAT-HERBAUTM, MAR-
COLIN G. Safety of intracavernous injections using an
alpha-blocking agent. J Urol,141(6):1364-7, 1989
4. COSTA P, SARRAZIN B, BRESSOLLE F, COLSON
MH, BONDIL P, SAUDUBRAY F. Efficiency and side
effects of intracavernous injections of moxisylyte in
impotent patients: a dose-finding study versus placebo.
J Urol; 149(2):301-5, 1993
5. HERMABESSIERE J, COSTAP, ANDRO MC. Effica-
cy and tolerance of intracavernous injection of moxisy-
lyte in patients with erectile dysfunction: double-blind
placebo-controlled study. Prog Urol; 5(6):985-91, 1995
6. NAVRATIL H, COSTA P, LOUIS JF, ANDRO MC,
SAUR P. Effectiveness of and tolerance to intracaver-
nous injection of moxisylyte in patients with erectile
dysfunction: effect/dose relationship versus placebo.
Prog Urol; 5 (5):690-6, 1995
7. PIERRE COSTA, NÎMES, FRANCE, JEAN A. JACO-
VELLAAND AGNÈS A. Bouvet, Efficacy and toleran-
ce of moxisylyte and placebo injected intracavernously
in patients with ED - a multicentre, double blind study.
Abstract 1998 AUA
8. ARVIS G, RIVET G, SCHWENT B. Prolonged use of
moxisylyte chlorhydrate (Icavex) by intracavernous self-
injections in the treatment of impotence. Evaluation of
long-term tolerance. J Urol;102(4):151-6, 1996
9. BUVAT J, LEMAIRE A, HERBAUT-BUVAT M. Intra-
cavernous pharmacotherapy: comparison of Moxisylyte
and prostaglandin E1. Int J Impot Res; 8(2):41-6,1996
10. BUVAT J, COSTA P, MORLIER D, LECOCQ B,
STEGMANN B, ALBRECHT D. Double-blind multi-
center study comparing alprostadil alpha-cyclodextrin
with moxisylyte chlorhydrate in patients with chronic
erectile dysfunction. J Urol. 159(1):116-9, 1998.
11. BUVATJ, BUVAT-HERBAUTM, LEMAIRE A, MAR-
COLIN G. Treatment of impotence with intracavernous
auto-injections: moxisylyte diminishes the risks compa-
red to papaverine. Contracept Fertil Sex 21(2):173-6,
1993.
_________________________

III. INTRACAVERNOUS
BI THERAPY
1. PAPAVERINE-PHENTOLAMINE
The combination of papaverine and phentolamine
for intracorporeal therapy was first described by
Zorgniotti and LeFleur in 1985 [1]. Papaverine
increases intracellular levels of cyclic adenosine-
3-5 monophosphate, blocks calcium channels, and
increases calcium efflux from cells. It is acidic in
solution (pH 3-4) and may precipitate at a pH
greater than 5. Plasma half-life is 1-2 hours and it
is metabolized in the liver [2]. Phentolamine is a
competitive inhibitor of alpha-1 and alpha-2 adre-
nergic receptors. It also has an antiserotoninergic
action and a direct relaxant effect on smooth
muscle [3]. Unlike papaverine, it may not increase
resistance to venous outflow from the corpora [4].
Plasma half-life is 30 minutes, and it is extensive-
ly metabolized before excretion. Phentolamine, as
a single agent, has been largely ineffective in pro-
ducing usable erections [5].
Until 1985, papaverine was the standard for intra-
corporeal injection therapy. Zorgniotti and
LeFleur expanded these horizons in 1985 with
their introduction of combination therapy. They
reported coital penetration was possible in 59 of
62 patients with impotence of diverse etiologies
using a combination of papaverine and phentola-
mine [1]. Patients were injected with papaverine
hydrochloride solution (30 mg/1 ml) and 0.5 to 1
mg phentolamine mesylate. The injection was per-
formed slowly, alternating between sides and
patients were sent home to attempt intercourse.
Doppler ultrasonography detected an increase in
pulse amplitude of the dorsal artery within 30
seconds, and penile lengthening denoting tumes-
cence could be detected within 60 seconds. A
single patient required treatment for priapism.
Sidi, et al, reported results using the combination
in 100 men with organic impotence in 1986 [6].
All patients had organic dysfunction and were
injected with a mixture containing 25 mg of papa -
verine and 0.8 mg phentolamine per cc. Dosages
ranged from 0.1 to 1.5 cc, with average injection
volumes of 0.36 cc in the venogenic group, and
0.73 cc in the vascular group. Success, defined as
a functional erection superior to their spontaneous
323
erection, ranged from 66% in the vascular group,
to 100% in the neurologic group. Four patients
were treated for priapism, all in the neurogenic
group.
Nellans et al. reported on 69 patients in 1987 and
found an overall success rate of 67% with 74% of
these patients continuing on a self-injection pro-
gram [7]. 50% of patients on their self-injection
program noted a subjective improvement in the abi-
lity to maintain natural erections. One case of cor-
poreal fibrosis was noted and 8.7% of patients
reported prolonged erections, greater than 12 hours.
Bodner et al. studied a combination of papaverine
plus phentolamine in 20 spinal cord injury patients
in 1987 [8]. Six episodes of priapism in three
patients led them to recommend starting with
papaverine alone in this sensitive group.
Stief and Wetterauer in 1988 performed a prospec-
tive study in 15 patients proving the increased effi-
cacy of the combination over papaverine alone [5].
Alone six patients with papaverine and one with
phentolamine achieved a full erection. Combined,
13/15 patients achieved a full erection. They pro-
posed the combination as a first-line therapy for its
better efficacy and the theoretical prospect of
decreased scarring due to a lower total dose of
papaverine.
In 1989 a double-blind crossover study by Keogh
et al. again confirmed the superiority of the com-
bination [9]. In forty men, 40 mg of papaverine
produced 27% complete and 65% partial erec-
tions. A combination of 20 mg of papaverine and
0.5 mg of phentolamine achieved 48% complete
and 52% partial erections. The results were statis-
tically significant at p<0.05
Side effects of corporeal scarring with the combi-
nation were reported in 1989 by Levine et al. [10].
Starting with a group of 111 patients, they found a
percentage of men with intracorporeal scarring to
increase significantly over time. Scarring was
found in 8% at one month, 17% at three months,
32% at six months, and an astounding 57% at one
year. They also noted mild to moderate transient
elevations in alkaline phosphatase or lactic dehy-
drogenase in 40% of their patients over the one
year study. They recommended careful follow-up
in these patients.
Seidmon and Samaha looked at pH as a possible
cause of scarring [11]. The combination of papa-
verine plus phentolamine had a pH of less than 4
and could not be buffered without precipitation.
Prostaglandin E1 had a pH of less than 5, but could
easily be buffered to 7.4, remaining in solution.
The authors postulated the combination buffered
by blood within the corpora may precipitate, cau-
sing intracorporeal scarring.
Prostaglandin E 1 entered the arena in 1986 at the
Second World Impotence Meeting in Prague.
Adaikan [12] and Ishii [13] reported encouraging
preliminary results with its use. Papers by Stackl
et al. [14] Porst, [15] and Ishii et al. [16] confir-
med its efficacy and low incidence of priapism.
Lee et al. in 1989 studied prostaglandin E1 vs a
papaverine-phentolamine combination in a
double-blind trial [17]. In 25 patients, they found
E1 was equal or superior to the combination of
papaverine-phentolamine.
Floth and Schramek in 1991 compared papaverine
plus prostaglandin E1 to papaverine plus phentola-
mine in 49 patients, and papaverine plus prosta-
glandin E1 to prostaglandin E1 alone in 38 patients
[18]. Their findings were that papaverine plus
prostaglandin E1 was superior to either of the
other combinations or prostaglandin E1 alone.
They found moderate or severe pain occurring
only in the E1 monotherapy group, and no erec-
tions required treatment in any of these groups.
Their conclusions were that the combination of
papaverine and prostaglandin E1 was overall
superior.
Since its introduction by Zorgniotti and LeFleur in
1985, multiple studies have borne out an improved
efficacy of the combination of papaverine-phento-
lamine over papaverine alone [1,3,5,8,9]. Perhaps
the largest, most dramatic, studies were those of
Porst in 1993 [19]. Using dosages of 12.5 to 50 mg
of papaverine, he reported an efficacy (complete
response) of 39% in 950 patients. Using the com-
bination at dosages of 15-50 mg papaverine, plus
1-2 mg phentolamine, his success was 60.6% in
249 patients. Priapism rates, defined as an erection
greater than 6 hours, were identical at 5.3% and
5.2%, respectively.
In a review article by Fallon in 1995, [3] the com-
bination was effective (full erection) in 69% of
400 patients. This article also found identical pria-
pism rates at 4.3% in 232 patients on papaverine
324
vs 115 on the combination in patients treated at the
University of Iowa.
In a review of the international literature by Porst
in 1997, [20] papaverine alone at dosages of 30-
110 mg was effective (complete response) in 61%
of 2161 patients. The combination in dosages of
15-60 mg of papaverine with 1.25 to 2 mg of
phentolamine was 68.5% effective in 3016
patients. Again, priapism was little changed at
6.8% for the papaverine vs 6% for the combina-
tion.
The above studies all confirm the superior effica-
cy of the combination of papaverine/phentolamine
over papaverine alone [1, 3, 5, 9, 10, 19, 20]. The
majority of these studies also revealed a similar
rate of priapism between papaverine alone and the
combination, ranging from 4.3 to 7.8% in two
large reviews [3,20].
Other complications with papaverine-phentolami-
ne combinations are changes in liver function
tests, especially alkaline phosphatase and fibrosis
of the corpora. Changes in liver function tests are
related to the papaverine component and will be
covered in the review of that agent. Intracorporeal
fibrosis is a much more complicated topic that will
be explored more fully in the section on trimix.
(see below)
2. PAPAVERINE-IFENPRODYL
Ifenprodyl tartrate is an alphablocker with a very
low hypotensive capacity. It is stable in solution
and also when associated with papaverine, which
makes it very useful for use in dual or multiple
combination therapy. The mixture contains 20 mg
of papaverine and 1.25 mg of ifenprodyl tartrate
per ml. Individual doses are adapted to the initial
testing. (see that section).
In a large retrospective study (Virag, ISIR Amster-
dam 1998) this mixture was used in 23% of
patients at the endpoint. Cheap, stable and giving
a lower rate of local complications than papaveri-
ne-phentolamine, it might be proposed as a basic
treatment for economically low income patients
and countries.
3. VIP-PHENTOLAMINE
a) Vasoactive Intestinal Polypeptide (VIP) and
Phentolamine Mesylate
Vasoactive intestinal polypeptide (VIP) is a 28
amino acid peptide which is widely distributed in
the male and female urogenital tracts as well as the
central and peripheral nervous systems. VIP has
been shown to produce a wide range of effects
including potent vasodilation, inhibition of
contractile activity in many types of smooth
muscle, stimulation of cardiac contractility and sti-
mulation of many exocrine secretions. It produces
vasodilation by binding to a specific VIP smooth
muscle membrane receptor which stimulates Gs
protein, activates smooth muscle membrane enzy-
me adenylate cyclase, elevating intracellular
cyclic adenosine monophosphate (cAMP), thereby
lowering intracellular calcium.
VIP has since been found in the skin, circulatory
system, gastrointestinal and respiratory tracts [1].
VIP-immunoreactive nerves are abundant in the
male and female urogenital tracts. VIP has been
demonstrated in the nerves of the epididymis, vas
deferens, seminal vesicles, prostate, corpus caver-
nosum and spongiosum, and penile arteries and
arterioles [2,3,4]. VIP-immunoreactive nerves
have been demonstrated in the vagina, cervix, ute-
rus, fallopian tubes and ovaries [5]. VIP is widely
distributed in the central [6] and peripheral ner-
vous systems where immunoreactive nerve fibers
may have an important clinical role in the nervous
regulation of urogenital functions.
In the rat model, ageing is accompanied by a decli-
ne in male erectile function [7] but was not asso-
ciated with any significant change in the density
and pattern of VIP-immunoreactive nerve fibers in
the penis crura, cavernosal artery or helicine
branches. The cause of reduced male erectile per-
formance in old age in the rat does not appear to
be a direct result of impaired VIP-ergic innerva-
tion of the penile tissues [8]. However, a marked
depletion of VIP-immunoreactivity in the penile
tissue was evident in the ageing boar [9].
Ottesen et al. [10] reported that induction of an
erection by either visual sexual stimulation, intra-
cavernosal injection of vasoactive agents or saline
administration resulted in an increase in the
median concentration of VIP in the cavernous
blood. He suggested that the increase in VIP in
cavernous blood samples was due in part to local
release of the polypeptide.
Shirai et al. [11] demonstrated that VIP content of
325
and the distribution of VIP nerve fibers in human
cavernous tissue were lower in men with organic
ED than in men with psychogenic ED or in a
control group. A reduction in VIP immunoreactivi-
ty was found in tissue from human diabetics with
ED, suggesting that depletion of the peptide may
play a key role in the development of impotence. In
summary, these data suggest that VIP plays an
important role in penile erection and that, in some
patients, organic impotence is associated with low
VIP content and poor distribution of VIP nerve
fibers.
Intracavernosal injection of VIP in anaesthetized
dogs induces a relatively small dose-dependent
erectile response and an increase in intracaverno-
sal pressure which is blocked by administration of
VIP-antibody [6]. In the anaesthetized cat, intraca-
vernosal injection of VIP alone induced penile
erection and had the same maximal effect on intra-
cavernosal pressure as observed with the control
combination of intracavernosal papaverine, pros-
taglandin E1 and Phentolamine [12]. These fin-
dings suggest that intracavernosal VIP induces
penile erection in both the anaesthetized dog and
cat, increasing arterial flow, decreasing venous
flow and inducing sinusoidal relaxation. Intraca-
vernosal injection of VIP in potent men induced
tumescence and increases in penile length and dia-
meter [13] but failed to produce a rigid penile
erection in men with ED [13, 14, 15] or healthy
volunteers [16] with doses up to 60 µg [13, 15, 17,
18]. In contrast, when used in conjunction with
visual or vibratory stimulation, intracavernosal
injection of VIP did facilitate a rigid erection res-
ponse.
The vasodilator effect of VIP is potentiated by
blockade of the α-adrenergic receptors by Phento-
lamine mesylate. Phentolamine is an α-1 and α-2
receptor antagonist. Phentolamine reduces intra-
cellular calcium by reducing the α-1 receptor
induced elevation in inositol triphosphate and the
α-2 receptor induced Gi protein inhibition of
membrane adenylate cyclase enzyme activity.
In vitro, Phentolamine mesylate potentiates the
VIP-induced relaxation of phenylephrine contrac-
ted corpus cavernosum tissue strips in a
dose-dependent manner [19]. In contrast,VIP does
not appear to potentiate the modest dose-dependent
relaxation effect to Phentolamine. Clearly, α-adre-
nergic contractility is the dominant force in modu-
lation of corpus cavernosum smooth muscle
contractility and attenuation of α-activity with
Phentolamine should enhance the smooth muscle
relaxation of other pharmacologic agents, including
VIP.
Several authors have reported their experience
with the combination of VIP and Phentolamine
[20, 21, 22, 23] and conclude that a combination
of 25 µg of VIP and 1 or 2 mg of Phentolamine
mesylate (Invicorp ™, Senetek UK) is a safe and
effective treatment for erectile dysfunction with a
range of organic etiologies.
Hacket [23], in a large open label study of 548
patients with ED, reported that Invicorp™ produ-
ced erections suitable for sexual intercourse in
82% of patients. In a subsequent double-blind,
placebo-controlled of 411 patients, 74% of the
Invicorp™ injections resulted in an erection sui-
table for intercourse, whereas only 12% of the
matching placebo produced such responses.
McMahon [21], in a study of 20 men with chronic
impotence of various etiologies reported an erec-
tion, after sexual stimulation, sufficient for sexual
intercourse in 16 patients (80%) following admi-
nistration of Invicorp™. The erectile response was
dose-dependent and inversely related to the seve-
rity of penile vascular disease, with only 1 of 3
patients with cavernosal venous leakage achieving
an erection.
Dinsmore et al. [22] in a study of 70 men with ED
of various etiologies who were previously refrac-
tory to intracavernosal alprostadil or Phentolami-
ne/papaverine, reported a Invicorp™ response rate
of 67%, suggesting a potential salvage role in
patients resistant to other agents.
Current evidence suggests that VIP + Phentolami-
ne is highly efficacious and well tolerated in a
wide range of organic etiologies. Reported adver-
se effects were mild and transient and included
facial flushing (15-53%), truncal flushing (5-9%),
injection pain (10-11%) and bruising (20%). Pria-
pism appears rare with only two cases reported in
one study (<0.1%) [23].
VIP + Phentolamine has received regulatory
approval in the UK and several other countries. Its
clinical use is currently undergoing safety and effi-
cacy testing in international multicentre, place-
bo-controlled, double-blind, randomized clinical
trials in men with organic ED.
326
REFERENCES
1 KOEHN, F.-M., MISKA, W., SCHILL, W.-B., WEID-
NER, W. AND WEISKE, W.-H.: Concentrations of
vasoactive intestinal polypeptide in corpus cavernosum
and peripheral venous blood during prostaglandin
E1-induced erection. Arch Androl 31:217, 1993.
2 WILLIS, E.A., OTTESON, B., WAGNER, G., SUND-
LER, F. AND FAHRENKRUG, J.: Vasoactive intestinal
polypeptide (VIP) as a putative neurotransmitter in
penile erection. Life Sci. 33:383, 1983.
3 SHIRAI, V.D., MAKI, A., TAKANAMI, M., ANDO,
K., NAKAMURA, K., YANAIHARA, N., YANAIHA-
RA, C., IGUCHI, K., FUJIOTA, T. AND IWANAGA,
T.: Content and distribution of vasoactive intestinal
polypeptide (VIP) in cavernous tissues of human penis.
Urology 35:360, 1990.
4 POLAK, J.M., GU, J., MINA, S. AND BLOOM S.R.:
VIPergic nerves in the penis. Lancet 2:217, 1981.
5 PALLE, C., OTTESON, B., JØRGENSON, J. AND
FAHRENKRUG, J.: Peptide histidine methionine and
vasoactive intestinal peptide: occurrence and relaxant
effect in the human female reproductive tract. Biol.
Reprod. 41:1103, 1989.
6 JUENEMANN, K.-P., LUE, T.F., LUO, J., JADAL-
LAH, S.A., NUNES, L.L. AND TANAGHO, E.A.: The
role of vasoactive intestinal polypeptide as a neuro-
transmitter in canine penile erection. J. Urol. 138:871,
1987.
7 STEGER, R.W., HUANG, H. AND MEITES, J.: Repro-
duction. In: Masoro, EJ (ed) Handbook of physiology in
aging. CRC Press, Boca Raton, Florida, 1981.
8 AMENTA, F., CAVALLOTTI, C., DE ROSSI, M., FER-
RANTE, F. AND GEPETTI, P.: Vasoactive intestinal
polypeptide levels and distribution in the penis of old
rats. Neural Transm. 70:137, 1987
9 DALIN, A.-M. AND RODRIGUEZ-MARTINEZ, H.:
Vasointestinal polypeptide (VIP)- immunoreactive
nerves in the boar penis. J. Vet. Med. 39:792, 1992.
10 OTTESEN, B., WAGNER, G., VIRAG, R. AND FAH-
RENKRUG, J.: Penile erection: possible role for
vasoactive intestinal polypeptide as a neurotransmitter.
BMJ 288:9, 1984.
11 SHIRAI, M., MAKI, A., TAKANAMI, M., ANDO, K.,
NAKAMURA, K., YANAIHARA, N., YANAIHARA,
C., IGUCHI, K., FUJITA, T. AND IWANAGA, T.:
Content and distribution of vasoactive intestinal poly-
peptide (VIP) in cavernous tissue of human penis. Uro-
logy 35:360, 1990.
12 WANG, R., HIGUERA, T.R., SIKKA, S.C., MINKES,
R.K., BELLAN, J.A., KANDOWITZ, P.J., DOMER,
F.R. AND HELLSTROM, W.J.: Penile erections indu-
ced by vasoactive intestinal peptide and sodium nitro-
prusside. Urol. Res. 21:75, 1993.
13 ROY, J.B., PETRONE, R.L. AND SAID, S.I.: A clinical
trial of intracavernous vasoactive intestinal peptide to
induce penile erection. J. Urol. 143:302, 1990.
14 ADAIKAN, P.G., KOTTEGODA, S.R. AND RAT-
NAM, S.R.: Is vasoactive intestinal polypeptide the
principal transmitter involved in human penile erection?
J. Urol. 135:638, 1986.
15 KIELY, E.A., BLOOM, S.R. AND WILLIAMS, G.:
Penile response to intracavernosal vasoactive intestinal
polypeptide alone and in combination with other
vasoactive agents. Br. J. Urol. 64:191, 1989.
16 WAGNER, G. AND GERSTENBERG, T.: Intracaver-
nous injection of vasoactive intestinal polypeptide (VIP)
does not induce erection in man per se. World J. Urol.
5:171, 1987
17 WAGNER, G. AND GERSTENBERG, T.: Vasoactive
intestinal peptide facilitates normal erection. In: Procee-
dings of the Sixth Biennial International Symposium for
Corpus Cavernosal Revascularization and the Third
Biennial World Meeting on Impotence. Boston, MA,
Oct. 6-9, p.146, 1988.
18 OTTESON, B., WAGNER, G., VIRAG, R. AND FAH-
RENKRUG, J.: Penile erection: possible role for
vasoactive intestinal polypeptide as a neurotransmitter.
BMJ 288:9, 1984.
19 KIM, N.N., GALLANT, C., DHIR, V., GOLDSTEIN,
I., KRANE, R.J. AND TRAISH, A.M.: Potentiation of
VIP-induced relaxation by phentolamine in corpus
cavernosum. Abstract presented at ISIR, Amsterdam,
1998.
20 GERSTENBERG, T.C., METZ, P., OTTESON, B. AND
FAHRENKRUG, J.: Intracavernous self-injection with
vasoactive intestinal polypeptide and phentolamine in the
management of erectile failure. J. Urol. 147:1277, 1992.
21 MCMAHON, C.G.: A pilot study of the role of intraca-
vernous injection of vasoactive intestinal peptide (VIP)
and phentolamine mesylate in the treatment of erectile
dysfunction. Int. J. Impot Res. 8:233, 1996.
22 DINSMORE, W.W. AND ALERDICE, D.K.: Vasoacti-
ve intestinal polypeptide and phentolamine mesylate
administered by autoinjector in the treatment of patients
with erectile dysfunction resistant to other intracaverno-
sal agents. Br. J. Urol. 81:437, 1998.
23 HACKETT, G., CHARIG, C., DEAN, J., DINSMORE,
W., GINGELL, C., KELL, P., SANDHU, D. AND
SAVAGE, D.: The results of a 6 month multicentre pla-
cebo controlled study of Invicorp in the treatment of
non-psychogenic dysfunction. J. Urol. 159:240, 1998.
4. NITROSYLATED ADRENERGIC RECEPTOR
ANTAGONISTS
Nitric oxide (NO) is a potent molecule that causes
endothelium-dependent and neurally mediated
relaxation of vascular and trabecular smooth
muscle in the penis. The importance of NO in the
complex physiological response of erection is well
established by a review [1] and by several authors
[2-7].
327
Erectile dysfunction is often clinically evaluated
and treated by the intracorporal injection of a mix-
ture of drugs, each drug action in synergism at a
different point of the complex neurovascular cas-
cade of physiological events that results in an erec-
tion. This mixture often includes an α-adrenergic
antagonist such as phentolamine, a smooth muscle
relaxant such as alprostadil and a phosphodieste-
rase inhibitor such as papaverine.
Saenz de Tejada recently reported the concept of
the synthesis of new molecules with a dual phar-
macological action by chemically altering existing
α-adrenergic antagonists so that they become
nitric oxide donors while retaining the parent drug
action [8]. An example of this new class of mole-
cules is NMI-221 or nitrosylated moxisylyte
(SNO-mox., Nitromed Inc. MA. USA). Nitrosyla-
tion of α-antagonists potentially offers both
increased blood inflow by vasodilation of caver-
nosal and helicine arteries and relaxation of trabe-
cular and lacunar smooth muscles, which are
required for a full erection. Alpha receptor antago-
nists promote vascular dilatation while nitric oxide
promotes relaxation of both vascular and caverno-
sal smooth muscles.
In vitro, nitrosylated moxisylyte is more effective
than moxisylyte alone in relaxing isolated endo-
thelin contracted corporal smooth muscle strips
[8]. Elevated tissue cGMPlevels are measured fol-
lowing incubation with the nitrosylated moxisyly-
te derivative compared with either control or
moxisylyte incubated tissues. In anaesthetized rab-
bits, intracorporal injection of nitrosylated moxi-
sylyte produces significantly higher and more sus-
tained elevation of intracorporal pressure than
moxisylyte alone.
In vitro, the potent erectogenic activity of these
compounds after intracavernosal injection in rab-
bits was confirmed [8]. A 1 mg dose of SNO-mox
produced a comparable erectile response to the
standard triple combination of papaverine, alpros-
tadil and phentolamine. Moxisylyte was less effec-
tive and the response was ten-fold shorter than
with SNO-mox. The incidence of systemic adver-
se effects including mild transient hypotension,
was comparable with SNO-mox and moxisylyte.
Similar results have been achieved with another
nitrosylated alpha blocker, SNO-yohimbine
(SNO-yoh).
Enhancement of the NO pathway in the erectile
response can also be achieved by nitrosylation of
molecules that inhibit phosphodiesterases. Follo-
wing the successful introduction of drugs such as
sildenafil that potently and selectively inhibit
phosphodiesterases and elevate cytosolic cGMP
levels, the next generation of drugs may extend
this concept into dual-acting pharmacology. Retai-
ning the actions of NO while adding an additional
mechanism of action, such as alpha receptor bloc-
kade or inhibition of phosphodiesterases into a
single molecule may provide an even more effec-
tive therapy.
REFERENCES
1. BURNETT, A.L. Role of Nitric Oxide in the Physiolo-
gy of erection. Biol Reprod 52, 485-489 (1995)
2. IGNARRO, L. J., BUSH. P.A., BUGA, G.M., WOOD,
K.S., FUKUTO, J.M. AND RAIFTER, J. Nitric oxide
and cyclic GMPformation upon electrical field stimula-
tion cause relaxation of corpus cavernosum smooth
muscle. Biochem. Biophys. Res. Commun. 170,
843-850, (1990)
3. KIMOTO,Y., KESSLER,R., CONSTANTINOU,C.E.
Endothelium dependent relaxation of human corpus
cavernosum by bradykinin. J. Urol 144, 1015-1017,
(1990)
4. BUSH, P.A., ARONSON,W.J., BUGA, G.M., RAIFER,
J. AND IGNARRO, L.J. Nitric oxide is a potent relaxant
of human and rabbit corpus cavernosum. J. Urol 147,
1650-1655 (1992)
5. AZADZOI, K.M., KIM, N., BROWN, M.L, GOLD-
STEIN, I., COHEN, R.A. AND SAENZ DE TEJADA,
I. Endothelium-derived nitric oxide and cyclooxygenase
products modulate corpus cavernosum smooth muscle
tone. J. Urol 147, 220 -225 (1992)
6. KIM, N., VARDI, Y., PADMA-NATHAN, H., DALEY,
J., GOLDSTEIN, I. AND SAENZ DE TEJADA, I. Oxy-
gen tension regulates the nitric oxide pathway: physio-
logical role in penile erection J. Clin. Invest. 91,
437-443 (1993)
7. BURNETT, A.L., LOWENSTEIN, C.J., BREDT, D.S.,
CHANG, T.S.K. AND SNYDER, S.H. Nitric Oxide: a
physiologic mediator of penile erection. Science 257,
401-403 (1992)
8. I. SAENZ DE TEJADA, P. CUEVAS, B. CUEVAS, A.
FERNANDEZ, S. GABACHO, MADRID, SPAIN, L.
G. LETTS, J. D. SCHROEDER, T. SHELEKHIN, S. W.
TAM AND D. S. GARVEY. Nitrosylated-Adrenergic
Receptor Antagonists as potential drugs for the treat-
ment of erecile dysfunction (ED). Abstract 1998 AUA
_________________________
328
IV. INTRACAVERNOUS TRIPLE
AND MULTIPLE COMBINATION
THERAPY
1. THE CONCEPT OF MULTILEVEL ACTING
MEDICATIONS
Clinical experience has shown that combination
therapy with one or two agents had several limits
in terms of efficacy and use: a maximum of 60%
of the overall population of patients were respon-
ders, several other agents were available corres-
ponding to other routes for producing an erection,
synergistic action lowered the volume injected and
improved the response rate to almost 85 to 90% of
the impotent population.
2. PAPAVERINE, IFENPRODYL, PIRIBEDIL,
ATROPINE, DIPYRAMIDOLE WITH OR
WITHOUT ALPROSTADIL
This rather complicated mixture appeared in the
English literature in 1991 (Virag et al). The ratio-
nale for its use was a careful study of each of its
compounds and the various routes they activate in
the erectile process. In addition to the well known
effects of papaverine and alphabockers, Virag et
al. added a dopaminergic agent, an acetylcholine
receptor blocker and a long-acting additional
phosphodiesterase blocker. Initially yohimbine
was also used in this mixture, then abandoned for
redundant activity. In the initial study, 102 patients
who had failed to respond to papaverine alone
and/or papaverine ifenprodyl were "rescued"
with this mixture named "ceritine". The use of
atropine in this mixture has been controversial; it
is based on the property of this agent to activate
erection, at a low dose. Goldstein et al. have
confirmed (Virag et al) the enhancement of erecti-
le function by adding atropine to trimix (see
below): 73% of the patients failing with other mix-
tures responded to the atropine+trimix mixture.
Montorsi reported that 96% of his patients with
vasculogenic impotence responded to the same
regimen. With the availability of alprostadil pow-
der, it became obvious that PGE1 should be able to
enhance the strength of "ceritine". Thus the use of
"ceritine +" was designed with three versions:
20µg in 4ml, 2ml and 1ml of the initial mixture.
The response rate in organic or mixed etiology
patients was 90%.
A simplified version of "ceritine" is a triple com-
bination of 10 mg of papaverine, 2.5 mg of ifen-
prodyl tartrate and 5 mg of alprostadil powder in a
1ml solution which gives almost the same results
as the US trimix.
3. PAPAVERINE, PHENTOLAMINE, PGE1 (TRI-
MIX)
Earlier in this chapter we discussed combination
therapy with papaverine and phentolamine intro-
duced by LeFleur and Zorgniotti in 1985 [1]. The
synergism between the smooth muscle relaxant
papaverine and the alpha blocking agent phentola-
mine, has been unequivocally shown to be more
effective than either agent alone, with similar rates
of priapism [1,3,5,9,10,19,20]. Unfortunately
intracorporeal scarring and changes in liver func-
tion tests remain a significant problem [10]. The
introduction of prostaglandin E 1 by Ishii, Adaikan
and Virag in 1986 opened a new era for injection
therapy [12,13]. Multiple abstracts discussed ear-
lier in the section on prostaglandin E1 confirm a
similar efficacy and a much lower rate of priapism
and intracorporeal scarring than the combination
of papaverine plus phentolamine. Unfortunately
penile pain, reported in up to 40% of patients,
continues to be a significant drawback to prosta-
glandin E1 monotherapy [21,22].
Prostaglandin E1 (PGE1, alprostadil) belongs to
the family of eicosanoids, which represent a large
group of oxygenated metabolites of polyunsatura-
ted 20-carbon fatty acids, including prostaglan-
dins, thromboxanes, leukotrienes, lipoxins,
epoxyeicosatrienic acids, hepoxilins and other
compounds. Within the human corpora PGE1
leads to increased cyclic AMP by a modulation of
the enzyme adenyl-cyclase. The accumulation of
cyclic AMP after exposure to PGE1, leads to a
decrease in free calcium concentration and, subse-
quently, to relaxation of the cavernous smooth
muscle. PGE1 also possesses antiadrenergic
effects by means of inhibition of noradrenalin out-
put. The plasma half-life of PGE1 is less than one
minute due to rapid pulmonary clearance of up to
65-80% during the first passage through the lung.
A second local pathway exists within the penis for
local metabolism of prostaglandin E1 [20].
Bennett et al. introduced a combination of papave-
rine, phentolamine and prostaglandin E1, that we
329
now term trimix, in 1990 [23]. They reported a
mixture of 2.5 mg of papaverine (30 mg per cc),
0.5 cc of phentolamine (5 mg per cc), 0.05 cc of
alprostadil (500 micrograms per cc), and 1.2 cc of
0.9% normal saline to produce a vial of 4.25 cc.
The solution was reported to be physiologically
active for six months (refrigeration was recom-
mended), with a pH of 4.0. This initial report,
documented use in more than 100 men for both
diagnostic testing and home therapy. The efficacy
was felt to be good with only one prolonged erec-
tion and no pain or corporal fibrosis noted. A fol-
low-up study published in 1991, looked more clo-
sely at the results in this group of 116 patients
with a follow-up of 3 to 18 months [24]. Ninety-
one percent (105/116) of patients tested had a
usable erection at home. Prolonged erections
requiring treatment were found in only two
patients, pain at the injection site in two patients,
and no patients were noted to have fibrosis.
Goldstein et al. presented data at the 1990 AUA
meeting on "rescue" using trimix. Thirty-two
patients who failed combinations of papaverine/
phentolamine (8 of whom also failed prostaglan-
din E 1 ) were treated with trimix. Sixty-two per-
cent reported restoration of erectile potency with
an average dose of 0.47 cc [25]. Goldstein conclu-
ded "the fact that the three drugs used in combina-
tion had previously failed to restore erections at
higher dosages individually, and are successful in
lower doses in combination, suggests a synergistic
drug action."
McMahon reported a randomized cross-over study
in 228 patients in 1991 [26]. The patients were eva-
luated and divided into arteriogenic (36%), venoge-
nic (18%), mixed vasculogenic (23%), neurogenic
(4%), and psychogenic (19%) impotence. Each
patient received injections of prostaglandin E1,
papaverine plus phentolamine, and triple mix in a
randomized manner. Dosages were standardized
depending on the etiology. Erectile responses were
quantified using real time Rigiscan monitoring and
adjuvant visual sexual stimulation. No difference in
the response of prostaglandin E1 compared to the
combination of papaverine plus phentolamine was
found in any of the groups. The erectile response to
the combination of triple mix was statistically
superior compared to responses of the other two
agents in men with severe arteriogenic impotence
and mild venogenic impotence (P < 0.05).
In all other patients, although the trend suggested
that triple mix was more effective, no statistical
difference in response was found. Prolonged phar-
macological erections lasting more than 5 hours
occurred at a rate of 7.9% with papaverine plus
phentolamine, 1.3% with prostaglandin E1, and
0.9% with triple mix. Persistent penile pain occur-
red in 24% after the injection of prostaglandin E1,
and no pain was noted after the injection of triple
mix in any patient. The authors theorized that the
"use of combination intracavernous pharmacothe-
rapy seems to produce a greater vasodilatory res-
ponse of the cavernous smooth muscle effector
junction than single agents. This response possibly
relates to synergism of these agents, perhaps due
to their differing sites and mechanisms of action
on the cascade of neurovascular events which
leads to erection." The authors concluded that
triple mix is significantly more effective in men
with severe arteriogenic impotence and mild
cavernosal venous leakage and has a role in salva-
ging these patients. Authors also concluded that
the triple mixture combination is associated with a
significantly lower incidence of prolonged erec-
tions or injection pain than the other two agents
studied.
Hamid et al. reported a response rate of 88% in a
trial of 100 patients in the International Journal of
Impotence Research in 1992 [27]. The authors
found pain to be present in less than 5% and found
only one episode of priapism.
Allen et al. performed a double-blind cross-over
study utilizing papaverine plus phentolamine,
papaverine plus prostaglandin E1 and trimix[28].
The study included only 7 patients. They found
those combinations containing prostaglandin E1
to have a longer duration but no significant impro-
vement in rigidity. Triple mixture was no better
than papaverine plus E1 in terms of duration or
rigidity.
Von Heyden et al. reported trimix again as a form
of salvage therapy for prostaglandin E1 failures in
1993 [29]. In a retrospective review of 101
patients on injection therapy, 31 of cases were on
trimix. These 31 patients had failed earlier
attempts using prostaglandin E1 as monotherapy
due to either insufficient erections or penile pain.
The authors stressed the use of low dosages of
medications and their average volumes of trimix
injected were 0.34 to 0.46 cc.
330
Govier et al. reported usable erections in 81%
(170/210) of patients with trimix in 1993 [30].
These patients were seen over a 26-month period,
starting in December 1989. Early on, only those
patients failing injections with other more establi-
shed agents (papaverine, papaverine/phentolami-
ne, prostaglandin E1) or those having significant
pain with prostaglandin E1, were given the triple
mixture. As experience grew, trimix became more
of a first-line agent, largely due to the pain pro-
blems encountered with prostaglandin E1 mono-
therapy. One hundred forty-six patients were fol-
lowed an average of 11.2 months (1-26 months) on
a pharmacologic erection program. Injection
volumes averaged 0.36 cc (0.01-1 cc). Excluding
those patients given larger doses for a duplex scan
(9 patients); priapism (tumescence greater than six
hours) occurred in only 3 patients (1.7%). Pain
was encountered in 6 patients (3.5%) and intracor-
poreal scarring was found in 7 (4.2%) patients.
The authors felt the superior dose response over
other agents, and a low incidence of pain, pria-
pism, and scarring made this a first-line agent for
intracorporeal therapy.
Valdevenito and Melman reviewed a large injec-
tion program in 1994 [31]. In 301 patients, with
a variety of etiologies, 84% could obtain effective
erections with intracorporeal therapy and all
entered a home injection program using a variety
of agents. Initially, 80 patients utilized the triple
mixture and by the time of their review, several
patients having failed other agents were moved to
triple therapy, leaving a total of 111 on triple the-
rapy at the time of their review. Thirty-nine per-
cent of their patients dropped out of the program at
some point over the course of a 6-year period.
They noted scar tissue in 1.8% of those patients on
trimix (5.9% in the entire group). Priapism was
found in 2.7% of patients on trimix (1.6% of the
entire group).
Bechara et al. in 1996 reported on 32 patients
having failed with a combination of papaverine
plus phentolamine [32]. Twenty-two percent of
these patients responded to prostaglandin E1 and
50% to trimix. Pain was reported in 41% of those
receiving prostaglandin E1 and 12.5% receiving
trimix. The authors concluded that trimix was
more effective than prostaglandin E 1 with a lower
incidence of pain.
 Table 1: Efficacy of trimix

YEAR NUMBER % AGENT

REPORTED OF PATIENTS EFFICACY USED

Bennett [24] 1991 116 92% Trimix only

Hamid [27] 1992 100 88% Trimix only
Fallen [3] 1995 160 77% Trimix only
Casabe [35] 1998 189 85% Trimix only
Govier [30] 1993 210 81% Multiple agents
and Trimix
Valdevenito [31] 1994 301 84% Multiple agents
and Trimix

1076 85%

Table 2a: Priapism with trimix in a home injection program

YEAR NUMBER OF NUMBER OF % PRIAPISM TYPICAL USE

PATIENTS PRIAPISMS
Bennett [24] 1991 105 1 1% Injection program
Hamid [27] 1992 100 1 1% Injection program
Govier [30] 1993 170 3 1.7% Injection program
Collins [33] 1993 202 7 3.4% Injection program
Valdevenito [31] 1994 111 3 2.7% Injection program
Fallen [3] 1995 160 3 1.9% Injection program

848 18 2.1%

Table 2b: Priapism with trimix for diagnostic injections

YEAR NUMBER OF NUMBER OF % PRIAPISM USE OF AGENT

PATIENTS PRIAPISMS

McMahon [26] 1991 228 2 .9% 1 injection various agents

Govier [34] 1995 280 12 4.3% Duplex scans

Bechara [32] 1996 32 0 0% Rescue

Casabe [35] 1998 189 4 3.7% Diagnostic

729 18 2.5%

Table 3: Incidence of pain with trimix

YEAR NUMBER OF PTS WITH PAIN % OF PAIN
PATIENTS
Bennett [24] 1991 105 2 1.9%
McMahon [26] 1991 228 0 0%
Hamid [27] 1992 100 5 5%
Govier [30] 1993 170 6 3.5%
Collins [33] 1993 202 4 2.0%

805 17 2.1%

331
Tables 1-4 summarize the literature on trimix.
Table 1 looks at the efficacy of the triple drug mix-
ture in several larger series. The first four groups
listed were patients given only trimix. The second
two studies were in larger groups of patients who
were treated with multiple agents, but were all
given a trial of trimix before therapy was deemed
ineffective. In this population of more than 1000
patients, 85% responded to the triple drug mixtu-
re, including many patients who had failed single
agents and other combination therapy. Many
authors [25,26,29,30,31,32] have shown triple mix
to be effective when prostaglandin E1 or papaveri-
ne phentolamine combinations are ineffective.
Table 2a looks at the incidence of priapism in
patients on home injection therapy with trimix. A
variety of dosage combinations was utilized, as
well as different techniques to titrate patients.
Overall, in 850 patients, priapism requiring treat-
ment occurred in 2.1%. Table 2b looks at the use
of trimix during diagnostic injections. Again, dif-
ferent concentrations of medications were utilized
and in 700+ patients, the priapism rate was 2.3%.
Clearly these incidences are significantly lower
than papaverine alone or papaverine plus phento-
lamine. Prostaglandin E1 monotherapy unequivo-
cally has the lowest incidence of priapism, recent-
ly reported at 0.36% in almost 3000 patients in a
recent review [20].
Table 3 looks at pain associated with injection of
trimix. In approximately 800 patients, the inciden-
ce of pain during injection was 2.5%. This is a
significant advantage over the use of prostaglan-
din E1 monotherapy with reported pain rates as
high as 40% [21,22].
The ability to achieve superior efficacy with a low
Table 4: Penile scarring with trimix
YEAR NUMBER OF PATIENTS WITH
PATIENTS SCARRING
Bennett [24] 1991 105 0 0%
Govier [30] 1993 170 7 4.2%
Valdevenito [31] 1994 111 2 1.8%
Casabe [35] 1998 189 10
575 19
332
incidence of pain are the two factors that stand out
for the utilization of trimix as a first-line agent.
The slightly higher incidence of priapism, espe-
cially with the diagnostic use of trimix, would
favor E1 therapy as the optimal first-line agent.
The last important aspect to consider is penile
fibrosis. Table 4 looks at the incidence of penile
fibrosis/nodules with trimix. In 575 patients, peni-
le fibrosis and/or nodules were noted in 3.3%.
While efficacy, prolonged erections/priapism, and
pain are relatively easy parameters to define and
report; penile scarring and/or nodules are complex
at best. In 1989 fibrotic nodules were reported in
5.4% of 1573 patients collected from different
series using papaverine plus phentolamine combi-
nations [36]. Yet Levine et al. also in 1989, repor-
ted nodules in 57% of their patients on papaverine
phentolamine combinations with an injection
duration of only 12 months [11]. How does one
explain such a discrepancy?
In an exhaustive review of the literature in 1996
[20], Porst found the following fibrosis rates;
papaverine, 1527 patients, 5.7%; papaverine plus
phentolamine, 2263 patients, 12.4%, and prosta-
glandin E 1, 2745 patients, 0.8%. In the Schwartz
pharma scientific product information on Virilan
(Alprostadil)[37], the incidence of penile fibrosis
and penile deviation was listed as 0.05% based on
pooled data from 44 studies involving 6145
patients. Yet in the product information on Caver-
ject (Alprostadil) dated 17 March, 1995[38],
Upjohn Pty. Ltd. warned of a frequency rate of
4.8% of penile fibrosis. Chen et al. in 1996 repor-
ted penile scarring in 16% of 92 patients on pros-
taglandin E1 [39]. The scarring was not severe,
and most patients continued injection therapy.
Only one patient had progression and had to dis-
INCIDENCE OF FOLLOW-UP
SCARRING (MONTHS)
14-24
11.2
(mean)
1-24
5.3% 16.95
(mean)
3.3%
continue therapy. Chew et al. [40], in 1997, repor-
ted a 23.3% incidence of fibrosis in 245 patients
performing injections of prostaglandin E1 for an
average of 29 months. Again, how do we explain
these wide discrepancies?
At present, our reporting of penile fibrosis
includes too many variables to be of much value.
How much fibrosis is really fibrosis? Do we need
ultrasound confirmation? Does the patient, or exa-
miner, note a deformity of the penis other than the
fibrosis? Does the fibrosis need to persist or pro-
gress? If the fibrosis resolves, was it fibrosis?
How often was the patient examined and by
whom? Were variables of injection volume, need-
le diameter, and injection technique accounted for,
and how frequently were the injections performed
and over what period of time?
Although our current literature will not answer
these questions precisely, some consensus can be
derived from this review and the author's personal
experience.
1. Penile fibrosis is probably caused by a combi-
nation of trauma from the injection itself and a
toxic effect of the agent involved.
2. Papaverine or papaverine-containing mixtures
have a higher incidence of penile fibrosis than
prostaglandin E1 monotherapy.
3. The penile fibrosis secondary to papaverine or
papaverine-containing mixtures tends to be
more severe and is less likely to resolve than
that of prostaglandin E 1.
4. A longer duration and higher frequency of peni-
le injections leads to a higher incidence of
fibrosis.
5. Good injection technique using small needles,
small volumes of agents, and penile pressure
after the injection will lower the incidence of
penile fibrosis.
Overall, trimix has a superior efficacy and lower
incidence of pain than prostaglandin E1 monothe-
rapy. While the risk of priapism is low, it clearly
is higher than that of prostaglandin E1 alone.
While the literature on nodules and fibrosis is
confusing, E1 monotherapy again has the edge.
Hopefully in the future, we will have a single
agent capable of achieving the best qualities of
both prostaglandin E 1 monotherapy and trimix.
333
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_________________________

V. TRANSURETHRAL DRUG
THERAPY
1. ALPROSTADIL (PROSTAGLANDIN E1)
Intraurethral alprostadil (IUA) is a novel delivery
system design to administer a micro-pellet of
alprostadil (PGE 1) topically to the urethral muco-
sa for absorption and transfer to the erectile
bodies. Padma-Nathan and associates reported, at
the AUAin 1995, for the first time, that men recei-
ving intraurethral administration of alprostadil
(500µg) could achieve a penile erection [1]. It has
been approved for clinical use in USAsince Janua-
ry 1997.
a) Presentation
It is a single-use translucent hollow polypropylene
applicator designed to deliver medication to the
male urethra. The medicated pellet (semi-solid
micro-suppository measuring 1.4mm in diameter
by 3-6 mm in length) resides at the tip of the hol-
low applicator. The stem of the applicator mea-
sures 3.2 cm in length and 3.5 mm in diameter.
Alprostadil is the active medication. It is suspen-
ded in polyethylene glycol 1450 (as excipient) and
formed into the micro-pellet [2].
b) Pharmacology
1. ACTIONS
Alprostadil is a synthetic prostaglandin with simi-
lar pharmacological actions to prostaglandin E1
(PGE1). Alprostadil is a potent vasodilator acting
through the cAMP pathway. Hedlund and Anders-
son showed that alprostadil caused relaxation of
isolated strips of corpus cavernosum and spongio -
sum in vitro which have been pre-contracted with
norepinephrine [3]. An increase of cAMP, induced
by the activation of adenylate cyclase, is associa-
ted with this event. This increase activates ATP-
dependent pumps that release calcium ions out of
the smooth muscle cell, which trigger relaxation.
PGE1 may also show various pharmacological
actions. It produces transient platelet antiaggre-
gant effects at high plasma levels [4]. PGE1can
also promote mucus secretion in the stomach, sti-
mulation of intestinal smooth muscle and stimula -
tion of uterine smooth muscle.
2. PHARMACOKINETICS
Intraurethral administrations of alprostadil must
335
be preceded by urination. The residual urine will
disperse the micro-pellet, allowing alprostadil to
be absorbed by the urethral mucosa in a biphasic
phase. Initial absorption is rapid. About 80% of
alprostadil is absorbed within 10 minutes [5-7].
The concentration of PGE1 in the semen after
using intraurethral alprostadil does not seem to be
significantly altered [8]. Alprostadil is absorbed
initially into the corpus spongiosum from the ure-
thra. A fraction (approximately 20%) of the drug is
then transfered through intercommunicating ves-
sels to the corpora cavernosa [9,10]. The rest
passes into the systemic venous circulation. The
peak plasma concentration of PGE1 is reached
within 16 minutes. The plasma concentrations,
however, are low and require gas chromatography
to be detected.
Alprostadil is a well known drug, which has been
studied extensively. After its intravenous use,
alprostadil is metabolized rapidly (first to 15-keto-
PGE1 and then to 13,14-dihydro, 15-keto-PGE1,
both inactive) during its passage through the lungs
and 90% is excreted in the urine as metabolites
within 24 hours – the rest in the feces [11]. The
enzyme that catalyzes the first reaction is present
in the urethra, prostate, corpus cavernosum and
lungs. After one pass through the pulmonary capil-
lary beds, between 60-90% of systemic PGE1 is
inactivated [11,12]. Alprostadil half-life varies
between 30 seconds and 10 minutes according to
the patient’s physiological status.
c) Indications and contraindications
1. INDICATIONS:
IUA is indicated in the treatment of erectile dys-
function of any etiology.
2. CONTRAINDICATIONS:
It is contraindicated in men with the following:
• Known alprostadil hypersensitivity.
• Abnormal penile anatomy: urethral stricture,
balanitis, severe hypospadias and curvature,
and acute or chronic urethritis.
• Patients who have a hyperviscosity syndrome
such as multiple myeloma, polycythemia,
thrombocythemia, sickle cell anemia or trait.
• For sexual intercourse with a pregnant women
unless a condom barrier is used
• In men for whom sexual activity is inadvisable.
e) Clinical experience
In 1996, Hellstrom and associates reported the
results of a double-blind, placebo-controlled mul-
ticenter study evaluating 68 men with long-stan-
ding organic erectile dysfunction. In this study,
63.6% (42 of 66) of patients reported intercourse
while 49.2% (32 of 65) judged their erection to be
sufficient for intercourse with IUA [13]. Padma-
Nathan and associates published the largest series
in the New England Journal of Medicine in Janua-
ry, 1997 [14]. They reported the results of a
double-blind, placebo-controlled multicenter (in
USA) phase III study using alprostadil delivered
transurethrally that included 1511 men, 27 to 88
years of age, suffering from chronic erectile dys-
function due to various organic causes. In this
trial, men were first administered alprostadil
intraurethrally in the clinic (titration phase) up to
four doses of the drug (125,250,500 and 1000 µg).
During that phase of the study, 996 men (65.9%)
had an erection response sufficient to enter the pla-
cebo-controlled “at-home” phase of the study. The
authors reported that 299 of the 461 patients
(64.9%) treated with alprostadil at home had inter-
course, on at least one occasion, as compared with
93 of the 500 men in the placebo group (18.6%,
p<0.001). Overall, 57% of applications or admi-
nistrations of alprostadil (2797/4933) resulted in
intercourse, orgasm, or an erection sufficient for
intercourse for at least 10 minutes compared to
15.4% (669/4331) in the placebo group (p>0.001).
Among the men in the alprostadil group who had
sexual intercourse at least once, 7 of 10 applica-
tions of IUA resulted in intercourse. The authors
reported that there was no difference in the effica-
cy of intraurethral alprostadil regardless of age or
etiology of ED. The authors indicated that the in-
clinic response to IUA was not predictive of inter-
course at home (64.9% of the clinical responders
had intercourse at home). A similar double-blind,
placebo-controlled multicenter study was conduc-
ted in Europe on 249 patients [15]. In the clinical
phase of the study, 159 patients (64%) achieved an
erection sufficient for intercourse and were rando-
mized either to placebo or the active medication
for home treatment. In the IUA arm, 69% of men
reported intercourse at least once as compared to
11% of men in the placebo arm (p<0.001).
Using the same patient cohort enrolled in the USA
multicenter study [14], Engel evaluated the effica-
336
cy of transurethral alprostadil IUAin patients with
ED who underwent prior intracavernous injection
(ICI) therapy [16]. Of the original 1511 men
enrolled, 452 reported prior ICI therapy. Prior ICI
therapy was reported to be effective by 238 men,
sometimes effective by 119 and not effective by
95. In the group that reported prior ICI as not
effective, 58% obtained an erection sufficient for
intercourse in the clinic using IUA; 47% of these
responders achieved intercourse during the home
treatment phase of the study. On the other hand,
for men reporting ICI therapy as effective or
sometimes effective, following IUA therapy 68%
achieved an erection sufficient for intercourse in
the clinic setting and 67% of these clinical respon-
ders reported intercourse at home. In another
report, using the same patient population, the effi-
cacy of transurethral alprostadil was evaluated in
patients suffering from ED following radical pros-
tatectomy (n=384 patients) [17]. The authors
reported that 70.3% of these men had an erection
sufficient for intercourse in the clinic and 57.1%
of these responders on active medication had
sexual intercourse at least once at home.
Other reports about the efficacy of IUA show
varying results. Werthman and Rajfer reported the
results of their first 100 cases in the clinical setting
[18]. All patients had previous intracavernosal
injection therapy. Using IUA, only 7% had well-
sustained, rigid erection while 30% had full erec-
tions but with partial rigidity sufficient for pene-
tration as compared with 49% who presented a
well-sustained, rigid erection and 40% who had a
full erection but with partial rigidity using intraca-
vernosal injections. They concluded that injection
therapy was more effective. In a similar study,
Porst reported a total response rate of 43% using
IUA (up to 1000 µg) vs 70% with intracavernous
alprostadil (up to 20 µg) in 103 patients with ED
[19]. In a letter to the editor in response to Porst’s
article, Lewis made several points before conside-
ring this article to indicate that transurethral
alprostadil is an ineffective therapy [20]. Lewis
feels that IUA should be considered more as an
intercourse facilitator rather than an erection indu-
cer like injection therapy, making the comparison
difficult between the two therapies. He stated that
facilitatory treatment may be more desirable for
couples as they work with ED as a couple. Fur-
thermore, he mentioned that the concurrent use of
a venous flow controller device with IUA impro-
ved both the patient’s degree of erection and res-
ponse and reduced the side effects [20]. Fulgham
and associates evaluated the response to intraure-
thral alprostadil administration using IUA in men
(n=115) with ED in an office setting study [21].
Only 27% of patients (31 of 115) tested in their
office achieved an erection sufficient for inter-
course (patients received up to 1000 µg IUA).
Mulhall, at the AUA in 1998, presented data indi-
cating that in clinic responders demonstrate wide
variability of response to IUA therapy at home
[22]. At home, in clinic responders (n=100
patients), 50±20% (range 25-75%) of administra-
tions resulted in erections sufficient for penetra-
tion. In a study of 107 patients who either refused
or failed prior ICI therapy, 7 patients developed
erections rated good or very good, while 72% had
partial erections. At three months follow-up, 24%
of patients were satisfied and 8% refilled their
prescription [23].
Bodner and associates evaluated the efficacy of
intraurethral alprostadil using IUA in treating ED
following spinal cord injury (SCI) in 15 patients.
All of these patients had previous effective ICI
therapy. Only 3 patients achieved an erection suf-
ficient for intercourse in the clinic (with the use of
a constrictive ring) and used it at home. At home,
all 3 were dissatisfied with the quality of the erec-
tion and returned to ICI therapy [24]. It is possible
that the urethral lining might be different in these
patients because of metaplasia (frequent catheter
users).
In order to increase the success rate of at-home IUA
therapy, an adjustable penile constriction band
(ACTIS®) to block venous outflow was developed
and is used in combination with administration of
transurethral alprostadil to promote arteriolar
inflow in men suffering from ED [25-27]. The IUA-
ACTIS Study group reported that of the 144
patients who completed home titration, 71%
(102/144) reported successful intercourse. Using
the penile band, 75% of applications of transure-
thral alprostadil resulted in intercourse while 74%
of patients were satisfied or very satisfied with the
therapy [26]. Padma-Nathan reported an erection
sufficient for intercourse in 6 of 8 patients who had
previously failed IUA therapy [27].
Donatucci, at the 1998 AUA, reported the use of
IUA as an effective alternative therapy in a small
337
group of patients (n=11) who had undergone pros-
thesis placement or removal [28]. Five patients
responded to IUA alone with erection sufficient
for intercourse and two responded to the combina-
tion of IUA and vacuum therapy. Hellstrom et al.
presented results at the 1999 AUA concerning the
efficacy of IUA in patients who failed sildenafil.
221 patients were enrolled at 62 sites in a post-
marketing study either because they failed to
respond to sildenafil or had a side effect resulting
in discontinuation of sildenafil. Patients used 1 or
2 doses of transurethral alprostadil in the clinic,
and the investigator and patient judged the erecti-
le response. Overall, 125/221 (57%) of the
patients achieved an erection sufficient for inter-
course with transurethral alprostadil in the clinic.
Of the 125 successful patients, 34 (27.2%) had to
use the ACTIS® constriction band. Most patients
(>70%) used either 500 or 1000 µg of IUA. Of the
221 patients, 14 (6%) rated their erectile dysfunc-
tion as mild, 100 (45%) as moderate, and 107
(48%) as complete [29]. At the same meeting,
Nehra et al. reported their results of a combination
therapy (IUAand Sildenafil) in patients who failed
prior use of either medication alone. Sixteen
patients (11 post radical prostatectomy and 5 with
a diagnosis of organic erectile dysfunction, were
part of this study. Combination therapy was initia-
ted using 100 mg Sildenafil orally 60 minutes
prior to intercourse and 500µg of IUA immediate-
ly before intercourse. The combination was effec-
tive in inducing an erection sufficient for inter-
course. At three months, all patients reported
excellent results. This might represent a salvage
therapy, although more studies are needed before
we can conclude on their effectiveness [30].
One of the advantages of IUA over injection the-
rapy is the fact that IUA does not require the use
of needles. In fact, 88% of men receiving or using
IUArated the transurethral application of alprosta-
dil as either “neutral”, “comfortable”, or “very
comfortable” [14].
d) Adverse effects
Penile pain is the most frequent reported side
effect. During home treatment, penile pain was
reported about 30% of men (29 to 35.7%) in 7.8 to
18.3% of IUA administrations (not every applica-
tion leads to pain). Urethral pain was reported in
12%, minor urethral bleeding occurred in 5%, tes-
ticular pain in 5% and dizziness in 2%. Penile
fibrosis were observed in 1.4% and priapism in
less than 0.1% [13,14,16,19,31]. No man reported
urethral stricture, penile fibrosis or priapism in
series [14].
In the clinic, dizziness and hypotension occurred
in 4% and 3-4%, respectively [13,14,16,19,31].
The frequency of hypotension increased with the
dose in the series reported in the New England
Journal of Medicine [14]. Defined by strict crite-
ria, Fulgham reported, in his series, 41.2% of pos-
tural hypotension [21]. Syncope occurred in 0.4-
3% [14,18,19]. Because of this potential effect,
IUA titration should be carried out under medical
supervision according to the monography [2].
However, Morales and the Canadian IUA investi-
gators reported at the annual Canadian Urological
Association meeting last June, 1999 that titration
of IUA in clinic is not required. In fact, they ran-
domized 643 patients to either titration in the cli-
nic or at home with the use of a video explaining
the use of IUA and its side effects. During the
titration phase, they reported no differences in effi-
cacy and safety between the at-home and in-clinic
titration groups. In fact, no hypotension occurred
in the at-home titration phase suggesting that titra-
tion could be safely done at home instead of the
clinic [32].
The female partner reported vaginal burning/
itching in 5.8% of partners on active medication
compared to 0.8% in the placebo group.
e) Dosage and administration
IUA is available in 3-4 dosage depending of the
country (125-250-500-1000µg). Patient should
receive the lowest dose to achieve sexual inter-
course. The system is used on a prn basis, 10-15
minutes before intercourse, with a maximum of
one unit every 12 hours. The patient must be ins-
tructed to urinate before insertion of the device.
In summary, IUA has been shown to be safe and
effective for use in the treatment of erctile dys-
function. Because of its limited systemic side
effects and its acceptance by the patient, it can be
offer as an option as a first line therapy for patient
suffering from erectile dysfunction.
2. LYOPHILIZED LIPOSOMAL ALPROSTADIL
Using a lyophilized liposomal PGE1delivered
intrameataly- a compound different from the one
338
found in IUA, a group of California, USA, repor-
ted an in-clinic success rate of 56% (10 of 18
patients) in a small study [33]. Engelhardt com-
pared the intraurethral application of liposomal
PGE1with intracavernous injection of PGE1in a
clinical setting in 25 patients (10 with psychogenic
and 15 with organic ED). Intraurethral liposomal
PGE1produce sufficient rigidity in only 6 of 25
patients (all responders had psychogenic ED) [34].
Because of the limited data on this new lyophili-
zed liposomal PGE1, we can’t yet determine its
role in ED treatment.
3. ALPROSTADIL (PROSTAGLANDIN E1) /PRA-
ZOSIN
Because transurethral alprostadil using IUA deli-
very system has been shown to cause erections,
the potential benefit of adding prazosin HCL, an
α1–blocker (as for ICI therapy) to alprostadil has
been studied.
Pharmacology Prazosin hydrochloride is a quina-
zoline-derivative post-synaptic α1-adrenergic
blocking agent. It reduces vascular resistance as a
result of its vasodilating effects on both arterial
and venous vessels. It produces a selective com-
petitive inhibition of α1-adrenergic receptors. The
plasma half-life after oral administration has been
reported to be 2-4 hours. It is metabolized exten-
sively in the liver, principally by demethylation
and conjugation, and excreted as unchanged drug
(5-11%) and metabolites. Four of its metabolites
have been shown to posses 10-25% of the hypo-
tensive effect of prazosin. Between 90-94% of a
dose is excreted in the feces and the remainder in
the urine [36].
a) Clinical experience
At the VII World meeting in San Francisco (1996),
Padma-Nathan reported two randomized, double-
blind, placebo controlled study evaluating the
safety and efficacy of alprostadil (A), prazosin
HCL (P) and a combination of both (A/P) admi-
nistered intraurethrally to 460 men with chronic
ED. Alprostadil was more potent than prazosin
alone but some combination were better than
alprostadil. The exact numbers were not publi-
shed [37]. In another study, 415 patients were
dosed (double-blind) with up to 4 alprostadil and 9
alprostadil/prazosin combinations on different
days to allow within-patient comparisons. In the
study, 68% of men reported intercourse on at least
one dose. Each of the 9 combinations resulted in
higher rates of intercourse than the alprostadil
component alone [38]. Assessing the erectile res-
ponse to transurethral alprostadil, prazosin and
combination of A/P in a double-blind, placebo-
controlled study, Peterson and associates showed
that prazosin alone (9 to 2000 µg) was not better
than placebo (12.7 vs. 2.7%) [39]. The most effec-
tive alprostadil dose (500µg) resulted in full enlar-
gement or rigidity in 51.8% of administrations.
The 500/2000µg A/P combination slightly impro-
ved the response rate to 58.9%. The combinations
of 125/500 and 250/500µg A/P were more effecti-
ve than 125 and 250µg of alprostadil given alone,
respectively (p>0.01). Combination therapy could
be beneficial for a subset of patients who do not
respond to alprostadil alone. In another study com-
paring intraurethral alprostadil vs. combination
therapy, intercourse was reported by 70% of men
(276/394) [35]. Of the 276 responders, 89 succee-
ded only with the combination and did not have
erection with alprostadil alone. These results indi-
cate that transurethral alprostadil/prazosin combi-
nation could be an alternative therapy.
b) Adverse effects
Penile pain occurred in 7.6 to 19.8% of adminis-
trations. Hypotension occurred in 1.5 to 9.2% of
applications, most frequently with high doses of
the combinations [35,38].
4. DINOPROSTONE (PROSTAGLANDIN E2)
Prostaglandin E2 is an oxytocic agent with vasodi-
latory effects similar to those of alprostadil. Wolf-
son and associates reported its use intraurethrally
[40]. They formulated a dinoprostone cream
(using dinoprostone suppository, 10 ml lidocaine
2% gel and 40 ml surgical lubricant gel) with a
final concentration of 400µg/ml. Two ml were ins-
tilled into the urethra with a syringe. A full penile
tumescence was achieved in 30% of the men and
40% showed partial tumescence. Rozas and asso-
ciates reported an erection sufficient for intercour-
se in 19 of the 25 patients (patients with ED follo-
wing prostatectomy) that they studied using a
somewhat similar solution [41]. This medication
has not been widely tested and a placebo-control-
led study must be performed before we can draw
any conclusions on its use as intraurethral therapy.
339
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_________________________
VI. TOPICAL THERAPY FOR
ERECTILE DYSFUNCTION
Intracavernosal injections (ICI) and intraurethral
suppositories (IUS) of vasoactive substances have
improved the treatment of erectile dysfunction
(ED) and enjoy widespread acceptance by patients
and urologists. However, despite their initial
acceptance, at least 50% of men using such thera-
pies eventually discontinue treatment for reasons
relating to pain, loss of effectiveness, and lack of
interest [1]. This de facto dissatisfaction with pro-
ven effective treatments is the rationale for alter-
native routes for the delivery of vasoactive sub-
stances.
Topical therapy for ED has been proposed as one
means to circumvent some of the negative factors
associated with ICI and IUS thereby presenting an
intrinsic appeal to many patients. Topical therapies
for the treatment of erectile dysfunction remain
and are currently confined to clinical trials and
have yet to be released for widespread use. They
have the potential to avoid the systemic effects
noted with oral therapies while being perceived as
minimally invasive inasmuch as they do not requi-
re needles or intraurethral instrumentation. Topical
therapy may also provide benefit to patients unres-
ponsive to systemic therapy or who use medica-
tions which cannot be taken along with such oral
treatments (nitrates). Questions regarding less
invasive therapies for the treatment of ED using
oral, topical or intraurethral methods are often rai-
341
sed by patients at the time of treatment discussion.
This being the case, it is important that the practi-
tioner be aware of the issues pertaining to alterna-
te therapy use such as topical treatments.
1. GENERAL PRINCIPLES OF TOPICAL AGENTS
There have been several advances in the unders-
tanding of the pharmacokinetics of topical thera-
py. The transdermal route has a well established
technology to provide durable and constant plas-
ma levels of drugs such as hormone replacements,
narcotics and vasodilators. When it comes to local
penile therapy using direct smooth muscle
relaxants, the durability and onset of action of
such methods may not be useful attributes. In this
regard there are several issues worth mentioning:
1) High systemic levels are undesirable as they
may result in an unacceptable level of adverse
events.
2) Agents may be largely metabolized in the first
pass through the lungs or liver.
3) Vasoactive agents need to reach the corpora
cavernosa rapidly with an effective (highest)
concentration.
Topical penile therapy has an unique set of ana-
tomic and physiologic issues that must be consi-
dered. There are several anatomic/fascial layers
between the penile skin and the corpus caverno-
sum. The tunica albuginea is presumed to be dif-
ficult to penetrate due to its thick layers of colla-
gen. Therefore, topical treatment trials have
emphasized exposure to the glans penis as it has
direct venous communication to the corpora
cavernosa [2,3]. The skin itself is a relatively
impermeable tissue due to the stratum corneum.
The horny cells of the stratum corneum are bonded
with a very tight intercellular lipid matrix bilayer
that makes the passage of drugs challenging [4].
To overcome this barrier, investigators have used
penetration enhancers which permeate this layer
and reach the subdermis. Fortunately, the penis
and scrotum are unique in that their stratum cor-
neum is the most permeable of all anatomic loca-
tions tested. Depending on the molecular structure
of the agent tested there can be nearly 100%
absorption of topical agents applied to these areas.
Again, exposure to the glans affords a more easily
"breached" layer. Other skin regions (e.g. back and
palms) are particularly impermeable [5]. An addi-
tional factor confounding efficient drug delivery is
the rich vasculature of the deep dermis which may
"steal" the drugs to the systemic circulation.
With the above assortment of confounding factors
one wonders exactly how gel applied to the penis
could ever induce an erection. One attractive pos-
sibility is gel applied to the glans that is rapidly
absorbed through the porous skin of the glans into
the venous vasculature of the corpora spongiosum.
From that location it could travel into the corpora
cavernosa akin to intraurethral drug delivery [6,7].
The known absorptive nature of the penile skin
and glans makes this a real possibility [5]. If this is
the case, then drug delivery to the shaft of the
penis would seem superfluous and possibly only
contribute to penile skin discomfort. Alternatively,
the drug applied to the skin of the penis could
theoretically be absorbed through the skin, the
tunica of the corpora cavernosa and thus into the
cavernous tissues. The large distance, multiple tis-
sue layers and unknown permeability of the tunica
make this a formidable drug delivery challenge. A
third more remote possibility involves the syste-
mic absorption, recirculation and delivery of drug
to the penile tissues. Systemic levels have been
measured following penile skin application of
papaverine and minoxidil proving that absorption
does occur. However, its presence in the systemic
circulation does not prove is role in the erectile
response [8,9]. All of the above mentioned possi-
bilities are expected to be inefficient to transfer
active agents, thus requiring a large amount of
drug to compensate for losses in the pathway.
Anticipating that topical agents could be transfer-
red through the skin and tunica to the cavernous
tissues, Borges [10] tried to overcome the presu-
med permeation problem by performing a surgical
procedure consisting of excision of a small area of
tunica and covering the defect with a patch of deep
dorsal vein, in order to apply a local medication
onto the skin immediately above the defect. This
concept did not progress perhaps related to failure
of the patch, problem of absorption inherent to the
skin or failure in the formulation of the topical
agent.
Most of the delivery systems currently in use for
topical therapy are intended for slow and steady
release of medications such as those used in hor-
monal, analgesic or narcotic patches. This slower
342
process is not effective as an erection initiator as
drug absorption is likely to be low. Investigators
are currently trying permeation enhancers to
increase the drug absorption rate. In order to
achieve rapid and effective penetration, the formu-
lation needs to have sufficient penetration enhan-
cer to help transfer (flux) the active agent with
good tolerance (no significant irritation), and
release the drug at the site of action (right bonda-
ge).
Several transdermal enhancers incorporated as one
of the excipients in topical formulations have been
reported [2,3,11,12]. The role of these enhancers
is to:
1) Disrupt the stratum corneum lipid bilayer,
2) Interact with membrane keratin,
3) Produce a weak interaction with the drug mole-
cule, and
4) Rapidly reverse all actions. The effectiveness
of one of these agents (SEPA®) to enhance the
transport of a variety of agents through human or
porcine skin in vitro has been well established
[12, 13]. The available evidence indicates that this
agent enhances skin penetration by altering the
fluidity of lipids in the stratum corneum, without
any interaction with the chemical whose skin per-
meability is enhanced. A study by Morganti et al
[14] examined the effect of SEPA on stratum cor-
neum by performing FT-IR spectroscopy, differen-
tial scanning calorimetry and scanning electron
microscopy on samples of isolated human stratum
corneum. Changes seen suggested reversible
conformational modification in stratum corneum
lipids by SEPA, consistent with general lipid flui-
dization. When SEPA is removed in vacuo, the
effect is reversed, suggesting that SEPA's effects
are temporary, with lipid organization and barrier
function being readily and spontaneously restored.
During the phase of lipid fluidization, drugs can
diffuse through the stratum corneum at a much
higher rate than normal.
2. TOPICAL THERAPY FOR ERECTILE DYS-
FUNCTION - B ACKGROUND
Organic nitrate donors were the first topical agents
to be used in the treatment of erectile dysfunction
[15]. Case reports have demonstrated that blood
flow to the penis and tumescence are increased
after application of a nitro-based paste [16, 17].
The local effects on penile blood flow appear to be
crucial since application of such gels elsewhere on
the body does not induce erections. Topical minoxi-
dil has also been reported in placebo- controlled
double-masked trials [9, 18]. In one study, Cavalli-
ni reported 2% minoxidil to be superior to 10%
nitroglycerin cream in inducing improved penile
hemodynamics with fewer side effects.
3. TOPICAL PGE-1
a) Introduction
Alprostadil is a naturally occurring prostaglandin
E1. Alprostadil and other prostaglandins in the E
series are naturally present in the seminal vesicles,
the cavernous tissues of males and in the placenta
and ductus arteriosus of the fetus. Various formula-
tions and techniques (injections, urethral supposito-
ries and gels) using PGE-1 have been used in the
treatment of erectile dysfunction over the past 15
years.
b) Mechanism of action
For the treatment of impotence, alprostadil relaxes
smooth muscle of the corpus cavernosa. However,
the exact mechanism of action is unknown. Its
effects are due to increased intracellular concen-
trations of cAMP. Alprostadil interacts with spe-
cific membrane bound receptors that stimulate
adenylate cyclase and elevate intracellular cAMP
leading to activation of protein kinase and resul-
tant smooth muscle relaxation. Alprostadil may
also antagonize the vasoconstrictive actions of
norepinephrine by preventing the neuronal release
of norepinephrine and may enhance the actions of
non-adrenergic, non-cholinergic vasodilatory
transmitters. In treating impotence alprostadil
induces erection by relaxing trabecular smooth
muscle and dilating cavernosal arteries and their
branches. Dilation of the cavernosal arteries is
accompanied by increased arterial inflow velocity
and increased venous flow resistance. As a result,
the lacunar spaces expand and blood becomes
entrapped secondary to compression of venules
against the tunica albuginea. To achieve adequate
tumescence and rigidity the tunica albuginea must
be sufficiently stiff to compress the penetrating
venules and thus block venous outflow. This pro-
cess is also referred to as the corporal veno-occlu-
sive mechanism. Alprostadil does not directly
effect ejaculation or orgasm.
343
c) Pharmacokinetics
Alprostadil has been administered by intravenous
infusion, intracavernous injection, urethral suppo-
sitory and topical administration. Intravenous
administration of alprostadil requires a continuous
infusion of the drug because approximately 80%
of the dose is metabolized in the first pass through
the lungs mostly by beta and omega-oxidation.
Minimal systemic absorption occurs after caver-
nosal or intraurethral administration. Any alpros-
tadil absorbed by these routes is rapidly metaboli-
zed. Tolerance to the beneficial vascular effects
does not appear to occur when using alprostadil in
either injection or intraurethral forms. Whether
this is true of topical preparations has not been
reported. Once in the systemic circulation, alpros-
tadil is primarily bound to albumin (81%). No
significant binding to erythrocytes or white blood
cells occurs. Alprostadil is completely metaboli-
zed to several metabolites which are primarily
excreted in the urine. There is no evidence of tis-
sue retention of alprostadil or its metabolites fol-
lowing administration.
d) Response rates
Kim and McVary in a placebo-controlled phase
I/II trial of a topical PGE1 gel reported significant
increases in systolic blood flow velocity as mea-
sured by color Doppler ultrasonography [11, 19].
In this largely neurogenic impotent population
only 2 of 10 patients responded with a clinical
erection (no response in the placebo group).
Becher reported a double masked placebo study
investigating the effect of 0.2% and 0.4% alpros-
tadil combined with a skin penetration enhancing
gel in 52 impotent men [20]. There was no sta-
tistically significant difference between active
drug and placebo (66% vs. 39%, respectively) in
this patient population. In a noncontrolled study
using a formulation of 0.4% alprostadil and an
enhancer, 0.5 g of the gel produced comparable
cavernosal arterial changes to intracavernosal
injection when measured with color Doppler. This
suggested that the drug penetrates the skin and
reaches the corpus cavernosum in a concentration
sufficient to cause smooth muscle relaxation [2].
McVary reported a phase I/II single-blind study
with a formulation of alprostadil (0.5 mg, 1 mg
and 2.5 mg) using 5% SEPA as skin penetration
enhancer [3]. Application of the PGE1 gel correla-
ted positively with erectile response in a majority
of patients on active drug. A significant response
(clinical erection) to the 0.5 mg, 1.0 mg and 2.5
mg PGE1 doses was found in 67%, 75% and 67%,
respectively (placebo 17%, p<0.001). This repre-
sented an advance over previous topical adminis-
tration studies as significant erectile responses
could be obtained with gel applications. Interestin-
gly, the majority of patients had modest or absent
responses to gel application in the initial 25
minutes after application. With the addition of
visual or tactile stimulation this response was
greatly augmented suggesting the role of topical
gels in facilitation rather than initiation of erec-
tion. Facilitation was not seen in the placebo
group. The augmentation of response with tactile
stimulation has been found with several oral,
intraurethral and intracorporal injection treatments
[7, 22, 23].
4. CONTRAINDICATIONS
Anticoagulant therapy, bleeding disorders, polycy-
themia, sickle cell disease, thrombocytosis, and
multiple myeloma are conditions in which the treat-
ment of impotence with alprostadil is contraindica-
ted. Alprostadil is also contraindicated in patients
who are prone to venous thrombosis or who have
hyperviscosity syndrome and are therefore at
increased risk of priapism. This includes patients
with sickle cell disease, thrombocytosis, polycythe-
mia or multiple myeloma. In clinical trials of
alprostadil urethral suppository, priapism (defined
by rigid erection lasting greater than 6 hours) and
prolonged erection (rigid erection lasting 4 but less
than 6 hours) were reported in 0.1% and 0.3% of
patients, respectively. Patients receiving intracaver-
nosal alprostadil also reported prolonged erections
(4%) and priapism (0.4%). Whether topical alpros-
tadil induces a similar rate of priapism has not been
reported. Alprostadil in any form should be used
cautiously in patients with cardiovascular disease.
Symptomatic hypotension and syncope occurred in
3 and 0.4% respectively of patients during in clinic
dosing of alprostadil urethral suppository. Topical
alprostadil has not been shown to have a similar risk
[3,11].
5. DRUG INTERACTIONS
No drug interactions have been reported for any of
the formulations of alprostadil. Prostin VR pedia-
tric has been used with the standard therapy for
344
neonates with restricted pulmonary or systemic
blood flow which includes antibiotics (penicillin
and gentamicin) vasopressors (i.e. dopamine, iso-
proterenol) cardiac glycosides and diuretics. Sys-
temic drug interactions with IUA(alprostadil) ure-
thral suppository are unlikely because low or
undetectable amounts of the drug are found in the
peripheral venous circulation following IUA
administration. One would expect topical alprosta-
dil to behave similarly. The potential for pharma-
cokinetic drug interactions between alprostadil
administered via injection, topically or urethral
suppositories and other agents has not been for-
mally studied.
6. ADVERSE REACTIONS
Adverse reactions of alprostadil are reported more
frequently following intravenous administration,
and may therefore not be relevant to a discussion
of topical agents. Apnea has been reported in
about 12% of neonates with congenital heart
defects treated with alprostadil and was mostly
seen in neonates weighing less than 2 kilograms at
birth. Other respiratory adverse reactions occur-
ring in less than 1% of patients include bradypnea,
bronchial wheezing, hypercapnia, respiratory
depression, respiratory distress, and tachypnea.
Other common adverse reactions include fever
(14%) and seizures (4%).
Local adverse reactions associated with alprostadil
used to treat impotence are usually mild and tran-
sient. However, as many as 7% of patients with-
draw from therapy during trials because of adver-
se reactions. With alprostadil given intraurethral-
ly, vaginal irritation (vaginal burning/itching) was
reported by 5.8% of female partners of patients on
active treatment vs 0.8% of patients on placebo. It
is unknown whether these adverse reactions in
female partners were the result of medication or
sexual intercourse. Importantly, Becher performed
a female safety study in 18 healthy volunteers
using 1g of a gel consisting of 0.4% alprostadil
(4,000 mcg) and applied on the vaginal wall and
introitus. Ten postmenopausal and 8 premenopau-
sal women showed good tolerance to this formu-
lation despite one patient who experienced minor
bleeding at the cervix. All patients showed labial
and clitoral engorgement that was not described as
uncomfortable [20].
Discomfort at the application site was reported in
85% of participants after topical application of an
alprostadil/SEPA® gel [3]. Most patients (85%)
who received the SEPA® formulation, whether or
not it contained PGE1, experienced a sensation of
warmth that abated within 5-20 minutes after
application. This time frame suggests that the
SEPA formulation was the mediating substance.
About 20% of patients classified this warmth as
severe burning. As this severe discomfort was not
noted in the placebo group, it appears that the acti-
ve drug was the responsible agent. This discomfort
was primarily localized to the shaft of the penis
rather than the glans penis. One wonders whether
application of the gel to the glans but not to the
penile shaft could avoid this discomfort. It was
probably related to both the carrier formulation
and the active drug as it was noticed in the place-
bo group and increased in intensity with the addi-
tion of PGE 1.
Considering the ubiquitous anatomic distribution
of the large family of eicosanoids to which PGE1
belongs, it is no surprise that an alprostadil gel
would influence other processes besides erection
when applied to the penis. Eicosanoids exist in
nearly all somatic tissues and are known mediators
of a large number of physiologic processes. Pain
is one known side effect of this class of com-
pounds. Receptors for PGE1 have been isolated in
a diverse array of tissues including the nervous
system [24]. The role of prostaglandins in the sen-
sory afferents of pain perception is well documen-
ted although intermediates such as CGRP may be
involved [25]. Interestingly, in the study by McVa-
ry et al. [3] there was no correlation between skin
reaction, discomfort, side effects nor erythema
with erectile response. This is important as the dis-
sociation of the side effects from the positive attri-
butes of erectile response allows the application
site or drug to be modified to reduce adverse
events without compriomsing erection.
7. TOPICAL MINOXIDIL
a) Introduction
Topical minoxidil has been used in the recent past
as an investigational drug in the treatment of erec-
tile dysfunction. Although little can be said about
its role in that regard, there is an extensive litera-
ture on its use as an antihypertensive and alopecia
medication. Much of the information regarding
this drug is drawn from the literature detailing its
345
use in the former rather than latter circumstance.
Minoxidil is an antihypertensive agent while topi-
cal minoxidil is used for alopecia. Due to its
potency and adverse reactions, oral minoxidil is
used mainly for patients with severe drug-resistant
forms of hypertension. Tolerance to prolonged
therapy with oral minoxidil does not appear to be
a problem. Subsequent to the oral dosage (appro-
ved by the FDA in 1979 for use in hypertension)
topical formulations were approved for the treat-
ment of alopecia in 1988. Investigation of topical
formulations in the treatment of erectile dysfunc-
tion are limited and follow on the heels of its
approval for alopecia.
b) Mechanism of action
Minoxidil does not have a direct vasodilatory
minoxidil-O-sulfate effect on arterial smooth
muscle. Instead it is converted to minoxidil-O-sul-
fate by the hepatic enzyme sulfotransferase [26].
This metabolite does have a direct vasodilatory
effect on arterial smooth muscle causing a reduc-
tion in peripheral resistance in blood pressure. It
does not inhibit CNS or adrenergic neuronal bloc-
king effects. Minoxidil retains its activity despite
adrenergic denervation. Minoxidil-induced delay
in the hydrolysis of cAMP via inhibition of phos-
phodiesterase may also contribute to the drug’s
vasodilatory action. All direct vasodilators produ-
ce a sympathetic response including an increase in
heart rate, stroke volume, cardiac output, and a
marked increase plasma renin activity. The latter
effect leads to increased sodium and water reten-
tion. The mechanism responsible for minoxidil
induced hair growth is not known. Although syste-
mic therapy will stimulate hair growth, topical the-
rapy does not cause hypotension. Minoxidil may
either activate the hair follicle directly or stimula-
te the microcirculation around the follicle increa-
sing cutaneous blood flow. Minoxidil may also
alter the metabolism of androgens in the scalp.
With regard to the treatment of erectile dysfunc-
tion, it is assumed that the active metabolite acts
via a direct vasodilatory effect on arterial smooth
muscle causing a reduction in peripheral resistan-
ce and cavernosal muscle relaxation. Presumably
this promotes the veno-occlusive mechanism and
results in erection. Such an effect from topical
minoxidil is interesting when one considers that it
is a prodrug that requires hepatic metabolism to
become active [26]. For this to be effective the
topically absorbed minoxidil would have to be
metabolized through the liver then recirculated to
the penis to be active. This appears to be a sub-
stantial task. Issues regarding the site and efficacy
of absorption have been addressed above.
c) Pharmacokinetics
Minoxidil can be administered topically or orally.
Approximately 90% of an oral dose is absorbed
from the GI tract, while topical minoxidil is poor-
ly absorbed through the skin. The systemic
absorption of topical minoxidil averages 2%
(range 0.3-4.5%). The drug distributes widely
throughout the body tissues and is extensively
metabolized by the liver. Both the unchanged
drug and its metabolites (primarily the glucuroni-
de conjugate of minoxidil) are excreted in the
urine. Antihypertensive effects are achieved
within 30 minutes and although the plasma half-
life of the drug is 4 hours, antihypertensive effects
can last 2-5 days. Despite the prolonged duration
of action, no drug can be detected in the plasma
after 24 hours. This prolonged effect may be
explained by retention of the drug in vascular
smooth muscle tissues. Minoxidil is not signifi-
cantly bound to plasma proteins. It is freely filte-
red, has no tubular secretion, thus renal clearance
depends on glomerular filtration. This filtration
accounts for approximately 10% of total clearan-
ce. Approximately 95% of a topical dose is elimi-
nated after 4 days.
In topical administration of minoxidil, solutions
should only be applied to the skin of interest.
Absorption is best when the hair and the skin are
dry. If applied with finger tips the hands should be
thoroughly washed after applying. Systemic
effects resulting from topically administered
Minoxidil are unlikely, but theoretically could
occur if the drug is overused. Skin abrasion or
irritation such as excoriations, psoriasis, or sun
burn can increase the systemic absorption of topi-
cal minoxidil.
Minoxidil is relatively contraindicated in patients
with cardiac disease, recent myocardial infarction
or cerebrovascular disease because reflex
increases in heart rate and decreases in blood pres-
sure can exacerbate these conditions. Since
approximately 10% of the active drug is elimina-
ted unchanged via the kidney, minoxidil can be
346
used safely in patients with renal impairment.
Minoxidil should not be used in patients with
pheochromocytoma because the hypotensive
effects of the drug can stimulate catecholamine
secretion.
d) Response rates
There are a limited number of reports of response
rates for the treatment of erectile dysfunction.
Using Rigi-scans to measure penile circumference
changes induced by a topical 2% minoxidil solu-
tion, Cavellini reported a significant increase
when compared to topical 10% nitroglycerin or
placebo ointment [18]. Similarly, he reported a
significant increase in penile rigidity with topical
minoxidil when compared to the nitroglycerin or
placebo controls. Doppler ultrasonography of
cavernosal arterial flow was reported greater with
minoxidil than to be with control, but no quantita-
tive information was supplied. No mention of
sexual intercourse was reported. In a slightly dif-
ferent study design, Clark reported on the treat-
ment of erectile dysfunction in diabetic males
using a 2% minoxidil solution combined with a
penetration enhancer (SEPA®) [9]. Response was
recorded by spring tonometer (rigidity), strain
gauge (circumference change) and patient diary
(vaginal penetration). He reported moderate, but
no significant changes in erectile response to
visual stimulation, penile tumescence or penetra-
tion.
e) Drug interactions
Reported drug interactions almost exclusively
concern minoxidil used in its oral form. Little is
known about its topical use for the treatment of
erectile dysfunction. Regardless, drug interactions
of minoxidil include antihypertensive agents,
nitrates, diazoxide, diuretics, estrogen, nitroprussi-
de, non-steroidal anti-inflammatories and sympa-
thomimetics. Estrogens can cause fluid retention
increasing blood pressure and thereby antagoni-
zing the antihypertensive effects of minoxidil.
Non-steroidal anti-inflammatories can reduce the
antihypertensive effects of minoxidil by inhibiting
prostaglandin synthase and/or increasing sodium
and fluid retention. Sympathomimetics such as
cocaine, dolbutamide, dopamine, ephedrine, epi-
nephrine, norepinephrine, phenylephrine or phe-
nylpropanolamine can antagonize the antihyper-
tensive effects of minoxidil when administered
concomitantly.
f) Adverse reactions
The adverse reaction profile of minoxidil depends
on its use. Systemic adverse reactions are unlikely
from topical administration. Placebo controlled
trials with topical minoxidil only showed an
increase in dermatologic effects from the active
drug. Oral minoxidil has occasionally been asso-
ciated with the appearance of a bullous rash and
Stevens-Johnson syndrome. Topical minoxidil
therapy produces local dermatologic reactions
including contact dermatitis, local burning pruri-
tus, erythema, and xerosis. Many adverse effects
have been reported during the administration of
topical minoxidil preparations but none has been
directly attributed to the drug.
8. TOPICAL PAPAVERINE
a) Introduction
Since the introduction by Virag in the early 1980s
of injection of papaverine into the corpora caver-
nosa for the treatment of sexual dysfunction has
become a widespread and well accepted method
[27]. Its use as a topical therapy has a much shor-
ter experience which has not progressed beyond
preliminary clinical trials.
b) Mechanism of action
The most characteristic effect of papaverine is
relaxation of smooth muscle, especially when it
has been spasmodically contracted. Papaverine
acts directly on the muscle itself by inhibition of
the oxidative phosphorylation mediated inactiva-
tion of cAMP (via phosphodiesterase-PDE) and
interferes with calcium mobilization during muscle
contraction. This results in an increased half-life of
the secondary messengers cGMP and cAMP. This
relaxation is noted in the vascular system, bron-
chial musculature, gastrointestinal/biliary tracts
and urinary tract (including the corpora cavernosa).
This relaxation may be prominent in the presence
of spasm. The relaxation is direct and unrelated to
muscle innervation, as the muscle still responds to
drugs and other stimuli causing contraction. Papa-
verine has a minimal action on the central nervous
system, although very large doses tend to produce
some sedation and sleepiness in selected patients.
In certain circumstances, mild respiratory stimula-
tion can be observed, but this is clinically inconse-
quential.
347
c) Pharmacokinetics
Serum papaverine levels after topical administra-
tion have been measured in a single study [8] with
a high performance liquid chromatography assay.
At 60 minutes mean serum levels increased 50%
suggesting that absorption did occur, but not signi-
ficantly over baseline values. The papaverine
levels in this study indicated that topical absorp-
tion is less than 1% of a comparable intravenous
dose indicating minimal systemic uptake after
topical administration to the genitalia. In contrast,
papaverine is present in the blood at levels of 335
to 761 ng/ml within 3 minutes of IC injection of 40
mg as measured by similar techniques [28]. The
pharmacokinetics and bioavailability of topical
papaverine have been studied in animal models. 9-
12.4% of papaverine is detected in the serum. The
marked differences between animal models and
clinical trials have been attributed to the gel for-
mulation [29].
d) Response rates
The use of topical papaverine was reported by
Kim et al [8] in a phase I/II single-blind placebo-
controlled trial on 20 patients with organic impo-
tence. The formulation included 5.5% papaverine
HCl gel, and 7%, 15% and 20% papaverine base
gel along with a proprietary skin permeation
enhancer. After application of the gel onto the
penis, scrotum and perineum, a dose-dependent
hemodynamic effect was found during duplex
ultrasonography. Only 3 patients achieved full
erections (also when exposed to placebo). The
tolerability was good both locally and systemical-
ly. Similar findings were reported using up to 20%
papaverine base gel [30].
e) Contraindications
Intravenous injection of papaverine is contraindi-
cated in the presence of complete atrio ventricu-
lar heart block. When contraction is depressed,
the drug may induce transient ectopic rhythms of
ventricular origin either premature beats or
paroxysmal tachycardia. Papaverine does not
have FDA approval for the treatment of impoten-
ce by intracorporal injection or topical applica-
tion. Intracorporal injection of papaverine is
known to result in persistent priapism requiring
either surgical or medical intervention. Whether
or not topically applied drugs would have any
impact on these types of complications is a mat-
ter of conjecture at this point. Based on the bio-
availability studies mentioned above it is unlike-
ly that a sufficient amount of topical drugs would
be absorbed.
f) Adverse reactions
Opiate derived compounds such as papaverine may
cause cholestatic hepatic dysfunction. This finding
has been observed in geriatric patients taking papa-
verine for vascular insufficiency as well as with
intracavernous injection [31, 32, 33]. Topical thera-
py has not been shown to have a similar risk in one
study [8]. The following side effects have been
reported for papaverine when given by injection:
general discomfort, nausea, abdominal discomfort,
anorexia, skin rash, malaise, vertigo, headache,
intensive flushing of the face, perspiration, increa-
sed depth of respiration, increased heart rate, slight
increase in blood pressure, and excessive sedation.
Few of these effects have been reported when papa-
verine was administered topically.
9. TOPICAL NITROGLYCERIN
a) Introduction
The use of topical nitroglycerin is a standard treat-
ment for unstable angina pectoris because predic-
table blood levels can be achieved. The use of
nitroglycerin ointments, pastes, plasters or patches
for the treatment of erectile dysfunction has been
tried in several studies.
b) Mechanism of action
Relaxation of vascular smooth muscle is the prin-
ciple pharmacologic action of nitroglycerin. Nitro-
glycerin produces, in a dose-dependent manner,
dilatation of both arterial and venous beds, dilata-
tion of the post-capillary vessels including large
veins and decreases in venous return. This results
in a reduction of left ventricular diastolic pressure.
Arteriolar relaxation reduces systemic vascular
resistance and blood pressure. Myocardial oxygen
consumption and demand is decreased by both the
arterial and venous effects of nitroglycerin resul-
ting in a more favorable supply-demand ratio.
Whether topical nitroglycerin for the treatment of
erectile function can have similar effects on car-
diac status is not known. Contraindications to the
use of topical nitroglycerin include a history of
allergic reactions to organic nitrates. These are
extremely rare, but they do occur. Allergies to the
adhesives used within the nitroglycerin patches
have also been reported.
348
c) Pharmacokinetics
Nitroglycerin transdermal delivery systems are
designed to provide continuous controlled release
of nitroglycerin through intact skin. The rate of
release is linearly dependent upon the area of the
system applied. In FDA-approved patch systems,
each square centimeter of applied system delivers
approximately 0.02 milligrams of nitroglycerin
per hour. In general, after approximately 12 hours,
each system has delivered about six percent of its
original nitroglycerin content. Nitroglycerin is
cleared from the body at extremely rapid rates
with the resulting serum half-life of approximate-
ly three minutes. The observed clearance rate
greatly exceeds hepatic blood flow suggesting
extensive peripheral metabolism. Known sites of
extrahepatic metabolism include red blood cells
and vascular walls. The first products in the meta-
bolism of nitroglycerin are inorganic nitrate and
dinitroglycerols. Dinitrates are less effective vaso-
dilators than nitroglycerin, but they are longer
lived in the serum. Dinitrates are further metaboli-
zed to nonvasoactive mononitrates and ultimately
to glycerol and carbon dioxide. In healthy volun-
teers, steady-state plasma concentrations of nitro-
glycerin are reached by about two hours after
application of a patch and are maintained for the
duration of wearing of the system. Whether any of
these pharmacokinetic issues are relevant to topi-
cal nitroglycerin applied to the penis is not known.
d) Response rates
Owen et al. [16] reported a double-blind placebo-
controlled study using a 2% nitroglycerin paste
applied to the penile shaft in 30 impotent patients.
The evaluation included penile tumescence measu-
rement and duplex ultrasonography. Although the
patients who received nitroglycerin achieved a bet-
ter response, it was not significantly different from
placebo. Headache was a common side effect that
developed tolerance over the applications. Heaton
et al. [34] reported a study in 174 patients who
underwent duplex ultrasonography for an erectile
dysfunction workup and received a topical applica-
tion of nitroglycerin paste at the penile shaft. There
was a significant difference in the four vessels dia-
meter before and after drug application.
Clinical evaluations in a home use environment are
limited. Nunez et al. [17] reported 3 successful
cases using 2% nitroglycerin paste. Sonksen [35]
reported "clinical response" in 12 of 17 spinal cord
injured patients. However, only 5 achieved a
"usable response" at home. Meyhoff studied 10
patients with nitroglycerin patches, 4 patients achie-
ved a "usable" response and 3 preferred the patches
over their usual I.C. papaverine treatment [36].
e) Adverse reactions
The most frequent adverse reaction in patients
who are administered nitroglycerin is headache,
which occurs in approximately two percent of
patients. Other reactions occurring in less than one
percent of patients are tachycardia, nausea, vomi-
ting, apprehension, restlessness, muscle twitching,
retrosternal discomfort, palpitations, dizziness and
abdominal pain. In a smaller number of patients,
additional adverse reactions such as cutaneous flu-
shing, weakness, drug rash or exfoliative dermati-
tis have been reported.
f) Conclusion
Advances in the understanding of penile physiolo-
gy, basic erectile pharmacology and alternate drug
delivery systems constitute an evolving technology
that is potentially useful for the treatment of erecti-
le dysfunction. With the association of modern skin
penetration enhancers it is now possible to achieve
acute transfer of drugs to the corpus spongiosum in
order to take advantage of its vascular communica-
tions with the corpus cavernosum. The main
advantages of topical therapy for erectile dysfunc-
tion are its safety and good tolerability in terms of
local and systemic effects. Even in the era of oral
treatments, an effective, safe and easy to apply
topical agent will have its place in the physician's
armamentarium to treat patients with erectile dys-
function in the near future.
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1. LAKIN, M.M., MONTAGUE, D.K. MEDENDORP,
S.V., TESAR, L. AND SCHOVER, L. R.: Intracaver-
nous injection therapy: analysis of results and complica-
tions. J. Urol., 143: 1138, 1980
2. BECHER E, BORGHI M, MOMESSO A, et al: Penile
hemodynamic findings with a new topical formulation
of alprostadil. J Urol, 159 No5 Suppl: 239; 1998.
3. MCVARY KT, POLEPALLE S, RIGGI S, PELHAM
RW: Topical PGE-1/SEPA Gel for the Treatment of
Erectile Dysfunction, In press J Urol
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4. GURNY R, TEUBNER A: Dermal and transdermal
drug delivery: new insights and perspectives. Stuttgart:
Wiss. Verl.-Ges., 1993.
5. MAIBACH, H.I., FELDMAN, R.J., MILBY, T.H. AND
SERAT,W.F.: Regional variation in percutaneous pene-
tration in man. Arch. Environ. Health, 23: 208, 1971.
6. WOLFSON, B., PICKETT, S., SCOTT, N.E., DEKER-
NION, J.B. AND RAJFER, J.: Intraurethral prostaglan-
din E-2 cream: a possible alternative treatment for erec-
tile dysfunction. Urology, 42: 73, 1993
7. PADMA-NATHAN, H., HELLSTROM, W., KAISER
F., LABASKY, R., LUE, T., NOLTEN, W., NOR-
WOOD, P., PETERSON, C., SHABSIGH, R., TAM, P.,
PLACE, V., GESUNDHEIT, N.. Treatment of Men with
Erectile Dysfunction with Transurethral Alprostadil. N
Eng J Med 1997;336-1-7.
8. KIM ED, EL-RASHIDYR, MC VARY KT: Papaverine
topical gel for treatment of erectile dysfunction. J Urol,
153:361-365; 1995.
9. CLARK, R.V., MURRAY, F.T., HIRSHKOWITZ, M.,
FERRY, J., LIN, T., MURPHY, T.C. AND FRANCOM,
S.F.: Treatment of erectile dysfunction in men with dia-
betes mellitus using a penetration-enhanced topical
minoxidil solution. J. Androl, January/February supple-
ment: abstract 140, p. 55, 1994
10. BORGES, FD: A new approach to the pharmacologic
treatment of impotence. Int J Impot Res, Vol.6 (3):137-
143; 1994.
11. KIM ED, MCVARY KT: Topical Prostaglandin-E1 for
the Treatment of Erectile Dysfunction, J Urol
153(6):1828-1830, June 1995.
12. SAMOUR, C.M., DONARUMA, L.G., DASKALA-
KIS, S., FULTON, B.S., MARTY, J.P., DERVAULT,
A.M., CHANEZ, J.F. AND DOUCET, O. SEPAS, A
New Class of Percutaneous Absorption Enhancers.
Proc. Intern. Symp. Control. Rel. Bioact Mater 16: 183-
184, 1989.
13. PELHAM, R. AND SAMOUR, C. SEPA-009-Safety
and Efficacy Studies of a Broad Spectrum Transdermal
Enhancer. Proceed. Intern. Symp. Control. Rel. Bioact
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14. MORGANTI, F., BRAMANTI, E., SOLARO, R.,
NANNIPIENI, E., NARDUCCI, P., KRAUSER, S. F.,
SAMOUR, C. M., BENEDETTI, E. AND CHIELLINI,
E. Thermal and Spectroscopic Characterization of Inter-
actions Between 2-Nonyl-1,3-dioxolane and Stratum
Corneum Components. J. Control Rel., (in press).
15. MUDD. J.W.: Impotence responsive to glyceryl trini-
trate. Amer. J. Psych., 134: 922, 1977.
16. OWEN, J.A., SAUNDERS, F., HARRIS, C., FENE-
MORE, J., REID, K., SURRIDGE, D., CONDRA, M.
AND MORALES, A.: Topical nitroglycerin: a poten-
tial treatment for impotence. J. Urol., 141: 546, 1989.
17. NUNEZ BD, ANDERSON DC Jr: Nitroglycerin oint-
ment in the treatment of impotence. J Urol, 150:1241-
1243; 1993.
18. CAVALLINI, G.: Minoxidil versus nitroglycerin: a
prospective double-blind controlled trial in transcuta-
neous erection facilitation for organic impotence. J.
Urol., 146: 50, 1991.
19. MCVARY KT, KIM ED:Topical PGE1 Gel as treatment
for Erectile Dysfunction. J Urol 153 Suppl: 982A; 1995.
20. BECHER E, MOMESSO A, BORGHI M, et al: Topical
prostaglandin E1 (PGE1) for erectile dysfunction. (abs-
tract) J Urol 155 Suppl: 296A; 1996.
21. BECHER E, COHEN-SABBAN H, MOMESSO A, et
al: Estudio de seguridad en mujeres con un gel de pros-
taglandina E1 para la disfuncion erectil. Proceedings of
the IV Latin American Congress for Impotence Resear-
ch. Linares, Chile. Abstract L25, p.41; 1997.
22. DONATUCCI CF, LUE TF. The combined intracaver-
nous injection and stimulation test: diagnostic accuracy.
J Urol 148(1):61-2, 1992 Jul.
23. GOLDSTEIN I, LUETF, PADMA-NATHAN, H,
ROSEN RC, STEERS WD, WICKER PA. Oral Silde-
nafil in the treatment of Erectile Dysfunction. N Eng J
Med 1998: 338: 1397-1404.
24. MOLTZ, H.: E-series prostaglandins and arginine vaso-
pressin in the modulation of male sexual behavior. Neu-
rosci. Biobehav Rev., 14:109, 1990.
25. VASKO MR., Prostaglandin-induced neuropeptide
release from spinal cord. Prog Brain Res 104: 367-80,
1995).)
26. MCCALL, J. M., AIKEN, J. W., CHIDESTER, C. G.,
DU CHARME, D. W., AND WENDLING, M. G. Pyri-
midine and triazine 3-oxide sulfates: a new family of
vasodilators. J. Med. Chem, 1983, 26: 1791-1793).
27. VIRAG, R.: Intracavernous injection of papaverine for
erectile failure. Letter to the Editor, Lancet, 2: 938, 1982
28. TANAKA, T.: Papaverine hydrochoride in peripheral
blood and the degree of penile erection. J. Urol., 143:
1135, 1990
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29. SHAAYA, A.N., KRAUS, C., BAUMAN, D.H. AND
RITSCHEL, W.A. Pharmacokinetics and bioavailability
of papavervine HCl after intravenous, intracorporeal
and penis topical application in beagle dogs. Methods
Find Exp. Clin. Pharmacol., 14: 373, 1992
30. CHIANG HS, KAO, YH, SHEU MT: Papaverine and
prostaglandin E1 gel applications for impotence. Ann
Acad Med Singapore, 24:767-769; 1995.
31. LEVINE, S.B., ALTHOF, S.E., TURNER, L.A.,
RISEN, C.B., BODNER, D.R., KURSH, E.D. AND
RESNICK, M.I.: Side effects of self administration of
intracavernous papaverine and phentolamine for the
treatment of impotence. J. Urol., 141: 54, 1989
32. VIRAG, R. SHOUKRY, K., FLORESCO, J., NOL-
LET, F.,AND GRECO, E.: Intracavernous self-injec-
tion of vasoactive drugs in the treatment of impotence:
8 year experience with 615 cases. J. Urol., 145: 287,
1991
33. GOVIER, F.E., MCCLURE, R.D.,WEISSMAN, R.M.,
GIBBONS, R.P., PRITCHETT, T.R., AND KRAMER-
LEVIEN, D.: Experience with triple drug therapy in a
pharmacological erection program. J. Urol., 150 1822,
1993
34. HEATON JP, MORALES A, OWEN J, SAUNDERS
FW, FENEMORE J: Topical glycerylnitrate causes
measurable penile arterial dilation in impotent men. J
Urol, 143:729-731; 1990.
35. SONKSEN J, BIERING-SORENSEN F: Transcuta-
neous nitroglycerin in the treatment of erectile dysfunc-
tion in spinal cord injured. Paraplegia, 30:554-557;
1992.
36. MEYHOFF HH, ROSENKILDE P, BODKER A: Non-
invasive management of impotence with transcutaneous
nitroglycerin. Br J Urol, 69:88-90; 1992.
__________________

D. CLINICAL STUDIES
Since the beginnings of the clinical use of topical
therapy, studies have been published to compare
the effects of different compounds and medica-
tions. They are more and more controversial with
the launching of marketed products and new
routes of administration. Controversies rise from
two concomitant factors, the lack of "in depth"
evaluation of the etiology of ED and the weight of
marketing. This culminated after 1997 with the
launching of sildenafil.
I. COMPARATIVE EFFICACY OF
INTRACAVERNOUS
MEDICATIONS (FIG. 1)
Vickers [1], using the Medline, has studied 20 years
of publications dealing with intracavernous mono-
therapy and combination therapy, reaching the fol-
lowing conclusions:
1) In monotherapy papaverine and PGE1 are statis-
tically equivalent in efficacy and side effects; 2)
Drug combinations acting by different pharmacolo-
gical pathways are able to induce functional rigidi-
ty when single-agent testing and/or therapy has fai-
led. 3) By adding other agents, the pain induced by
PGE1 is significantly decreased 4) The ideal order
for combination therapy is not clearly defined
varying with personal habits and availability of the
medications.
II. COMPARATIVE EFFICACY OF
INTRACAVERNOUS AND
INTRAURETHRAL THERAPY
A great deal of controversy concerns this issue.
Generally, independent studies show a marked
advantage in efficacy for intracavernous vs intrau-
rethral. Percentages vary from 25 vs 80, to 40 vs 60
depending on etiology, age and selection criteria.
III. COMPARATIVE EFFICACY OF
ORALAND INTRACAVERNOUS
THERAPY
For methodological reasons there is no randomi-
sed, controlled studies comparing the oral versus
intracavernous treatments.
351
Shabsig et al have studied the efficacy of PGE1 in
145 patients who did not respond to 4 weeks of sil-
denafil treatment with dose adjustment: 88%
reported erection sufficient for intercourse. Mc
Mahon studied the response of 93 patients with
different etiologies, not reponding to intracaver-
nous therapy: 34% responded to sildenafil.
Virag [2] (independent study) studied the feasibili-
ty and effects of sildenafil in 317 consecutive non
selected patients who sought treatment during a 10
week period at the same istitution. This group
consited of 38% naive patients and 54% of
patients already on self intracavernous injections.
The acceptability rate for oral was 82%, feasabili-
ty 74.3%; global results were good for 32%, fair
for 29 and ineffective for 39%. 32% of the patients
after completing the trial were using sildenafil as
their sole treatment, 34% chose self-intracaver-
nous injections, and 25% decided to alternate bet-
ween oral and local therapy (Fig. 2). Presence of
non-sexually stimulated erection and absence of
caverno-venous leak are the prominent factors
predicting a good response to oral therapy.
In an open study conducted at 18 centers in
France and Italy Montorsi et al [4] evaluated the
success of switching patients with erectile dysfunc-
tion treated and stable with ICPGE1 to oral therapy
with Sildenafil. 124 men receiving ICPGE1 for a
mean of 21 months were switched to Sildenafil for
12 weeks. 75% of the patients choose to continue
onto long-term Sildenafil therapy.
IV. LONG-TERM FOLLOW-UP
Virag (see aboves p.302) studied the very long
term effects of injection therapy in 2348 patients
followed for between 5 and 14 years, not only in
terms of efficacy but also quality of life.
1. CHANGE OF MEDICATIONS:
Only 17% of patients did not change their treat-
ment, 20% diminished their dosage, 19% had to
increase the dosage and 43% had to change it,
mainly for more potent medications.
2. EFFICACY AND EJACULATION CONTROL:
The average duration of erection was 75 minutes.
The percentage of premature ejaculation decrea-
sed from 25 to 4%; 70% had a controlled unique
ejaculation, 12% were able to repeat ejaculation
and orgasm twice in the same session.
Figure 1: Local pharmacological treatment modilities, pharmacological agents: efficacy

Figure 2: Local treatment vs. Oral therapy, final therapeutic choice in 157 patients (54% of whom were already on self
injection) having tested sildenafil [2].

352
3. SEXUAL LIFE AND QUALITY OF LIFE:
75% of the treated patients have one partner, 17%
have two or more, and 8 none. 65% of the patients
have kept the same partner and improved their
relationships; for 25% the treatment helped in
constructing a sexual and family life; in 6% the
treatment, apart from its local efficacy, was unable
to produce a satisfactory sexual and personal life.
4. INTERCURRENT DISEASES:
25% are hypertensive and well controlled, 20%
have a high blood cholesterol and 10% are diabe-
tic. 15% have coronary heart disease with appea-
rance of a clinical event during the evaluation per-
iod in 5% of the treated population; none during
intercourse and no death related to the injection
therapy. Depression, present in 25% of the patients
at the begining of the treatment, was significantly
decreased at the endpoint of the study.
E. GUIDELINES FOR LPT
I. GENERAL OVERVIEW OF
PRACTICE
Today, the only universally available local treat-
ment is injection therapy. Intraurethral alprostadil is
not available in all parts of the world. Topical
alprostadil is still experimental.
1. DIAGNOSIS: THE NEED FOR PHARMACOLO-
GICAL TESTING:
There are three steps: 1) taking a medical and per-
sonal history, 2) evaluating spontaneous erectile
activity 3) intracavernous testing (with dopler ultra-
sound when available, to test efficacy and show
safety of the injection
2. WHICH MEDICATION FOR WHICH INDICA-
TION ?
One should consider cost, and use of the smallest
volume and possibly use an automatic injector
when the fear of injection is high. PGE1 monothe-
rapy is the safest medication, dual therapy (papave-
rine and alpha blocker or VIP phentolamine) is
more or less equivalent to isolated PGE1 therapy;
its use is related to economic necessity (cheaper for
papaverine) or comfort (integrated injector for VIP
phentolamine). Multilevel acting drugs have the
advantage of tailoring the IC therapy to almost all
etiologies at a relatively low cost. Association with
oral therapy is still under clinical investigation.
Intraurethral therapy at 500 or 1000 µg is an alter-
353
native and has some indications in patients fearing
the injection or in circumstances such as insuffi-
cient rigidity after surgery of the penis.
5. HOME ATTEMPTS
Titration and choice of medication should always
be performed with sexual stimulation, ideally tes-
ting with the usual partner. A set of three to four
tests of increasing doses is usually necessary to
define treatment. This installation period is the one
at major risk of priapism. Virag has proposed (see
below) to provide the patients with antidotes (self
injection of etilefrine or phenylephrine) to easily
overcome priapism. Patients should always be able
to contact the prescribing doctor day or night.
II. INJECTION TOOLS AND
TECHNIQUES
Injectors or applicators essentially minimize the
fear of injection. They therefore increase the accep-
tability rate of injection therapy. Every effort should
be made to simplify the technique: low dose and
volume to inject, no pain, simplicity and intimacy.
The use of any technique to enhance erections fre-
quently has to be integrated into a global approach
to sexuality including psychosexual therapy
III. BEHAVIOR TOWARDS
THE PARTNER
25 to 50% of local treatment users do not disclose
to their partner that they are using a treatment to
enhance their sexual performance (Virag, ISIR
meeting Amsterdam 1998). Prescribers should be
aware of the couple’s "real" situation when coun-
selling their patients in aspects of the therapy. The
partner’s attitude might be negative and ruin the
issue. When possible, counselling should be propo-
sed to the couple and specially the partners after
having convinced them of the advantages of parti-
cipating in therapy. In any case, therapy should be
minimized and fully integrated in the intimacy of
sexual activities without being prominent. Very few
couples are able to integrate it as part of the "love
games". It is usually better to perform injection and
immediately forget about it.
IV. FOLLOW-UP
Follow-up should be performed on a twice a year
basis. During the first two years after initiating
treatment, physical examination must evaluate any
complications such as nodules or fibrotic areas.
Dynamic ultrasound may be useful in such cases.
Long-term evaluation requires telephone or written
interviews and a yearly visit. Modifications of local
or general conditions have to be adressed. Prostate
cancer early diagnosis, decrease in testosterone,
evaluation of current associated diseases or risk fac-
tors are part of follow-up as well as the individual’s
and couple’s psychosexual environment.
V. PREVENTION AND TREATMENT
OF COMPLICATIONS
1. PRIAPISM
Priapism is prevented by careful teaching of titra-
tion and dosage in the initial steps of therapy. Still,
like any self-administered therapy, priapism may
occur due to overdosing. Although some authors
fixed the delay before medical intervention to six
hours, the recommendations are to restrict the time
of total pharmacologically induced erection to a
maximum of three hours: corresponding to the
time to inversion of the oxygen balance towards
anoxia. In addition, physical and/or pharmacologi-
cal treatment of priapism is much easier to achieve
within the first 3 hours. Muscular exercise, cold
local bathing might be sufficient to restore flaccidi-
ty. Otherwise, an intracavernous injection of an
alpha adrenergic agent (etilefrine or phenylephrine)
is able to relieve priapism in almost all cases seen
early (within three hours). Using self injection with
etilefrine, prevention of return to the clinic, has
been achieved in a series of 172 cases Virag [3]
without any complications.
2. NODULES AND FIBROSIS
Clinical examination with ultrasonography will
differentiate:
• isolated nodules generally related to small
local hemorrhages induced by injections. Beni-
gn and reversible after few weeks, they should
be avoided by a careful technique and the use
of thinner needles (30 gauge).
• larger area of intracavernosal fibrosis occu-
ring early in the first months of treatment,
requiring immediate stopping of treatment.
They are rare (less than 1%) and probably due
to special susceptibility of the cavernous tissue
and/or possibly larger hemorrhage secondary
to the puncture of a large branch of deep
arteries (?). More frequent with the use of
354
papaverine containing mixtures they can also
occur with any medication.
• development and/or increase of Peyronie's
like albugineal plaques. There are a lot of
unresolved controversies concerning the inter-
action of intracavernous injections with Peyro-
nie’s disease. Long-term surveys show that
there is no statistical link between these two
factors. Nevertheless, repeated injections in a
Peyronie's plaque may trigger an increase of
the plaque and the appearence of curvature. On
the other hand, repeated reoxygenation induced
by the local treatment might stabilize or even
reduce Peyronie's disease. Relevant data with
prospective studies are needed to conclude.
The advice is to manage, this issue case by
case, according to individual clinical status.
F. THE FUTURE OF TOPICAL
THERAPY
The better knowledge of the mechanisms of erec-
tion will encourage the development of more
powerful medications in the future. Manipulations
should enhance and/or delay the release of drugs to
ensure fewer injections and/or a longer duration of
action. Gene therapy may appear soon. Automatisa-
tion and miniaturisation of the injection technique is
one goal of local therapy as well as the development
of molecules that are truly effective by transalbugi-
neal percutaneous administration.
G. CONCLUSIONS
The penis is an easy target for local treatments.
At the present time, injection therapy gives the
impotent patient a combination of high efficacy
with a very low complication rate.
REFERENCES
1. VICKERS M. Personal communication
2. VIRAG R.Indication and early results of sildenafil in
erectile dysfunction. Urol. 54: 1073-1077, 1999.
3. VIRAG R. Traitement ambulatoire et prévention du
priapisme par medication α agonistes, à propos de 172
cas. Chirurgie, dec, 1996.
4. MONTORSI F., GIULIANO F., SWEENEYM. Patients
receiving intracavernosal (IC) PGE1 do well when swit-
ched to viagra (sildenafil citrate): results of a multina-
tional european study. ESIR - Barcelona, Junuary 2000.
 Committee 10

Surgical Treatment and

Mechanical Devices

Chairman
U. JONAS

Members
C. EVANS,
S. KRISHNAMURTI,
D. MONTAGUE,
J. P. SARRAMON,
M. SOHN,
E. WESPES,
H. WESSELLS

355
 CONTENTS
A. EXTERNAL DEVICES, DRUG
AND DELIVERY IMPLANTS
I. VACUUM DEVICES IN THE
TREATMENT OF ERECTILE
DYSFUNCTION
II. PENILE DRUG DELIVERY
IMPLANTS [22]
CONCLUSIONS
B. VASCULAR SURGERY
I. SURGERY FOR ARTERIAL
PATHOLOGY
II. SURGERY FOR CORPORO-
VENO-OCCLUSIVE DYSFUNCTION
III. DISCUSSION
C. PENILE IMPLANTS
I. INTRODUCTION / HISTORY
II. MALLEABLE DEVICES
III. INFLATABLE DEVICES
IV. SURGICAL TECHNIQUES
V. COMPLICATIONS FOLLOWING
PENILE IMPLANTATION
VI. POSTOPERATIVE
MANAGEMENT
CONCLUSIONS
356
D. PENILE INJURIES: THE ROLE
OF EARLY SURGICAL INTERVEN-
TION IN PREVENTING ERECTILE
DYSFUNCTION
I. INTRODUCTION
II. PENILE FRACTURE
III. PENETRATING INJURIES OF
THE PENIS
IV. PENILE AMPUTATION
V. BLUNT TRAUMAAND ERECTILE
DYSFUNCTION
VI. CONCLUSION ( TABLE 4)
E. PENILE RECONSTRUCTION
I. INTRODUCTION
II. REVIEW OF THE LITERATURE
ON TECHNIQUES FOR
PHALLOPLASTY
III. CONCLUSIONS
F. PENILE ENLARGEMENT
SURGERY
I. CONCLUSION
RECOMMENDATIONS
 Surgical Treatment and
Mechanical Devices
U. JONAS
C. EVANS, S. K RISHNAMURTI, D. M ONTAGUE, J. P. SARRAMON, M. S OHN, E. W ESPES,
H. WESSELLS
A. EXTERNAL DEVICES AND
DRUG DELIVERY IMPLANTS
I. VACUUM DEVICES IN THE
TREATMENT OF ERECTILE
DYSFUNCTION
1. OVERVIEW
The use of vacuum devices as part of the conser-
vative management of erectile dysfunction is quite
varied and relates to the judgement of the clinician
and patient’s preferences. Their overall use is not
common-place however.
2. VACUUM DEVICES : DEFINITION
Vacuum devices work by creating a vacuum nega-
tive pressure which increases the blood flow into
the corpora cavernosa. The erection is maintained
by trapping the blood in the penis by use of a
constriction ring at the base, cutting off the venous
outflow.
3. DEVELOPMENT
Experiments with vacuum air pumps were descri-
bed by J. van Musschenbrack in Leiden in 1694.
Illustrations of this are available at the Library of
the State University in Leiden. An American, John
King, is credited with the first clinical use in 1874
of a vacuum device [1] but compression was
added in 1917 by Dr. Otto Lederer who requested
a patent for his surgical device to produce erec-
tions with vacuum [2].
357
Gedding Osbon in 1960, in trying to improve his
own sexual performance developed a device
which became commercially available in 1975 but
took till 1982 to be granted permission to market
the device because of concerns with both safety
and efficacy. His device was called the youth equi-
valent device and is now called ErecAid [3].
In 1986 Nadig reviewed the use of the device in 35
men [4] and in 1989 reviewed a total of 340
patients over 6 years, 83% of whom used the devi-
ce [5]. Witherington also described the ErecAid
system and reviewed 1517 users favourably [6, 7].
Turner found that sexual satisfaction and self-
esteem improved whilst psychological symptoms
decreased [8].
In his early studies in 1986, Nadig [4] found the
device to be safe, provided the negative pressure
did not exceed 200 mm Hg and the constricting
bands were not on longer than 30 minutes.
Negative comments at this time were however
voiced: Benson stated “It is difficult to accept that
a non-physiological erection, predicated upon
trapping blood in the penis, with proximal crural
flaccidity, urethral compression hindering ejacula-
tion and general cooling of the phallus should eli-
cit such a high favourable response rate” [9].
4. TYPES OF EQUIPMENT
The initial devices used mouth suction and elastic
rings but are now much more sophisticated and
easy to use. The vacuum devices are made of a
clear plastic cylinder with either a battery or hand
pump attachable and a collection of sizes of rings.
The rings and applicator are also available separa-
tely, without the cylinder (table 1).
Table 1: Type of equipment ding device; choosing the size of the ring is done
MAKER NAME COST US $ by guesswork but most men start at the middle
size. The inside of the plastic tube is liberally
OSBON - ERECAID Classic 361.33 covered with lubricating jelly, to get a seal, and the
Standard 227.80 flaccid penis is then inserted and the tube pushed
Esteem Manual 432.03 against the pubic bone. The vacuum is then
Esteem Battery 502.72 applied, by hand or by battery pump, and tumes-
EUROSURGICAL Post-T-vac Battery: 389.61 cence occurs.
Manual: 188.52- 351.90
This initial tumescence may make it easier to put
GENESIS *Active II Battery: 234.08
Impulse 186.95
the penis in the cylinder before proceeding to
continue pumping, usually for up to 3 minutes, till
OWEN MUMFORD *Rapport 186.95
a satisfactory erection is achieved. Then the ring at
VET CO. UK Vet Co 141.39 the base of the tube is slipped onto the penis to
(not inc. VAT) maintain the erection. The rings should only stay
MEDWATCH Erectease 204.23 on for 30 minutes maximum.
MENTOR Response VES II 306.35 This will finally give an erection which is colder,
VCS II 392.75
slightly bluish and hinged at the base where the
FARNHURST Elite 212.09 ring is but many patients find it adequate for vagi-
nal penetration.
* Lifetime guarantee
Most patients are instructed on the use of the devi-
ce by verbal explanation, demonstration of the
Correctaid, a reinforced semi-rigid condom with a device, and watching a video. Additional technical
mouth tubing to apply suction was available in the advice is usually available from the manufacturer
1980s but fell out of favour. It was not effective by a freephone number. If patients have problems
and the silicon too thick to allow much feeling. with the device they can, in many instances, meet
The rings are now made of soft latex and have side with the company representative to review the
handles for ease of removal. Some manufacturers technique.
make a notch in the ring the place over the urethral It is also possible to combine the use of intracor-
bulb to prevent trapping of the ejaculate (Fig. 1). poral pharmacotherapy + oral treatment with both
rings alone and the vacuum device [12].
5. REQUIREMENTS AND TECHNIQUE
• Contraindications
Vacuum devices require enthusiasm on the part of
Contraindications to use are almost none. Nadig
the patient and a sympathetic partner. It is therefo-
stated that patients with scarring and deformity of
re less likely that single younger men are going to
the penis due to Peyronie’s or post penile implant
use them but the middle and old age groups tend to
removal for infection are not likely to attain rigidi-
choose this treatment modality. [10] The patient ty [13] but it is worth trying as others have had
requires manual dexterity and a penis which is good results in this group [14] especially in kee-
large enough to fit into the plastic tubing. ping penile length after explanted penile implant.
The patient requires practice and this technique is Features which are against the successful use of
not necessarily successful in the first few attempts. vacuum devices are it is fiddly, noisy, the ring pre-
[7, 11] It is advisable to loan this device for one sent makes the patient continually aware that he
month or more so that the patient can practice pea- has a problem.
cefully in the leisure of his home at least daily.
The device may be expensive for the patient to buy
In order to use the device, the constriction rings and the partner may just dislike the look of the end
are placed over the clear plastic tube with a loa- result of a coldish, bluish erection.

358

6. RESULTS
Patient satisfaction varies enormously and is rela-
ted to effectiveness.
Ease of use : In one study [11] 94 out of 127
patients (74%) found the device straightforward,
12 needed to contact the manufacturer and 14
patients not achieving good results or experien-
cing pain had an instructional session with the
manufacturer. Five out of these 14 then achieved a
satisfactory result.
7. COMPLICATIONS
Petechiae skin bruising, especially at the site of
the ring, occurs in 16 to 39% of patients. [11, 15,
16] Patients on anti-placelet therapy or warfarin
do not appear to have any increase in bruising or
ecchymosis.
359
B
Figure 1: New generation of vacuum devices (A), pump and
rings (B) handling (C)
Pain occurs at the site of the ring. This lessens
with use and also when an appropriate size ring is
selected and in less than 3% of the patients did
they stop using the device.
Ejaculatory changes, including pain on ejacula-
tion up to 16% (15) and blocked ejaculation occurs
in 25% [11].
Numbness during erection was a problem in 5% of
patients [15].
Pivoting at the base occurred in a 6% [15].
Satisfaction rate
Satisfaction rate, both short and long term, varies
considerably from as low as 27% to 68% short-
term, to as high as 69% with 2 year follow-up. [15]
The reasons for dissatisfaction [11, 15] are as fol-
lows:
• Inability to maintain full erection 12% mean increase in length was 3.7cm +/- 0.7 and the
increase in circumference 3.5cm +/- 0.9. This
• pain 4%
compared favourably with the increase in length
• inconvenience/awkwardness 4% and width for normal erections.
• marital problems 5% The vacuum devices which are on prescription are
partner dissatisfaction with: well tried and tested, these devices are approved
by the Food & Drug Administration for sale as
• performance 11% over-the-counter medical devices in USA.
• penile temperature 7%
• appearance 13% 9. S PONTANEOUS IMPROVEMENT
In one study [17], only 20 out of 74 patients were As with all other conservative forms of treatment
satisfied with the erections they achieved. These for erectile dysfunction, patients will report the
however, were patients who had all failed counsel- return of spontaneous erections in up to 25% of
ling and self-injection. All patients with psycholo- cases and many other patients will get improved
gical impotence failed. The authors did suggest erections. Daily use of a vacuum device for 30
that patient selection and lack of good initial ins- minutes each day not only maintain dexterity but
truction and freephone help may have contributed. make use of the device part of a routine even if
intercourse is not attempted as advocated in Shef-
However, many patients with erectile dysfunction
field, UK. [21]. The use of vacuum devices in Wes-
are reluctant to even try vacuum devices . Of 1,236
tern Europe is summarised in table 2.
patients who had the option to use vacuum device,
only 6% tried the device and continued to use it.
Table 2: Use of Vacuum Devices in Europe and America
[18]
1996 1998 1996 l998
8. SAFETY USE OF % UROLOGISTS
VACUUM DEVICES OFFERING DEVICES
Initially part of the hesitancy to prescribe these
devices was related to the effect of constriction of Western Europe 3% 6% 44% 49%
the penile blood flow. In order to have vaginal
U.K. 7% 13% 80% 88%
penetration, buckling pressures of between 60 and
100 mm Hg are needed, although usually in excess France 1% 1% 36% 22%
of 100mm Hg, this is certainly sufficient.
Germany 4% 8% 76% 80%
In 1998, using penile plethymography, the penile
Italy 0.1% 3% 6% 10%
blood flow was measured before, during and after
the use of the ring. [19]. There was a 70-75% Spain 1% - 22%
decline in the amplitude of the pulse volume curve
but continuous blood flow was maintained in each
case. In 33 patients, after removal of the ring there
was transient increased amplitude consistent with
post-ischaemic hyperaemia. These findings sug- At the request of American Medical Systems
gested an adequate penile blood flow and that the (AMS), N.O.P. Healthcare conducted quantitative
devices were safe. However, the thirty minute research amongst urologists in the U.K, France,
rule should be strictly adhered to, as the ring Germany, Italy and Spain. The purpose of the
causes significant reduction in blood flow and in study was to assess the share of various impotence
one report complete cessation. [20] treatments performed by urologists in these coun-
In 72% of patients [19] with penile plethysmogra- tries. 50 urologists, randomly selected in each
phy, the pressure achieved was greater than country, were interviewed by telephone, a total
100mm Hg buckling pressure. In addition, the sample of 250 respondents.

360
The table shows that most urologists, excluding
those in Italy and Spain, offer vacuum devices but
the take-up rate by the patient is low. This will
vary according to the enthusiasm of the urologists
for this form of treatment.
II. PENILE DRUG DELIVERY
IMPLANTS [22]
These implants consist of a cannula which is inser-
ted into the Corpus cavernosum and a combined
scrotal reservoir and pump, containing a vaso-acti-
ve drug. Compression of the reservoir pump gives
a bolus of the vaso-active drug into the penile tis-
sue to stimulate an erection.
The first implant was inserted in 1986 and 36 have
been implanted in 21 patients with varying causes
of erectile dysfunction. Initially, papaverine and
phentolamine was used but crystal formation cau-
sed tubal blockage so this has been replaced by
sodium nitroprusside. These implants remain acti-
ve for a mean of 14 months. 8 of the devices are
still working with a follow-up of 4 years. There are
a considerable number of failures; 7 leaking reser-
voirs, 6 blocked tubes, 9 mechanical failures, 3
infection. Two patients developed priapism. One
patient with recurrent priapism has been managed
with alpha sympathetico mimetic drugs.
This implant has undergone many modifications
but should continue to be considered investigatio-
nal as an alternative to self-injection.
CONCLUSIONS
Vacuum devices, although not in widespread
use, have advantages in that they are re-usable
(and therefore in the long-term less expensive),
satisfactory for many patients who are offered
them and safe.
They should be kept available for use, impro-
ving design will make them more user-friendly.
361
B. VASCULAR SURGERY
Several tests are available for evaluating the peni-
le vascular inflow and outflow tract, ranging from
simple pharmacotesting to enhanced pharmacotes-
ting such as in pharmacopenile duplex ultrasono-
graphy (PPDDU), cavernosometry, selective peni-
le angiography (Fig. 2 A, B, Fig.3).
I. SURGERY FOR ARTERIAL
PATHOLOGY
Cavernous body revascularisation procedures
have been proposed to correct penile arterial insuf-
ficiency. [1-5] Direct anastomosis of the inferior
epigastric artery to the corpus cavernosus has been
abandoned because of a high rate of priapism and
the short duration of success due to thrombosis.
Using an end-to-side anastomosis of the inferior
epigastric artery to the dorsal penile artery (Michal
II procedure). Michal et al. obtained a 60% suc-
cess rate. Other techniques for penile revasculari-
sation have been described using the inferior epi-
gastric artery anastomosed to the cavernous artery
or to an arterio-venous fistula created by anasto-
mosis of the dorsal penile artery and the dorsal
penile vein; or using a vein segment interposed
between the femoral artery and one or both of the
dorsal penile arteries or cavernous arteries.
Penile deep dorsal vein arterialisation (DDVA) has
been applied to patients with arterial, venous and
mixed impotence [6]. This technique is though to
produce a retrograde arterial flow into the caver-
nous bodies through the collateral deep dorsal
venous network or through a surgical fistula bet-
ween the arterialised vein and the corpus caverno-
sum. Several arterialisation procedures have been
developed by Virag. The most widely applied ope-
ration is the Virag-5 (inferior epigastric artery ana-
stomosed to deep dorsal vein, end-to-side, proxi-
mal and distal vein tied, circumflex and emissary
collaterals tied, fistula between the dorsal vein and
the corpus cavernosum). [6-7] This procedure was
modified by Furlow and Fisher [8] (no creation of
a veno-corporeal fistula but preservation of emis-
sary veins to carry the arterial flow into the caver-
 A B

Figure 2: Bilateral pudendal angiography reveals a total occlusion of penile arteries : a) Left side b) Right side

Figure 3: Left pudendal angiography shows multiples strictures (°) with respect to the common penile artery.

362
 Figure 4 :
a) Michal II procedure : arterio-
arterial revascularization.
A Epigastric artery (EA) is anasto-
mosed end-to-side to the dorsal
penile artery (PDA).
CA : cavernous artery.
b) Epigastric angiography :
demonstrates a revascularization
of the dorsal artery.

Figure 5: Different procedures of the deep dorsal

vein arterialization, DDVA Virag procedure and
modifications.

363
nous bodies) and appears to enjoy the same suc-
cess rate as the original Virag-5 procedure [9].
Globally, the success rate of DDVA for arterial,
venous or mixed impotence is reported to be 40-
75%. Hauri proposed anastomosis of the epigastric
artery on the deep dorsal vein together with the
dorsal artery [10].
1. SURGICAL TECHNIQUE DESCRIPTION
Both Michal II and DDVA procedures were per-
formed using the inferior epigastric artery. A para-
median incision was made along the external bor-
der of the rectus muscle. The inferior epigastric
artery and its accompaning veins were isolated
and divided at the level of the umbilicus. Papave-
rine was used to prevent arterial vasospasm. Five
minutes before vessels were divided, 5,000 units
of heparin were administered intravenously. The
artery and veins were brought through a subcuta-
neous tunnel to the root of the penis.
2. MICHAL II PROCEDURE
A dorsal longitudinal incision was made at the
base of the penis. Buck’s fascia was incised and
the dorsal penile artery was dissected with the aid
of a microscope to prevent nervous system inju-
ries. An end-to-side anastomosis was performed
between the epigastric artery and the proximal part
of the dorsal penile artery. Interrupted sutures of 9-
0 nylon were employed using standard microsur-
gical techniques (Fig. 4 A, B).
3. DDVA PROCEDURE
After incision of the skin and Buck’s fascia at the
penile root, the deep dorsal vein was dissected
from the suspensory ligament to the distal retroco-
ronal plexus. A modified Furlow-Fisher procedure
was performed (preservation of circumflex and
emissary collaterals and no destruction of deep
dorsal venous valves by a stripper). The dissection
was performed with the aid of a microscope to pre-
vent arterial or nervous system injuries. The epi-
gastric artery was anastomosed end-to-side to the
proximal part of the deep dorsal vein using inter-
rupted sutures of 9-0 nylon. When the anastomosis
was completed the dorsal vein was ligated proxi-
mal to the arterio-venous anastomosis and proxi-
mal to the distal retrocoronal plexus (Fig. 5).
4. HAURI’S PROCEDURE
The inferior epigastric artery is isolated by means of
pararectal incision, severed at the level of the umbi-
364
licus and transposed ingiunally to the base of the
penis. The penis is opened at the dorsal aspect by
longitudinal incision and the superficial penile ves-
sels are dissected. One of the dorsal penile arteries
and the deep dorsal penile vein are opened by a lon-
gitudinal incision of approx. 2 cm, and the median
wound margins of both penile vessels are closed by
7-0 non-absorbable continuous sutures. The trans-
posed inferior epigastric artery is then opened by a
longitudinal incision of approx. 2 cm and anasto-
mosed to the common arterio-venous lumen by a 7-
0 non-absorbable continuous suture with a funnel-
shaped opening (Fig. 6).
5. ANTITHROMBOTIC THERAPY
The patients received postoperative intravenous
heparin for 72h, after which they were placed on
subcutaneous calciparin 0.3 cm3 t.i.d. for 2 months
and then on dipyridamole 75 mg o.d. and aspirin
500 mg o.d. for 3 months.
II. SURGERY FOR CORPORO-
VENO-OCCLUSIVE DYSFUNCTION
The treatment of patients with caverno-venous
insufficiency is based mainly on the reduction of
venous outflow during erection. [11-12] Until now,
it has been applied to the penile veins, although the
defect of corporeal venous malfunction was within
the penis itself. Success is defined as good erection
during normal sexual intercourse. Embolisation of
the deep venous network with detachable balloons
and coils introduced through the deep dorsal vein
dilated surgically provides satisfactory clinical
results with a minimum follow-up of 1 year. The
surgical approach addresses ectopic veins, deep
dorsal veins and/or cavernous or crural veins (Fig.
7). Spongiolysis [13] or peri-cavernoplasty [14]
with or without insertion of a prosthetic venous
tourniquet or simple crural plication [15] has also
been proposed. Also combined approaches of the
before mentioned procedures have been published
[16]. The different surgical procedures described do
not invade the corpora cavernosa and are restricted
to the veins. For this reason, the immediate results
are satisfactory but relapse can be observed a few
months later. Peri-operative measurement of the
erectile flow rates is mandatory and makes it pos-
sible to monitor the operation. If they are not lower
after resection of several veins then leakage is still
occurring through other veins, which also must be
ligated.

Figure 6: Hauri’s Procedure.
Figure 7: Resection of the deep venous system.
Patient selection is highly important, and those with
arterial disease must be excluded. If the arterial
inflow is severely reduced, ligation of the veins
does not lead to adequate penile tumescence for an
erection [12]. Such patients might benefit from
deep dorsal vein arterialisation if they are younger
than 55 years but the results are not completely
satisfactory.
Anastomosis of the epigastric artery on the deep
dorsal vein could decrease the venous outflow, and
retrograde penile revascularisation through the
emissary veins could improve the insufficient arte-
rial inflow. [6-7] However, angiography of the epi-
gastric artery performed after this surgery is unable
to demonstrate opacification of the cavernous
bodies when a deep dorsal vein-tunica albuginea
fistula is not realised [17, 18].
This surgical approach improves intracorporeal
pressure during erection but the resting pressure is
also elevated. In older patients vaso-active intraca-
vernous injections make pharmacologically indu-
365
ced erections possible even when they were not pre-
sent before correction of the caverno-venous leak.
Reduction of the venous outflow decreases the
amount of drug to be injected and avoids secondary
effects attributable to immediate release of the drug
into the systemic circulation [19].
It appears that potency remains stable if the effect of
the surgical treatment persists beyond 6 months.
Reassessments for secondary leakage reveal abnor-
mal venous return, in most cases into the cavernous
vein (when previous surgery has been limited to the
deep dorsal vein) or into the Corpora spongiosa,
ectopic veins or small veins not ligated during pre-
vious surgery. There is no significant difference in
age between the patients whose potency improves
and those with persisting impotence. [12] The
extent of the leakage does not seem to have a role in
the degree of success achieved. [12] Major resec-
tion of the venous return should provide the best
immediate and also long-term results. [12] Emboli-
sation of the venous system deeper under the pubic
could provide greater reduction of the venous out-
flow and, therefore, better results than surgery. [18]
However, in a long-term follow-up the success rate
is similar. Venous surgery should not be restricted
solely to the veins seen to be opacified on caverno-
sography but it must be extended to the 2 main drai-
nage routes of the corpora: the deep dorsal vein and
the cavernous veins.
III. DISCUSSION
The role of vascular surgery in erectile dysfunc-
tion is still not well defined. In 1993 a Consensus
Development Conference Statement of the Natio-
nal Institutes of Health on Impotence stated, that
the tests for venous disease are incompletely vali-
dated [18]. Therefore it will be difficult to select
patients with predictably good outcome. The
conference concluded, that venous penile surgery
should best be done in an investigational setting.
Referring to revascularization procedures to the
clinical investigational setting in specialized medi-
cal centers, due to the incompletely standardized
preoperative measurements, interpretations and
indications. In 1996 the Clinical Guidelines Panel
on Erectile Dysfunction of the AUA searched the
MEDLINE data base for all articles from 1979
through 1994 on treatment of organic erectile dys-
function by penile revascularization and venous
ligation procedures and concluded that for both
types of surgery, chances of success do not appear
high enough to justify routine use in urological
practice [19]. In 1996 Vickers et al. [20] reevalua-
ted all literature data available on penile revascu-
larization and penile venous surgery and conclu-
ded, that the efficacy of these procedures have not
been evaluated by studies which have utilized the
criteria of any ideal experiment.
In 1997 De Palma on the other hand concluded,
that randomized clinical trials will not be possible
in the field of vascular penile surgery for erectile
dysfunction [21]. Only 5 to 7 percent of all
patients, non-responsive to medical treatment,
would be candidates for such procedures. He advi-
sed surgeons on that field to perform well structu-
red case control studies of their patients to fulfill
the critera for Evidence-Based-Medicine success-
evaluation. Anyhow, such studies have not been
published up to now.
In the following conclusions and contradictions
with respect to indications, contraindications and
long-term results from the actual literature shall
be presented: In 1993 30 studies were available
in the literature on short-term-success of venous
ligation procedures [18]. The range of success
went from 10 to 95 % with an average value of
62,3 %. Only 4 studies used objective methods for
success evaluation. 22 studies presented long-
term data of more than 12 months follow-up for
success ranging from 13 to 74 % with an average
value of 41,4 %. 12 studies presented longitudinal
follow-up data with a drop of success from 70% to
37% (average values). A recent report on a well
selected patient material with long-term follow up
confirmed these results with a short term success-
rate of 45%, which dropped to a long-term suc-
ALGORITHM FOR THE CHOICE OFTHE ADAPTED TECHNIQUE IN VASCULAR SURGERY
Figure 8: Algorithm for the choice of the adapted technique in vascular surgery
366
cess-rate of 30,2 % [22]. Positive prognostic fac-
tors were preoperative duration of erectile dys-
function less than 7 years, a normal CC-EMG and
a maintenance flow of less than 45 ml/min. [23,
24]. The same drop from reasonable good short-
term success to less than satisfying long-term
results could be seen after percutaneous vein
embolisation [25]. In the field of penile revascula-
rization a compilation of all published data from
1988 to 1993 revealed an overall success-rate of
33 to 100% (average 72 %) [26]. Long-term data
are difficult to find, a recent longitudinal follow-
up study of 30 months revealed a drop of subjec-
tive success from an initial 85% to 54 %. Nearly
half of these patients could only reach sufficient
erections with the additional aid of intracavernous
injection. Another longitudinal study showed a
similar drop from an initial 53% to 40% after five
years follow-up [27].
Concerning indications and contraindications for
penile revascularization, it must be stated, that no
agreement exists in the actual literature [28]. Man-
ning et al. advised to select patients without
venous leakage, with reduced erections after intra-
cavernous injection and with an age lower 55
years for surgery [29]. For most authors diabetes
mellitus, neurologic disorders and nicotine abuse
are contraindications for penile revascularization.
The role of venous arterialization (Virag I-V, Fur-
low-Fisher) remains obscure. A retrograde arteria-
lization of the corpora could not be proven in the
literature [15, 30, 31]. The fact that no single sur-
gical technique seems to be superior to the others
from the point of success, casts doubt on differen-
tial therapeutic algorithms as presented below.
An algorithm for vascular surgery is summarised
in fig. 8.
As long as no objective selection criteria exists for
penile revascularization, venous arterialization or
venous ligation procedures, it may only be
concluded, that these operative techniques may
have subjective success in less than 50% of
patients in long-term follow-up studies.
Recently, single potential analysis of cavernous
electrical activity, another method for studying
smooth muscle competence, has been suggested
to be an important prognostic factor for the pro-
gnosis after venous surgery [23]. Histological
study of the intracavernous structures seems also
able to predict venous surgical outcome [24,32].
However, penile biopsies were mostly performed
during the operation when the therapeutic decision
was already made.
C. PENILE IMPLANTS
After having finally found the appropriate material
(silicone rubber) and the exact implantation site
(inside the tunica albuginea), prosthetic surgery
for the treatment of erectile failure became more
and more popular. In 1973, Scott and co-workers
described a completely new concept using infla-
table silicone cylinders which could be filled
voluntarily via a pump which became implanted in
the scrotum, transporting fluid to the cylinders
from a reservoir which was positioned behind the
rectus muscle. In 1976, Small/Carrion designed a
prosthesis which was much easier to implant and
had less complications, but which had the disad-
vantage of a more-or-less permanent erection due
to rigid rods which were positioned inside the cor-
pora cavernosa [9-10].
Table 3 summarises the individual features in the
malleable and inflatable penile implants.
Table 3: Comparison of the individual features in malleable
and inflatable penile devices:

MALLEABLE IMPLANTS INFLATABLE IMPLANTS

I. INTRODUCTION / HISTORY
ADVANTAGES DISADVANTAGES ADVANTAGES DISADVANTAGES

In contrast to other mammal species such as the Simple permanent «physiologic» mechanical
whale, dog, bear, gibbon, or otter, the human male design «erection» erection failure
does not have a penile bone inside his penis to
enforce erection. Despite earlier surgical efforts to Low costs impaired volontary hydraulic
micturition ? control: problems
treat erectile impotence by the resection of the dor- Simple surgery cosmetic erect - flaccid incidence for
sal vein of the penis it seemed logical that Bogoras appearance reop.
in 1936 used a part of rib cartilage in order to rein-
Need for
force rigidity in the penis. However, the rib cartila- pumping
ge and bone implants were reabsorbed after several prior to
months and therefore the effect abolished [1-3]. intercourse

The first alloplastic implants were described in

However, these two types devices started the
1952 - according to unpublished data by Scardino
development and design of numerous new pros-
- using acrylic prostheses. These devices were ori-
theses throughout the last 25 years such as the
ginally positioned between the corpora cavernosa;
penile implants described by Subrini, Finney,
however, they were less successful than polyethy-
Jonas, Mentor, Subrini and Krane [11 - 21].
lene prostheses which were implanted inside the
tunica albuginea. Loeffler et al. stated that «It
might seem like meddlesome surgery to insert a
II. MALLEABLE DEVICES
foreign body of considerable size into the adult
male penis, but to the patient with an organic
impotence, otherwise in good health and with nor- In 1976 Small and Carrion described their device;
mal desires, this is a real problem that is worth it consisted of a pair of silicone rod prostheses
trying for correction.» In 1966, Beheri already which were implanted through a midline perineal
reported on 700 penile implants. He used two incision. The prosthesis was available in 16 diffe-
polyethylene rods and placed each one inside the rent lengths and 3 diameters, which already
corpora cavernosa [2, 4-8]. emphasised the inability to make a proper length

367
determination prior to surgery. Therefore, different
sized prostheses had to be available in the opera-
ting room. In order to decrease hospital inventory,
individual device trimming at the tails of all
implants was finally introduced [10, 17, 22-23].
By December 1977 already a total of 260 patients
had received implants and only 3 of 106 implanted
patients had a poor result. However, due to the
rigid characteristics of the device a more-or-less
permanent erection resulted, and the need for
improvements became evident. One solution was
found by Subrini as well as by Finney; both
authors used softer silicone-preparations positio-
ned in the mid- part of the device in order to avoid
permanent erection in the «resting position»
[12,21].
Subrini described his preliminary experience in
1974 [24]. Between 1970 and 1982 he operated on
a total of 283 impotent patients with an overall fai-
lure rate of only 1.7%. Success ranked as high as
95% after primary surgery and 98.3% if surgery
had to be performed a second time [21, 24].
A different way of combining the features of mal-
leability with simple design was done by Jonas
when in 1978 he published a report on silicone sil-
ver penile prosthesis (fig. 9). This device was cha-
racterised by silver wires embedded inside the sili-
cone rubber to stabilise the penis in different posi-
tions: downwards or against the body during the
resting position or upwards for intercourse. Despi-
te the fact that the silver strands could break after
numerous bendings (following approximately
Figure 9: JONAS (ESKA) silicone-silver penile implant: A
total of 22 pairs of different sized devices (in 3 different dia -
meters) are available for individual fit. For further expla -
nation – s. text.
368
5000 double bendings at one specific point on a
simulator ), the silver never protruded the silicone
rubber nor was the function inhibited by fractures
of the silver wires (stability). In order, however, to
avoid future discussions of whether or not broken
silver strands could lead to negative results, since
1984, the individual silver strands were embedded
in thermoplastic Teflon, making further breakages
impossible [16 – 19].
The original device (standard version) was manu-
factured in three different diameters (9.5, 11, and 13
mm) in lengths between 17 and 24 cm. Atotal of 22
different prostheses were available.
In order to diminish costs the „trimming-tip ver-
sion“ was introduced, a device which could be
shortened at its proximal end making only two
pairs of different lengths necessary in two diffe-
rent diameters. In a multicenter trial performed in
the early 1980s based on 1834 patients with
implants, an overall success rate of close to 95%
was achieved. Early complications were seen in
5. 1 %, later complications in 2.8%; only 19 of the
1834 implants had to be removed (1.04%).
The concept of a metal strand inside the malleable
silicone prostheses for reliable and flexible stability
was copied later in the AMS Malleable 600 pros-
thesis in which instead of Teflon-coated silver
strands a steel-capped, fabric-wrapped stainless
steel core was used. Further features were the remo-
vable silicone jacket and the rear-tip extenders. The
AMS Malleable 600 prosthesis has been replaced
by the AMS Malleable 650 prosthesis (fig. 10).
Figure 10: AMS 650 malleable device, using a fabric-wrap -
ped stainless steel core and rear-tip extenders.
The MENTOR malleable penile prosthesis also device. The AMS 700 CX now has a 3-ply cylin-
contains a silver strand; however, this strand is der wall minimising the risk of cylinder bulging;
coiled in a spiral, giving a corkscrew appearance. the diameter of each cylinder can expand from 12
The silver strand is only positioned in the midpor- up to 18 mm, improving prosthetic erection in cir-
tion of the device, therefore the proximal end can cumference; and tubing connectors allow easy
be trimmed to the exact length required [25-30]. handling and safe connection of the tubes to and
from the cylinder [11, 13-14, 31-32]. The AMS
The Duraphase penile prosthesis is a device in
700 CXM prosthesis has a smaller reservoir,
which rigidity and flaccidity are controlled using
pump, and cylinders which expand from 9.5 to
articulating segments, a stainless steel cable, and a
14.2 mm. This smaller inflatable prosthesis is
spring on each end of the central part. It consists
especially useful in implant recipients who have
of 12 rigid polysulfone articulated disks with a
fibrotic corpora [42] (fig. 11).
centrally placed stainless steel cable and 2 spring
mechanisms. The allowed angle of all 13 disk The AMS 700 CX was developed from the origi-
interspaces is 220°. nal inflatable Scott device and consists of three
components: the cylinder, the pump and the reser-
According to the results of a multicenter trial
voir . This concept also became adapted in the
consisting of 63 patients published in 1990, Mentor inflatable penile prosthesis, described for
mechanical complications included cable breaka- the first time in 1983 [22] (fig. 12).
ge in four instances, and 55 out of 57 patients were
satisfied with the results. The authors were encou-
raged by this preliminary experience, which sho-
wed fewer complications than the inflatable
devices had and especially stressed the features of
excellent bendability, superior concealability, and
perfect rigidity. Longer follow-up, however, and a
larger patient population will be necessary for
final judgement of the quality of this specific devi-
ce [29, 30]. The original Duraphase prosthesis has
been replaced by the Duraphase II prosthesis.

III. INFLATABLE DEVICES

Figure 11: AMS 700 CX – 3 component inflatable penile
After the rather unsuccessful attempts before the implant, consisting of 2 cylinders, a reservoir and a pump to
control erection and deflation. Further explanations – s. text.
1970s (Lash, Loeffler [6-7], the tremendous break-
through in alloplastic surgery for the impotent men
came in February 1973 when the first inflatable
penile prosthesis was implanted by Scott and co-
workers [9]. Already by 1979, 21 physicians had
performed penile implantation in a total of 1243
patients at different centers. The success rate was
91.5%; however, as stated by practically all
authors in this period of time, there was a re-ope-
ration rate of around 30%.
1. THREE-COMPONENT PROSTHESES
From 1973 up to date numerous alterations and
improvements were applied. Today’s device, the
Figure 12: Mentor alpha I 3 component inflantable implant.
AMS 700 CX has apparently mastered the majori- Its charactristics are comparable to the AMS 700 CX device
ty of problems such as kinking of the tubings, (Fig. 11). However, Bioflex polyurethane is used instead of
cylinder wall aneurysms, and unequal filling of the silicone rubber. Further explanations – s. text.

369
The essential difference between the very similar
looking devices, however, is the material: the Men-
tor device is manufactured from Bioflex polyure-
thane, which was quoted to be more durable and
less elastic than silicone. Such material should last
longer and prevent cylinder aneurysms. In 1987 the
results on 202 implantations were reported: Re-ope-
ration was necessary in 8%, of these approximately
50% were due to technical problems, later, the rate
of complications dropped down to 3.5%. Again,
using this device good results were obtained in far
more than 90% [22]. The latest Mentor develop-
ment is the Alpha 1 inflatable penile prosthesis,
which features cylinders and pump that are firmly
connected, leaving only one connector between the
pump and reservoir. This diminishes mechanical
problems [33-34].
The latest improvement in the three-component
inflatable device is the AMS 700 Ultrex penile
prosthesis which expands in circumference from
12 to 18 mm and extends in length within the cor-
pora cavernosa depending on tissue elasticity. This
should give the patient a more natural prosthetic
erection than before. The cylinders consist of an
inner and outer silicone layer and a woven Lycra
and Dacron middle layer. The two-way stretch of
this middle layer permits girth expansion and
length extension.
Recent experience shows that the AMS 700 CX
device has a 5 year mechanical failure rate of 9.1%
while the AMS Ultrex device has a 5 year mecha-
nical failure rate of 35%. [35] Decreased cylinder
survival is the primary reason for the increased fai-
lures seen with the Ultrex prosthesis. In 1993 the
Ultrex cylinders were improved; the magnitude of
improvement in survival with these modified
cylinders remains to be demonstrated.
2. TWO-COMPONENT PROSTHESES
In order to reduce the possibility of mechanical fai-
lure many attempts have been made to reduce com-
ponents, connectors, tubes in the concept of infla-
table devices. Another consideration was the ease of
surgical implantation, to offer a penile implant as
«pre-prepared» as possible so as to reduce fitting,
trimming, and fillings to an acceptable minimum.
The Mentor Mark II prosthesis is an inflatable peni-
le prosthesis which is preassembled and has no
connectors, making any trimming and connecting
procedures unnecessary (Fig. 13). The device,
however, has to be filled interoperatively by the sur-
370
geon. Due to the connectorless one-piece device,
depending on the surgical approach, scrotal and
infrapubic types are available. In this two-compo-
nent device, pump and reservoir are combined as
«resipump.» Twelve differently shaped devices are
offered for individual length fitting. In a Mayo Cli-
nic study of 84 patients followed up to 13 months,
especially the 13-mm prosthesis was seen to be
nearly equal to the three-component devices. Surgi-
cal implantation time was reduced to on average 30
min; complications were similar to other devices,
such as infection (3.6%), removal due to fluid loss
(1.2%), and cylinder erosion (1.2%). The overall
success rate was 95.2%.
The AMS Ambicor prosthesis is a two component
prosthesis produced by American Medical Sys-
tems (fig. 14). This device comes in 3 diameters
(11, 13, and 15mm) and lengths varying from 14
to 22cm. Adjustments between lengths are made
with the addition of rear tip extenders. Experience
with this new prosthesis is still limited.
3. ONE-COMPONENT PROSTHESES
The AMS Hydroflex self-contained penile pros-
thesis consists of two prefilled cylinders. In each
cylinder there is a reservoir at the rear end, an
inflation pump and deflation valve, and finally an
inflation chamber. Through repeated pumping
close to the glans the fluid moves from the rear
reservoir into the inflation chamber and the penis
becomes erect. When continuous pressure is
applied to the deflation valve which is just behind
the inflation pump, the fluid returns in the rear
reservoir, and the penis becomes flaccid. The devi-
ce comes in three different cylinder diameters, 11,
13, and 15 mm, and four different lengths, and all
typical surgical approaches may be used for
implantation. Preliminary clinical implantation
results in 140 patients showed uncomplicated sur-
gery with satisfactory results. A penoscrotal
approach mainly used, in 64%.
The Hydroflex is no longer available; it has been
replaced by the AMS Dynaflex (fig 15). Mechani-
cal device failure was seen in 7.5% of 120 reci-
pients of the Dynaflex prosthesis who were follo-
wed for a mean of 42 months [36], however, fur-
ther clinical experience has to provide proof of
satisfactory function [37-39].
Today, the principle types of penile implants are
the malleable, semi-rigid and (one- to three-com-
ponent) inflatable devices (fig 16). The still exis-
Figure 13: MENTOR MARK II 2 COMPONENT INFLA - Figure 14: AMS-AMBICOR 2 COMPONENT INFLA -
TABLE IMPLANT. Pump and reservoir are combined as TABLE IMPLANT. The device is Available in 3 diameters,
“Resipump” – Further details – s. text from 14 cm to 22 cm in length.

Figure 15: AMS – DYNAFLEX 1 COMPONENT

INFLATABLE IMPLANT. Combining cylinders, pump
and reservoir.

Figure 16: Different penile prosthesis alternatives available in 1999. Principally, 2 types are used: the malleable and infla -
table penile devices.

371
ting requests for further improvements are based
on the patient’s wish for a more and more normal
and «physiological» sex life. However, in the
assessment of success, next to the overall rate
from well above 90% «excellent results» in all
types used, the postoperative complication rates as
well as the chance for necessary repeated surgery
plays an important role.
Looking back to the beginning of penile implants
in the late 1960s and early 1970s it is evident that
an effective treatment choice was already avai-
lable without knowing too much (or anything at
all) about the mechanisms of erections and the
underlying pathophysiology. Only in the last 10-
15 years more and more knowledge has been
gathered to diagnose impotence and to distinguish
the different causes of erectile failure with the pos-
sibility of applying a cause-related therapy such as
intracorporal injections, reconstructive surgery or
venous ligation, shifting the role of penile
implants towards the end of all therapeutic efforts.
It is fair to say today that alloplastics should only
be discussed after all other therapeutic modalities
have failed or if the patient refuses one of the less
invasive or reconstructive treatment modalities.
The «mechanical success» rate following penile
implant at around 95% is excellent, and more and
more data are available indicating that patients and
partners are handling their sex lives very well,
even in impotence following spinal cord injury.
Still, more efforts should be devoted to the psy-
chological impact for patient and partner, and
sophisticated pre-, peri- and postoperative guidan-
ce for both partners is mandatory [40-43].
IV. SURGICAL TECHNIQUES
Different «classical» surgical approaches are
known which are more-or-less compatible and
may be used for the majority of the devices. The
choice of approach is finally based on the sur-
geon’s own experience; no general rule can be
established advocating one or the other specific
access. The surgical approaches are:
INFRAPUBICAL especially suitable for the
inflatable ( 3-component)
device
372
PENOSCROTAL also suitable for the infla-
table (3-component) device
(choice between infrapubic
and penoscrotal approaches
depends on the preference
of the surgeon)
MIDSHAFT in corpora fibrose and re-
operations
SUBCORONAL especially suitable for the
malleable device
PERINEAL only recommended if
crural identification is
necessary ( reop´s)
Small and Carrion initially suggested the perineal
approach. This, however, became more and more
abandoned due to the fact that perineally, the asep-
tic conditions are not the best and postoperative
wound care is more difficult.. On the other hand,
the most critical area of implantation is the distal
end of the corpora cavernosa underneath the glans.
Starting perineally, the corporal dilatation has to
be carried out a rather long way to the distal end,
and control of dilatation and prosthesis insertion
may be more difficult. Therefore, this technique
should be reserved only to those cases, where cru-
ral identification ( following e.g. perforation ) is
necessary. If an inflatable device is used, the infra-
pubic approach seems to be appropriate, since all
components may be positioned from one incision.
This is also true for the penoscrotal incision;
however, only in case of a revision or in difficult
situation, a catheter should be placed during sur-
gery to avoid injury to the urethra. Criticism has
been made concerning the subcoronal approach,
generally a hemicircular incision in the sulcus
coronarius. It has been suggested that this approa-
ch may lead to injury of nerve supply with subse-
quent loss of sensitivity. This does not hold since
all interventions along the corporus cavernosum
are carried out in a longitudinal fashion, thus avoi-
ding trauma to the nerves and vessels by pushing
them away. The approach used by the one of the
authors (U.J.) is the subcoronal approach, which
has been applied in more than 300 cases. It is seen
as the method of first choice since no catheter is
necessary during implantation, and there is practi-
cally no visible scar left behind after surgery. The
implantation of a penile implant (first surgery) in a
non-fibrotic corpora does normally not cause any
problems and may even be performed under local
anaesthesia. However, it may be difficult follo-
wing previous surgery, after priapism or in trauma
patients when the corpora are fully or partially no
longer existing. In these patients the fibrotic cor-
pora may need to be cored or lyodura or vascular
prostheses used to cover the penile implant and
prevent proximal and distal migration. It also may
be difficult to dilate the corpora, or it may even be
almost impossible after repeated surgery and/or
infection or after priapism. In these cases a small
blade knife or the Otis urethrotom may be used to
core the corpus prior to dilatation.
For these manoeuvres it is wise to scalp the whole
penis down to the base, or if necessary through a
second infrapubic incision, in order to have good
control during corporal dilatation. In case of the
«Concorde» deformity surgical reposition of the
glans may be necessary. In patients with Peyro-
nie’s disease the malleable devices seem to be
superior to the inflatable ones in straightening the
deformity. Excising the plaques is generally not
necessary, still incising the plaques and inserting a
reinforced device, is a good alternative, even a
Gore-Tec patch might be unnecessary. However, if
one wishes to implant an inflatable prosthesis in a
man with Peyronie’s disease, the AMS 700 CX
prosthesis should be used rather than the AMS
Ultrex as CX cylinders will usually straighten the
penis without incision or excision of the plaque.
[44] Another very specific indication may be the
paraplegic patient who may need a malleable devi-
ce in order to give a better support for the condom
urinal [10, 16, 45-53].
V. COMPLICATIONS FOLLOWING
PENILE IMPLANTATION
Prosthetic infection is the most problematic com-
plication following surgery since the combination
of infection and foreign body requires removal of
the prosthesis; after 3 months of good healing,
however, a re-implantation may be done. The
patients most affected with infection problems are
the diabetics where special care must be taken to
avoid wound healing problems. The author’s own
373
experience has shown that local or systemic anti-
biotic treatment is completely unsuccessful if the
device is infected. Therefore, especially when the
device communicates through the open wound,
removal is the only possible treatment in order to
avoid septic exacerbation. In these cases place-
ment of suction drains may be useful. If, especial-
ly in case of the diabetic patient, the infection is
not controlled efficiently after removal of the devi-
ce, necrosis of the corpora may develop. This fact
further backs the absolute need for removal of an
infected device as soon as possible. The postope-
rative complication rates due to infection descri-
bed in the literature are seen to be as high as 8.3%.
Therefore specific attention has to be given to
preoperative preparation, intra-operative handling
and postoperative care [54-59].
Because penile prosthesis re-implantation after
removal of an infected prosthesis is often associa-
ted with significant difficulties due to fibrotic cor-
pora, there has been recent attention given to sal-
vage procedures. In these procedures the entire
infected device is removed and then the operative
area is copiously irrigated with antibiotic solution,
half strength hydrogen peroxide, and then half
strength Betadine solution. The patient is then re-
prepped and re-draped, the surgical team scrubs
and re-gowns and re-gloves, and then a new pros-
thesis is implanted using fresh instruments. Using
this protocol, Brant and Mulcahy were able to
achieve success in 10 of 11 patients (91%) with
mean follow-up of 21 months. [60]
VI. POSTOPERATIVE
MANAGEMENT
Once the devices have healed nicely, there are no
further problems to be expected besides infection
(see above) and erosion. An infection certainly
will provoke an erosion. The most crucial point for
an implant perforation is the distal end of the devi-
ce. The patient has to be informed to use the devi-
ce in a «physiological» manner, he has to be aware
that the friction during intercourse is an important
factor to provoke perforation of the prosthesis. If
the partner has no vaginal secretion during sexual
stimulation, a lubricant may be advisable.
Exact intra-operative length measurement is man-
datory: if the device is too long, post-operative
pain and finally prosthesis erosion may result.
However in too short a device, the «Concorde»
deformity with kinking of the glans during inter-
course may occur and perforation laterally through
the corpus cavernosum may be possible .
Endoscopy is possible after implantation, espe-
cially if an inflatable device has been implanted.
With a malleable prosthesis, the length of the penis
may be the limiting factor of endoscopy. Special
long instruments are commercially available
(Storz); however, the penis may also be twisted
around up to 270° for endoscopic work-up. Final-
ly, a perineal urethrotomy might be needed eg. to
perform a TUR B/P. This shortens the penis and
enables the examination, still it may become pro-
blematic if, for example, a tumour at the bladder-
dome has to be resected.
Prosthesis re-implantation may be necessary for
different problems. The data from the literature
show that re-implantation may also lead to satis-
fying results. However, due to scarring and fibro-
sis, the penis can shorten, therefore the first surgi-
cal attempt still offers the most promising results
[61-64].
Due to more and more sophisticated diagnostic
techniques, the specific causes of impotence can
be identified and a cause-related therapy will fol-
low. Due to the fact that treatment modalities
which are not or minimally invasive or surgically
reconstructive procedures are available, these
modalities should be used before considering the
implantation of a penile prosthesis. Nevertheless
penile implants still offer the best rate of success,
over 95% - inclusively partner’s satisfaction-,
independent of etiology or the type of prosthesis
374
used. The inflatable devices are the most elegant
and the ones which best imitate physiological
behaviour; however, they are still biased by the
possibility of mechanical failure. Therefore the
different types of devices must be presented to the
patient prior to surgery, and he should decide what
type of prosthesis he would like to have implanted,
after being fully informed of the advantages and
disadvantages of the individual types. In case of
complications or after removal of the device, re-
implantation is possible. This, however, requires a
more difficult surgical procedure with a decreased
chance of success. Proper indication, careful
patient selection, and sophisticated postoperative
control not only of the mechanical aspects but also
of the psychogenic impact is mandatory to fulfil
the patient’s and his partner’s need of sexual satis-
faction. However, the expectations of both the
patient and his partner are often too high and both
must learn to cope with the new situation.
In the judgement of postop. success it is important
to give the patients a realistic scenario of outcome
in order to bring his expectations in realistic range,
CONCLUSIONS
Penile implants are the last resort of treatment
despite the fact that with this type of surgery,
still the best outcome might be expected, Howe-
ver, only +/- 10% of all patients with erectile
dysfunction finally will receive an alloplastic
implant.

D. PENILE INJURIES: THE
ROLE OF EARLY SURGICAL
INTERVENTION IN
PREVENTING ERECTILE
DYSFUNCTION
I. INTRODUCTION
The mammalian penis is remarkably resistant to
injury; by allowing alternation between flaccidity
and rigidity, vascular erection provides protection
from serious injury to a structure vital to repro-
duction. The NIH Consensus Conference on
Impotence recognised that penile or pelvic trauma
can be an important cause of erectile dysfunc -
tion. [1] Penile amputation represents the most
severe injury requiring surgical intervention to
preserve function, but numerous penile injuries
may lead to erectile dysfunction. Whereas injuries
to the erect penis occur during intercourse, injury
to the flaccid penis is rare, mainly occurring as a
result of penetrating trauma and machinery acci-
dents. The rise in violent crimes has been paralle-
led by an increase in genital injury, which have the
potential to damage normal erectile mechanisms.
Still more epidemiological research is essential to
further understand the distribution as well as the
prevalence of ED as a result of surgery and trau-
ma. [2]
Mechanism of injury allows a general classifica -
tion of urogenital trauma causing erectile dys -
function.
1. Penile fracture, a unique injury of the tunica
albuginea which occurs only with full penile
rigidity
2. Penetrating trauma to the corpora cavernosa,
commonly associated with urethral and other
genital injuries.
3. Penile Amputation
4. Blunt penile, perineal, or pelvic trauma, which
may lead to arterial injury, neuropathic dys-
function, and high flow priapism.
Of these four injuries, penile fracture is the most
studied. Recovery of erectile function can be
expected after such injuries, and by extrapolation
after penetrating injury. Remarkably, many cases
375
of penile replantation successfully restore penile
erection. Unfortunately blunt injuries may be a
major cause of ED in young men but are usually
not amenable to early surgical correction.
II. PENILE FRACTURE
Penile fracture is a traumatic injury which, when
untreated, can lead to erectile dysfunction and
penile deformity. First reported approximately
1000 years ago by Abul Kasem, an Arab physician
in Cordoba Spain [3], this injury remains per-
plexing to the lay public and many physicians. The
injury is perceived to be uncommon, but many
cases are probably not reported in the literature.
[4] No prospective trials exist determining the
most appropriate management of this entity: case
reports and case series, subject to significant bias,
represent the evidence on which the present analy-
sis is based. [5]
1. MECHANISM OF INJURY
Rupture of the tunica albuginea results from
excessive buckling forces on the erect penis. Full
penile rigidity is necessary for this injury to occur;
one case has been reported after intracavernous
injection therapy. [6] The vast majority of cases
occur as a result of abnormal bending of the
penis during intromission into the vagina ,
although sexual manipulation, masturbation, rol-
ling over during sleep and other explanations have
been reported [7-8]. Increases in intracavernous
pressure due to acute bending, along with the nor-
mal thinning of the tunica with erection, lead to
rupture of the tunica. Acute abrupt loading of the
erect penis causes marked increases in intracaver-
nous pressure, with pressures exceeding 450 mm
Hg [9]. The normal thickness of the tunica when
flaccid varies from 0.8 to 2.2 mm, and is reduced
to 0.25 to 0.5 mm with normal erection. [10-11]
The ruptures occur at areas of stress and weakness,
commonly in the ventral and lateral pendulous
penis adjacent to the urethra, where the tunica is
thinner and weaker than other areas [12].
The tears in the tunica tend to be unilateral, trans-
versely oriented, and lead to haematoma forma-
tion, swelling, and skin discoloration [13]. Occa-
sionally both corpora are injured; urethral injury
has been reported with enough frequency to war -
rant a high index of suspicion [10, 14-16].
2. PATHOPHYSIOLOGY OF SEXUAL
DYSFUNCTION AFTER PENILE FRACTURE
Non-operative management was the mainstay of
treatment in the 1950’s, but the preponderance of
evidence based on over 500 cases reported in the
world literature suggests that surgical therapy
leads to better outcomes. Disruption of the tunica
albuginea of the corpus cavernosum may lead to
penile deformity and erectile dysfunction. The
unrepaired defect in the corpus cavernosum and
unevacuated haematoma are postulated to lead to
inflammation and fibrosis of the tunica. [7]
The resultant loss of tunical elasticity after trauma
can cause penile angulation and painful erection
similar to Peyronie’s disease. The incidence of this
complication is considerably higher in cases trea-
ted non-operatively than in surgically managed
patients. Although no prospective comparison has
been carried out, several investigators have com-
pared individual surgical series with historical
controls from the literature. Overall, the complica-
tion rate of operative intervention is very low, with
persistent angulation ranging from 2 to 15%. [8,
13, 17-20]
In contrast, significant numbers of men treated
non-operatively may develop angulation and coi -
tal (21) difficulty. The complication rate, inclu-
ding abscess, angulation, and need for subse-
quent surgery ranges from 39 to 53%. [13, 20]
Resumption of sexual intercourse is rapid after
surgical repair: in one series, mean time to sexual
activity was 13 days [18], and long-term erectile
dysfunction has not been reported. [8-14, 18-20,
22-26]
A more potentially serious complication of penile
fracture is damage to underlying corpus caverno-
sum vascular mechanisms. Site-specific veno-
occlusive dysfunction, arteriovenous fistulae,
and pseudoaneurysms all have been reported
after non-operative management of penile frac -
ture. [9, 26] Damage to the cavernous arterial sys-
tem as a result of the blunt trauma of penile frac-
ture may lead to arteriovenous fistula or pseudoa-
neurysmal vascular anomalies (fig. 17, 18), both
of which may impair normal penile erection. [26-
27] Penson et al (9) hypothesise that the focally
damaged tunica fails to provide an adequate back-
wall for subtunical venule compression, thus
376
contributing to the development of site specific
venous leakage. A second hypothesis for focal ven
o-occlusive dysfunction is the development of
focal poorly compliant areas of erectile tissue due
to intracavernous trauma. [9]
Thus, based on the existing data, immediate sur -
gical intervention in cases of suspected penile
fracture is likely to prevent the rare occurrence
of erectile dysfunction and reduce the incidence
of post-operative fibrosis and penile angulation.
In addition, evacuation of the haematoma and clo-
sure of the tunical defect should reduce post-ope-
rative convalescence and allow a shorter hospitali-
sation with less need for analgesics. [13]
3. CLINICAL PRESENTATION
The classic presentation of penile fracture
includes missed intromission, acute bending of
the penis, and a snapping or popping sound fol-
lowed by acute pain and immediate detumescen-
ce. The patients develop penile swelling which is
usually limited by Buck’s fascia to the shaft of
the penis. Deviation of the penis away from the
injured corpus is an inconsistent finding. Occa-
sionally, if the integrity of Buck’s fascia has been
violated, scrotal and perineal ecchymosis is seen.
A delay in presentation is not uncommon due to
embarrassment on the part of the patient; voiding
difficulties or haematuria prompt earlier evalua-
tion.
Urination is usually unimpeded unless an associa-
ted urethral injury is present, although compres-
sion of the urethra by haematoma may lead to obs-
tructive urinary symptoms or even urinary reten-
tion. [13, 28-29] The inability to void, gross hae -
maturia, or blood at the meatus are suggestive of
urethral injury and warrant further investiga -
tion.
4. DIAGNOSIS
The diagnosis of penile fracture is based on care-
ful history and physical examination. The combi-
nation of acute bending of the penis with pain,
sudden detumescence, and a haematoma is classic
and warrants surgical exploration (fig. 19).
Because the morbidity of exploration is no greater
than the morbidity of non-operative treatment, and
because imaging techniques can miss injuries [7],
radiographic studies are not routinely advocated
A B

Figure 17: Delayed presentation of penile fracture. A: Colour Duplex Doppler ultrasonography demonstrating large pseu -
doaneurysmal dilatation of the corpus cavernosum B: Operative appearance of corporal pseudoaneurysms. (courtesy of Gre -
gory A. Broderick, M.D.)

Figure 18: Duplex colour Doppler demonstrating abnor - Figure. 19: Ecchymotic appearance of penile shaft after
mal arteriovenous fistula after blunt penile injury documented penile fracture

377
to diagnose penile fracture or localise the site of sum is identified by active bleeding and a defect in
rupture. Rarely a ruptured or torn superficial or the fibrous tunica albuginea (fig. 20). Careful
deep dorsal vein may simulate fracture [19], but exploration and inspection of the corpus spongio-
the overwhelming majority of men with this sce- sum is mandatory, even if urethrography shows no
nario will have a tear in the tunica albuginea. extravasation. Catheterisation of the urethra under
direct vision, once the penis is degloved, allows
No well-designed, prospective studies exist to
easy identification of any defects, and prevents
define the appropriate use of radiographic tech-
further trauma in cases of partial urethral injury.
niques in the evaluation of penile fracture; thus at
[7] Tears to both the cavernosum and urethra are
the present time imaging studies should play a
generally transversely oriented and should be clo-
limited role in the evaluation of the suspected
sed in this same direction. Tunical ruptures some-
penile fracture. Cavernosography, ultrasonogra-
times extend behind the spongiosum and this
phy, and magnetic resonance imaging have been
structure may need to be mobilised and retracted
used to make the diagnosis of penile fracture [31-
in order to completely close the defect.
35]. Limited availability and dependence on expe-
rienced radiological interpretation make these Interrupted slowly absorbable sutures (3-0 or 4-
modalities of variable utility in the evaluation and 0) allow a strong hemostatic closure of the tuni -
management of penile fracture. Because virtually ca albuginea. Debridement and curettage have
all tears in the tunica can be identified and repai- been used in some series, but generally should be
red through a circumferential penile incision, the
use of cavernosography to lateralise the site of the
corporal injury is unnecessary. Advocates of a
direct incision over the site of rupture may find
this modality preferable to physical examination
alone.
In cases of suspected urethral injury (haematuria,
blood at the meatus, inability to void), retrograde
urethrography should be performed to document
the injury. If, as advocated by the authors, all
patients thought to have a penile fracture are
explored, passage of a catheter on the operative
field with inspection of the pendulous urethra
allows identification and primary repair of a lace-
rated or transected urethra.

5. SURGICAL REPAIR
Once the diagnosis of penile fracture has been
made on clinical grounds, prompt surgical explo -
ration is indicated. The patient is anaesthetised in
the supine position; a single dose of prophylactic
antibiotic is recommended prior to incision. In
cases of suspected or documented urethral injury,
the patient should not be allowed to void prior to
surgery to eliminate potential urinary extravasa-
tion.
A circumferential subcoronal incision allows ade-
quate exposure for corporal and urethral repair.
Once through the tunica dartos, the superficial Figure 20: Operative appearance of tear in tunica albugi -
layers and skin are bluntly degloved back to the nea due to penile fracture
base of the penis. Rupture of the corpus caverno-

378
reserved for late presentations after organisation of
the haematoma has progressed. In cases of urethral
injury, experience with penetrating injuries has
shown that a sutured closure is preferable to
simple urinary diversion with a urethral or supra-
pubic catheter. [36] Thus transverse closure of a
urethral laceration in one or two layers is recom-
mended. Fine interrupted slowly absorbable sutu-
re will minimise the likelihood of stricture forma-
tion. Extensive mobilisation of the urethra is gene-
rally not necessary since no tissue loss occurs with
these lacerations or transections.
Skin closure with interrupted chromic sutures pro-
vides a cosmetic incision and allows drainage of
residual blood between the sutures. A lightly com-
pressive dressing is sufficient; tight wraps may
lead to ischaemic necrosis of the swollen shaft
skin. Erections return quickly. Pharmacological
therapy to inhibit erections is probably unnecessa-
ry; an ice pack at the bedside can be used to cause
detumescence for painful nocturnal erections.
Patients should refrain from sexual intercourse for
1 month. In the event of a urethral injury, urethral
catheterisation for 3 weeks is sufficient urinary
diversion. A voiding cysto-urethrogram is recom-
mended to document resolution of extravasation.
III. PENETRATING INJURIES OF
THE PENIS
Penetrating genital trauma is increasing, both due
to the rise in civilian injuries, the advent of the
bullet-proof vest, and the exceptional destructive
power of modern explosives. While the flak jacket
prevents lethal chest and abdominal wounds, it
was associated with more bullet and shrapnel inju-
ries of the genitalia as reported in the Gulf war.
[37] In the war in Croatia, among those with uro-
genital trauma penile injury occurred in 9.15%.
[38]
As a rule all penetrating injuries to the penis
should be explored and repaired. Injury to the
tunica albuginea causes the same pathophysiolo -
gical changes seen in penile fracture, but the
likelihood of underlying corporal damage is
much greater . [39] Penetrating trauma can result
in traumatic occlusion of multiple arteries in the
hypogastric-cavernous bed. [39] Prompt repair of
379
the tunica is important, but associated urethral,
scrotal, pelvic, gastrointestinal and vascular inju-
ries make the management of these injuries much
more complex and are beyond the scope of this
review. [40]
The incidence of erectile dysfunction after pene-
trating injury is difficult to determine. Post-opera-
tive follow-up is notoriously difficult. Anecdotal
evidence of favourable outcomes with a non-ope-
rative approach should be viewed with a degree of
scepticism. Gunshot wounds to the penis vary
from the simple through and through injury of a
low calibre weapon to the tissue devitalization and
destruction due to high velocity close range
wounds (fig. 21, 22) If considerable loss of corpo-
ral tissue occurs, erectile dysfunction has been
reported. [36, 41]
A review of 65 penile injuries from Ben Taub Hos-
pital revealed a 67% incidence of injury to the cor-
pus cavernosum and a 32% incidence of urethral
injury. [42] No erectile dysfunction was reported in
the 40% of patients returning for follow-up. Gomez
et al reported normal erections in 6 patients who
underwent primary closure of corporal gunshot
wounds. [40] In a series of 26 patients with penile
gunshot injuries, all those returning for follow-up
had normal erections. [43] All but two underwent
exploration and repair, while the 2 managed non-
operatively had “minimal injuries” and did well.
Another large series concluded that good functional
integrity of the male genitalia after gunshot injury
can be maintained by following a strict diagnostic
and therapeutic regimen. [44]
In summary, penetrating injuries to the penis and
perineum may have a profound impact on sexual
function. Mechanism of injury clearly plays a role
in determining outcomes: low velocity gunshot
and stab wounds are not likely to cause permanent
erectile dysfunction if corporal injuries are closed
in an expeditious fashion. Large calibre weapons,
however, are more likely to lead to long-term
impairment. Management should be primarily
centred on identifying major associated injuries
of the lower urinary tract and bowel. Surgical
exploration and primary closure of corporal inju-
ries is the cornerstone of therapy. Non-operative
management should be reserved for cases in which
potentially life-threatening injuries preclude peni-
le exploration.
 Fig. 21: Low velocity gunshot wound to
the penis: A: shaft entry wound;

B: Through and through tunical inju -

ries before primary closure.

Figure 22: Gunshot wound of

glans with significant tissue injury.

380
• SURGICAL APPROACH
Penetrating injuries are usually explored through a
circumferential incision in a manner similar to
penile fracture. [45] Control of hemostasis is
achieved by closure of corporal defects; with large
glans injuries manual compression of the shaft
will usually allow repair in a clear field.. Unless
major contamination is present, the vast majority
of all gunshot and stab wounds can be closed pri -
marily at all levels. The vascularity of the skin and
glans is so abundant that healing is quite reliable. Figure 23: Photograph of amputated penis prior to replan -
tation. A Foley catheter has been placed through the ure -
Deeper injuries, proximal to the suspensory liga- thra in anticipation of re-anastomosis.
ment or in the crura, may require a penoscrotal or
perineal incision to gain access to the corpus skin and the possibility of a sensate glans and
cavernosum. Skin defects can often be closed pri- normal orgasmic function.
marily, although in close range shotgun blasts it
Reviews of the literature shows the advantages of
may be necessary to bury the denuded penis in the
the microsurgical technique, but also the astoni-
scrotum until subsequent grafting procedures can
shing results by the former, conventional tech-
be carried out.
nique of corporal reattachment without re-anasto-
mosis of the dorsal neurovascular structures.
IV. PENILE AMPUTATION Many of these men will have return of normal
erectile function. [46, 52-56]
Penile amputation, whether due to self-mutilation
or felonious assault at the hands of a jealous lover,
• SURGICAL APPROACH
is a catastrophic event (fig. 23). [46] Penile replan- Microsurgical replantation differs from simple
tation, first reported by Ehrich in 1929, has a very corporal reattachment in that the dorsal neurovas-
high likelihood of restoring erections [47]. cular structures are re-anastomosed in addition to
The advent of microscopic reconstruction now also urethral and tunical suturing. With corporal reat-
a l l ow s restoration of sensation and orgasmic tachment, a spatulated end to end urethral anasto-
function. [48-49] mosis is first performed with fine slowly absor-
bable suture over a urethral catheter. The adventi-
Preservation of the amputated phallus is critical
tia of the corpus spongiosum is re-approximated,
to successful restoration of function. The amputa-
after which the tunica albuginea and its septum are
ted part should be placed on saline-soaked gauze
also connected. [46] The corporal circulation
inside a clean bag, which is then sealed and placed
usually allows preservation of distal corpora, glans
inside a second bag of ice slush. [46] Cold ischae-
and urethra. Ischaemic skin loss is not uncommon
mia times greater than 24 hours are not unreaso-
without re-anastomosis of the dorsal artery and
nable, allowing most patients to be transported to a
vein. When microsurgical techniques are avai-
centre where replantation can be performed. Even
lable, the dorsal nerves, arteries, and the deep dor-
at normal temperatures, replantation 16 hours
sal vein are each re-anastomosed with fine non-
after injury has been successful. [50] absorbable suture. Meticulous closure of the
Microsurgical replantation was first reported in remaining dartos layer and skin completes the
1977 and numerous authors have documented that repair (fig. 24). Temporary ectopic replantation of
sexual function can be preserved. Erection has the penis is a useful salvage procedure when the
been documented by patient report, nocturnal perineum is heavily contaminated or too extensi-
penile tumescence, and more sophisticated testing vely damaged for immediate replantation. [58]
with corpus cavernosum electromyography. [51- Post operative care includes urinary diversion, bed
56] The advantages of microsurgical techniques rest, hydration, and monitoring of arterial flow in
include better preservation of the penile shaft the distal penis.

381

Figure 24: Postoperative appearance after microsurgical
reattachment of amputated penis.
V. BLUNT TRAUMAAND ERECTILE
DYSFUNCTION
Seemingly minor blunt injuries to the penis, peri-
neum, and pelvis may play a more important role
in the pathogenesis of erectile dysfunction than
presently recognised. [9, 59-62]
Pelvic fracture with prostatomembranous ure -
thral disruption is associated with a significant
incidence of ED which is related to the injury
itself and not therapies aimed at restoring urethral
continuity. [63] Up to half of men with this injury
have ED [64], and vasculogenic and neurogenic
aetiologies may be involved. [59]
Embolisation of the pudendal cavernous arterial
tree may also lead to impairments of penile erec -
tion. Selective embolisation of the internal puden-
dal artery to control pelvic haemorrhage may fur-
ther impair arterial inflow into the penis in men
with pelvic fractures (fig. 25 a+b). Blunt injury to
the penis can lead to high-flow priapism (fig. 26).
Embolisation of abnormal post-traumatic arterial
structures, while useful in controlling the abnor-
mal arterial inflow or bleeding, may lead to erecti-
le dysfunction.
Men with a history of trauma to the flaccid penis
may have haemodynamic abnormalities, which
included site specific venous leakage and arterial
insufficiency (fig. 27). [9, 65] A history of blunt
trauma to the penis was elicited in 37% of impo-
tent men versus only 11% of an age matched
control group. [62] Straddle injury is an obvious
mechanism by which penile vascular injury might
382
occur. A controversial but under-studied problem
is the significance of bicycle-riding associated ED.
Researchers at Boston University have documen-
ted a correlation between incidence of erectile
complaints and hours per week of bike riding. [66]
A cohort of men with ED related to cycling proba-
bly does exist, and both acute perineal crush inju-
ries and chronic compression can lead to vascular
and possibly neural pathologies. [67]
The common thread of these seemingly disparate
entities is that, unlike a penile fracture or gunshot
wound, surgical intervention plays no role in pre -
venting the development of erectile dysfunction
after blunt injury. The mechanisms of injury are
diverse, and include arterial and neural damage as
the pathophysiological process leading to ED. Ini-
tial management is non-operative, and if ED does
develop after the injury, detailed evaluation may
be indicated to identify correctable causes.
VI. CONCLUSION ( TABLE 4)
Acute injuries to the tunica albuginea, regard-
less of mechanism of injury, are best managed by
immediate repair. Failure to treat such injuries
may lead to angulation and erectile dysfunction
due to tunical fibrosis and site specific venous
leakage. Thus penile fracture as well as penetra-
ting injures do not need extensive diagnostic tes-
ting; the morbidity of a non-operative approach
appears to be greater than the operation itself.
Expeditious repair significantly reduces the like-
lihood of deformity and erectile dysfunction.
Penile amputation, while catastrophic, if reatta-
ched within 24 hours, has remarkably good out-
comes both cosmetically and functionally. Even
if the organ cannot be cooled and microsurgical
re-anastomosis is not possible, corporal reat-
tachment should preserve erectile function.
Finally, blunt injuries to the penis, perineum,
and pelvis represent a divergent group of clini-
cal entities that do not benefit from early surgi-
cal intervention. Efforts at prevention, and a
better understanding of the pathophysiology
leading to erectile dysfunction, may improve
outcomes for these younger men.
 B

Figure 25: Arteriogram of patient with pelvic fracture, urethral dis -

ruption, and bleeding due to lacerated internal pudendal artery.
A: prior to embolisation. (see arrow)
B: post embolisation with coils. (see arrow)

Figure 26: Colour Doppler of penis in

patient with high flow priapism due to
blunt penile trauma. Transverse of penis
demonstrating abnormal arterial blood
pooling in right corpus cavernosum.
Arteriography of right internal pudendal
artery was subsequently performed and
selective embolisation carried out.

383
Figure 27: Cavernosogram revealing right sided site specific venous leakage in young man who suffered pelvic fracture with
right proximal corpus cavernosum injury. Visible cavernosal and crural leak is evident.

Table 4: Traumatic injuries associated with erectile dysfunction

MECHANISM LIKELIHOODE OFED ETIOLOGY OFED MANAGEMENT

PENILE FRACTURE 0-2% Pseudoaneurysm Exploration and Repair

Arteriovenous Fistula
Site-specific CVOD1

PENETRATING PENILE Variable Arterial injury Exploration and repair

INJURIES Site-specific CVOD

PENILE AMPUTATION Very low Lack of sensation penile Immediate replantation

loss

PELVIC FRACTURE 19- 56%[64] Neurogenic Delayed evaluation of

Arteriogenic ED
Site-specfic CVOD

BLUNT INJURYTO unknown but potentially Arterial injury Delayed evaluation of

PERINEUM OR FLACCID important cause Site-specific CVOD ED
PENIS Post-embolization for priapism

1. CVOD: Corporal veno-occlusive dysfunction.

384
 surgical techniques and indications. Case reports
E. PENILE are only included in the analysis if they had or
RECONSTRUCTION have impact on actual or future surgical trends.
The analysis is limited to the fields of neophallus
formation and penile enlargement.

I. INTRODUCTION
II. REVIEW OF THE LITERATURE
ON TECHNIQUES FOR
The field of penile reconstruction is ample and not PHALLOPLASTY
well defined. It may cover topics like penile resto-
ration after traumatic lesions, penile neoformation
The development of techniques for phalloplasty
in intersex abnormalities, neophallus-construction
has paralleled the evolution of flap development in
in transsexual patients and penile enlargement or
reconstructive surgery [ 2] . The plethora of surgi-
elongation in patients with micropenises up to aes-
cal techniques in the literature is nearly as ample
thetic surgical procedures like uncircumcision. In
as in hypospadia repair. At this very moment,
many of these fields it will not be possible to defi-
more than 20 different flaps are recommended for
ne future guide-lines for indications and therapeu-
penile reconstruction[2-5, 6]. All these techniques
tic regiments without close co-operation with lea-
have been used in a broad variety of indications:
ding experts in psychiatry, paediatrics, plastic- and
penile agenesis, penile loss due to trauma or sur-
reconstructive surgery or gynaecology and endo-
gery, micropenis, intersex disorders or female- to -
crinology. This task would overstress the actual
male transsexualism. Whereas in non-transsexual
committee.
males without intersex-disorders scrotum and per-
In the following, only key topics of actual or futu- ineal part of the urethra do not have to be recons-
re numeric relevance in the field of penile recons- tructed, transsexuals and children with intersex
truction shall be discussed. A further obstacle to disorders represent the most challenging groups
the definition of possible standards of care or cli- for genital reconstruction. Phalloplasty has been
nical guide-lines is reflected by the actual rapid recommended as a single-stage operation or as
development in microsurgical tissue transfer tech- multi-stage procedures [ 4, 7, 8, 9]. General agree-
niques and in the new field of extracorporal in ment exists, that even in attempted single-stage
vitro tissue expansion on biodegradable carrier procedures subsequent corrective interventions in
systems. Most of the recent publications on these most cases are necessary [ 8, 10, 11].
techniques refer to small patient groups and lack
The first series of successful phalloplasties has
of long term follow up data. Most studies on peni-
been published in 1936 by Bogoras [12] using a
le reconstruction do not permit a stringent effica-
tubed abdominal flap. During the following
cy-evaluation based on the criteria of evidence-
decades the search for the best method encompas-
based-medicine (EBM) (1). After a profound ana-
sed numerous variations of abdominal flaps, scro-
lysis of all publications on penile reconstruction of
tal skin flaps, tubed thigh flaps , gracilis musculo-
the last ten years (MEDLINE research 1988 –
cutaneous flaps, groin flaps and iliac crest flaps.
1998), no randomised cohort-studies could be
[2, 3, 4, 5, 7, 13, 14 15, 16, 17, 18, 19]. In 1984
found. Even large series containing data of more
Chang and Kao published the first results of neo-
than 50 patients do not permit a potential meta-
phallus formation derived from microsurgically
analysis due to the lack of common inclusion cri-
transplanted free radial forearm flaps [20, 21]. The
teria, common surgical techniques or common
free radial forearm flap had been first described by
parameters for success evaluation. Most relevant
Song for other indications in face and neck surge-
surgical techniques have been published after
ry [ 22] . Laub combined this free flap for urethral
1992, which may explain the lack of long-term
reconstruction with a standard midline abdominal
follow up data.
flap and split-thickness skin grafts, which he later
Thus the task of this report shall be seen in a com- called «Postmodern Phalloplasty» [23]. Others
pilation of expert opinions on a limited number of changed the design of the forearm flap following

385
the „tube-in-a-tube“ principle and used it as a
single flap for both penile and urethral reconstruc-
tion ( 2,3, see fig. 28 a). The availability of micro-
surgical neuro-vascular anastomoses enabled
reconstructive surgeons to look for other less
exposed donor areas for free-flap retrieval, inclu-
ding upper medial arm, upper lateral arm, saphe-
nous, deltoid, latissimus dorsi and fibula osteocu-
taneous flaps [ 2, 3, 24, 25, 26, 27, 28, 29, 30, 31,
32, 33].
The actual variety of free and pedicled flaps used
for phalloplasty suggest that there does not exist
one single technique, which could fulfil all
demands in neopenis formation:
1. A one stage-procedure that can be predictably
reproduced
2. Creation of a competent neo-urethra to allow for
voiding while standing
3. Return of both tactile and erogenous sensibility
4. Enough bulk to tolerate the insertion of a pros-
thetic stiffener
5. A result that is aesthetically acceptable to the
patient
6. Minimal scarring or disfigurement
7. No functional loss in the donor area [3, 4, 8, 13,
24, 34].
In the following, the actually most promising tech-
niques shall be described. Indications are focused
on female-to-male transsexualism, because this
group of patients is assumed to be the most homo-
genous and at the same time numerous one.
The prevalence of transsexualism (ICD –10;
DSM-IV ) seems to rise during the last decades
and differs enormously world-wide. The most
recent information derives from Holland and
amounts a prevalence of 1:11900 for male-to-
female transsexuals and 1:30400 for female-to-
male transsexuals [35]. In the United States,
England and Sweden the incidence of transsexuals
is suspected to be around 1:50.000 overall [3].
Even if epidemiological studies established that a
similar base rate of gender identity disorders exis-
ted all over the world, it is likely that cultural dif-
ferences from one country to another would alter
the behavioural expressions of the disorder [36].
The requirements for genital reconstruction and
386
breast surgery have been defined by the „Harry
Benjamin International Gender Dysphoria Asso-
ciation“ . Actually the fifth version of „ The Stan-
dards of Care“ can be drawn from Draft Nine B
June 15, 1998 under http:// www. symposion.
com/ijt International Journal of Transgenderism
[36].
The most actual information on the desiderata of
female-to-male transsexuals can be drawn from a
study from Amsterdam from 1993 [37]. The
Amsterdam Transgender-Team is in a favourable
position for these surveys, because their data-base
includes information on about 97% of all hormo-
nally treated transsexuals in the Netherlands [35].
A questionnaire was sent to 200 female-to-male
subjects and was returned by 150. 52% of all
female-to-male transsexuals asked for a phallo-
plasty as part of reassignment surgery additional to
breast reduction, hysterectomy and bilateral
oophorectomy. Of these patients 96% desired to
have a scrotum, 92% a glans and 91 % respective-
ly 81% an aesthetically appealing look wearing a
tight swim-suit or being nude. 86% declared their
wish for a intrapenile stiffener or prosthesis and all
but one patient wanted to be able to void in a stan-
ding position [37]. Increasing knowledge by the
subjects on the technical boundaries of phalloplas-
ty will probably increase the percentage of
patients desiring the construction of a completely
functional aesthetically appealing penis [ 4, 8, 10 ]
Patients who do not want a neophallus but only
demand for a more masculine look of their exter-
nal genitalia can be advised to undergo clitoral
advancement and enlargement, combined with
urethral advancement enabling the patient to void
in the standing position. The resultant microphal-
lus depends in its size on the androgen- induced
enlargement of the clitoris after long time contra-
sexual hormonal therapy. The procedure is called
metaidoioplasty and may be combined with the
construction of a bifid scrotum by dorsal transpo-
sition of the labia majora and insertion of testicu-
lar prosthesis [23, 39].
The largest and best documented series has been
published in 1996 referring to the results of metai-
doioplasty in 32 patients operated by the Amster-
dam team [39]. In 20 patients a sufficient follow-
up of 6 to 36 months (average 22 months) was
evaluated. One flap loss and 7 urethrocutaneous
or urethrovaginal fistulae were noted. Urethral
strictures were seen in 3 patients. 50% of all
patients were able to void in a standing position.
Meatoidoioplasty is considered by the author as
the method of choice in cases were the clitoris
seems large enough to provide a phallus that will
satisfy the patient. Although this method repre-
sents the least extended procedure for phalloplas-
ty, it becomes obvious from the complications,
that it requires more than one operative session in
the majority of patients.
With few exceptions [9, 14] there is general agree-
ment, that the more recently introduced microsur-
gical free flap phalloplasties lead to better results,
compared to pedicled flaps [3, 4, 5, 6, 8, 10, 11,
24, 27, 28, 34, 38, 41, 42, 43]. The most com-
monly used free flap for phalloplasty today still is
the radial or ulnar free forearm flap [6, 28]. There
is no agreement on flap design , inclusion of auto -
genous bone, number of operative sessions or
prosthetic material. Most reports deal with inho-
mogeneous patient groups and only few reports
enclose more than 10 patients each. Follow up for
evaluation of success and complications is mostly
incomplete or too short for allowing comparative
conclusions. The following publications were
selected for quantity and quality of information on
patient material and results:
Hage et al published the results of 11 forearm free
flap procedures in transsex patients. Vascular ana-
stomosis had to be revised in two patients, no flap
was lost. Microsurgical nerve anastomoses bet-
ween a clitoral nerve and a subcutaneous forearm
nerve permitted recurrence of tactile sensibility of
the neophallus in all patients. 4 patients regained
erogenous phallic sensibility. The operation was
primarily planned as a two-session procedure,
while in the first session only the perineal part
(fixed part ) of the urethra was reconstructed inclu-
ding a complete vaginectomy [34]. The two-stage-
technique could not prevent the manifestation of
urethral fistulae or stenoses.
Levine et al most recently reported on 15 free
forearm flaps in penile reconstruction. 8 patients
(57 %) developed a neo-urethral stenosis which
required operative repair. Buccal mucosa grafts
showed the best results in fistula repair in this
patient group [40].
387
The largest study on 136 cases of penile recons-
truction has been published in 1995 by Cheng et al
[14]. 93 of these patients received a free radial
forearm flap. None of the patients were trans-
sexuals, the majority underwent phalloplasty for
micropenis ( 50,7%). The authors describe a post-
operative atrophy of the penis loosing from 12 to
21,7% of its circumference. The operation was
performed in one session in the majority of
patients. Even a penile stiffener (autogenous rib
cartilage) was inserted in all phalloplasties imme-
diately. The authors claim that cartilage absorption
did not occur. Only 18 patients developed compli-
cations. 6 partial necroses of the flaps occurred. 7
patients developed urethrocutaneous fistulae. In
53 patients nerve anastomoses to the proximal
stumps of the dorsal penile nerves were perfor-
med. About 20 to 24 months postoperatively 43
patients reported having erogenous sensibility in
their neophalluses. Vibratory sensation and tempe-
rature differentiation was confirmed in these
patients. Overall 77 percent of all patients, who
reported to have a sexual activity, regained sexual
satisfaction. The authors conclude, that the radial
forearm flap, the superficial inferior epigastric
artery flap and the superficial circumflex iliac
artery flap are the flaps of first choice in penile
reconstruction. In a subsequent discussion of the
paper the Amsterdam group lines out, that sensiti-
vity of nerve adapted free flaps is always better
than in pedicled flaps [ 44] . Postoperative atrophy
of free flaps shall be judged cautiously due to
immediate postoperative oedema and swelling
which renders the interpretation of serial circum-
ference measurements difficult.
In 1995 Gilbert et al published their large expe-
rience in 21 patients with ulnar forearm flaps in a
mixed patient group [28]. They used 3 different
flap designs, always incorporating the neo-urethra
in the flap and planning the operation as a one ses-
sion procedure without prosthesis-implantation.
No flap was lost, 7 patients developed urethral
complications. 14 patients regained sensibility in
their neophalluses. 5 of them received a success-
ful insertion of a multicomponent hydraulic pros-
thesis, covered by a Gore-Tex vascular graft.
Fang and co-workers reported on the use of free
forearm flaps without clitoral nerve anastomosis
in 56 patients with female-to-male-transsexualism
[38]. The operation was always done in two ses-
sions, in 28 patients the urethra was prefabricated
by implanting tubed vaginal mucosa into a subcu-
taneous tunnel, created in the radial side of the
forearm.
One flap loss occurred, partial loss was noted in 6
patients. 45 patients developed urethral fistulae or
stenoses. No fistulae were noted in the prefabrica-
ted neo-urethras 40 patients regained tactile sen-
sation of the neopenis. In a most recent report, the
same group summarised their experience with free
radial forearm osteocutaneous flaps in 22 patients
with primary female transsexualism. [64]. The
operation was now performed as a three-stage pro-
cedure and the donor defect was covered with a
pre-expanded abdominal flap. One partial flap loss
and a 40,9% fistula rate respectively 13,7% stric-
ture rate was noted. Significant donor forearm
morbidity and radius bone fracture was noted in
two cases.
In our own group 35 female-to-male transsexuals
have been operated during the last 8 years [10, 45,
52]. All operations were done in one session, using
the radial free forearm flap as only method in this
group. In the same session vaginectomy and scro-
tum reconstruction was performed. (Figures 28 A-
D) 1 flap loss and 2 partial necroses were obser-
ved. 27 patients developed urethral fistulae or ste-
noses which needed one to three operative ses-
sions for repair. Prostheses-implantation has been
done in 15 patients after recurrence of erogenous
sensation. In the first of these implantation-ses-
sions two testicular prosthesis and one penile
cylinder was implanted, covered by a Dacron
sheet [ 46] (figures 29 A, B). Three months later,
the pump replaced one testicular prosthesis and a
reservoir was implanted into the retropubic space
(Figure 29 C). None of the patients regrets to have
undergone these procedures. An infection rate of
20% has to be awaited, following the experience
in complicated prosthesis insertion in impotent
men [47].Tactile and temperature sensitivity retur-
ned in the majority of patients after microsurgical
clitoral dorsal nerve anastomoses, which coincides
with the experience of other authors [14, 28, 41,
42, 43, 48, 49].
Other authors tried to spare prosthesis implanta-
tion to their patients by including autogenous
bone with sufficient vascular supply into the flap
planned for phalloplasty [30, 42].
388
The first report on inclusion of vascularised
radial bone into the forearm free flap was publi-
shed as a case report by Koshima et al in 1986
[49]. Byun et al used a similar segment of radial
bone in 5 patients receiving free forearm flaps for
various indications [42]. 3 patients developed
urethral fistulae and mild to moderate bone
resorption was noted in 2 patients. Fang et al
recently reported a series of 22 neopenis recons-
tructions from free radial forearm osteocutaneous
flaps [64]. One case of consequent radial fractu-
re was noted.
Sadove et al reported on 6 successful osteocuta-
neous fibula flaps in 1993 [30]. In some of these
patients also the neo-urethra was formed from flap
tissue during the one-session procedure. Follo-
wing his recommendations Capelouto et al recent-
ly published a case report on the same procedure,
including a complete segment of the fibula into the
flap. The urethra was prefabricated from full-
thickness-skin and tubed into the flap in a previous
session [26]. The patient experienced no severe
complication or loss of ankle stability.
In 1996 the Amsterdam group published a further
case report on a fibula containing free flap phallo-
plasty, performed in 3 sessions [ 25] . The urethra
had to be prefabricated from full thickness skin,
tubed into the planned flap area. Several interven-
tions were necessary for relief of subsequent ure-
thral stenoses and the patient experienced reduced
ankle stability.
Unlike the phalloplasty results, the donor area
results after radial forearm flap removal are unde-
sirable [34]. The attempt to find more suitable
donor sites led to the development of lateral upper
arm flaps [3, 27, 31, 32, 50, 51].
Recently Khouri published the results of 4 prefa-
bricated lateral arm free flaps in 3 female-to-male
transsexuals and in one man after penile amputa-
tion [27]. In the first session the neo-urethra
constructed from tube skin grafts was embedded
in the region of the lateral arm flap. After 3 to 6
months the flap was raised and a neophallus for-
med and transplanted to the infrapubic area. Infla-
table penile prosthesis were implanted during the
same session without covering them with Gore-
Tex sleeves. All patients needed at least two fur-
ther interventions for complications, in two
patients the prosthetic device was lost.
Figure 28A: Radial forearm-flap based on the radial artery.
Urethra-formation following the “tube-in-a-tube” principle

Figure 28B :Vaginal exstirpation. Formation of the

proximal urethra by an anterior vaginal wall flap, based
at the urethral meatus.

Figure 28C: Schematic drawing of the vascular and nerve

anastomoses needed for penile neo formation from radial
forearm flap; lower epigastric artery, saphenous vein, dor -
sal clitoral nerve and branch of genito-femoral nerve.

Figure 28D: Completed neopenis and neoscrotum forma -

tion from radial forearm flap

389
 Figure 29B: Session I for Prosthesis implantation :
Figure 29A: Schematic drawing of implantation of a multi-
Dacron®-sock with cylinder implanted. Implantation of two
component prosthetic device (Cylinder in a Dacron® -
testicular prosthesis for tissue expansion. ( One testicular
sock).
prosthesis is removed in session II for pump placement ).

Figure 29C : End result after penile reconstruction and prosthesis

implantation . Deflated device (left), inflated device (right).

390

III. CONCLUSIONS
Use of free flaps seems to be the method of choi-
ce for penile reconstruction [ 6, 34]. If a prosthesis
of stiffener is desired, obtaining a phallus with at
least tactile sensibility is a condition of utmost
importance. This condition can best be fulfilled by
selective microsurgical nerve anastomoses to the
clitoral or dorsal penile nerves. Recurrence of tac-
tile or even erogenous sensibility to the neophallus
can be expected in up to 80 % of the cases. Most
experience in phalloplasty using free flaps has
been gained by using the radial or ulnar forearm
flap [6]. The major drawback of this flap is the
visible extended scar formation in the donor area.
Usually motor function of the arm and hand is
fully restored 3 months after flap transplantation.
Long-term reduction of grip strength or cold into-
lerance has not to be expected, as could be shown
in a large series of radial donor site defects [51].
Nevertheless other free flap donor sites to be used
for phalloplasty should be sought [3, 34]. Up to
now no other standard free flap seems superior to
free forearm flaps in penile reconstruction. On the
other hand it should be noted, that pedicle flaps
still remain a valuable option in phalloplasty , if
patients refrain from complicated free flap transfer
and only desire partial aspects of aesthetic and
functional penile reconstruction [8, 9, 14].
Penile reconstruction by free flap phalloplasty can
be done in a one-session or multiple-session pro-
cedure. If all goals of ideal phalloplasty should be
obtained [3, 4, 8, 13, 24, 34] multiple sessions
seem inevitable in the vast majority of patients [8].
Penile prosthesis implantation should not be
undertaken before urethral healing is complete and
sensibility of the neophallus has returned [10].
Apart from the ongoing discussion concerning the
ideal donor area for flap retrieval, several other
topics in penile reconstruction remain obscure
from the actual scientific literature:
1. Shall phalloplasty be recommended in children
with intersex abnormalities or ambiguous geni-
talia ?
2. Shall the urethra be prefabricated before phallo-
plasty ?
3. What is the ideal concept for restoration of erec-
tile function ?
391
ad 1.) Several reports describe the feasibility of
penile reconstruction even in young
infants. Microsurgical flap transfer and
micro-anastomosis of growing vessels can
be accomplished [54, 55, 56, 57]. The
newer possibilities to reconstruct a func-
tional neophallus cast doubt on the former
strategy to reassign children with ambi-
guous genitalia to the female sex [3, 54,
56]. If a phalloplasty in children and ado-
lescents is planned, only somatic growth
of the neophallus has to be expected
during puberty, due to the lack of enzyme
5-α-reductase in the flap tissue. The dis-
parity between the somatic and genital
growth curves has to be factored into the
calculation of the neophallic size [55].
ad 2.) The long distance of neo-urethra, which
has to be reconstructed especially in fema-
le-to-male transsexuals still is the main
source of complications in penile recons-
truction [57]. Actually no consensus exists
on the ideal tissue and timing for urethral
reconstruction. Staged procedures, which
are favoured by some authors cannot eli-
minate the risk of fistula or stenosis for-
mation [8,11, 28]. In vitro growth and
expansion of squamous or urothelial cells
on biodegradable carriers could be a futu-
re solution in this field [59].
ad 3.) Also in this field, future solutions can be
expected from in vitro cartilage expansion
and replantation on absorbable carrier sys-
tems, which recently has been realised in
animal models [58]. Even if synthetic
inflatable prosthesis implantation has led
to unsatisfying results in the hands of
others [60, 61], several reports recommend
this technique in combination with Gore-
Tex or Dacron sleeves for replacement of
the missing tunica albuginea [9, 10, 45, 46,
53, 62, 63 ]. The sleeve should be fixed to
the periosteum in order to eliminate migra-
tion of the prosthesis [63]. The implanta-
tion of inflatable multicomponent prosthe-
tic devices is technically more challenging
but permits superior results in conceal-
ment and rigidity . Protrusion is less pro-
bable in inflatable devices [45, 46, 53, 63].
There exist no data on long-term-function
of these devices in phalloplasty.

F. PENILE ENLARGEMENT
SURGERY
Penile advancement and lengthening have been
used for more than ten years in patients with web-
bed or buried penis, in patients with penile fibrosis
or in patients with spinal cord injury with retrac-
ted phalluses [1-5]. In children with a micropenis,
mostly in connection with the epispadia / exstro-
phy-complex , penile advancement also is a well-
known, beneficial procedure [4, 6-10]. The surgi-
cal steps of the procedure ( excising the fundiform
ligament, suprapubic lipectomy, tacking of the
suprapubic skin to the pubis, division of the sus-
pensory ligament, infrapubic Z-plasty or VY-plas-
ty) have been extensively described in this context
[4]. Nevertheless, there are no conclusive quanti-
tative data on penile length gain in the literature.
Whereas urologists have used these techniques for
many years with the intention to eliminate disease
and to treat deformities, the use in aesthetic surge-
ry in patients without obvious somatic pathology
or deformity is investigational [11].
Recently we have gained reliable data on average
penile length in the flaccid, erect and stretched
state [2, 13-15]. Mean stretched length of the penis
was 12,4 cm in a group of 80 physically normal
men with a mean erect length of 12,9 cm [12]. The
authors consider normal penile dimensions to be
any length within 2 standard deviations of the
mean. Consequently they recommend penile
lengthening procedures only in patients with a
stretched or erect penile length of less than 7,5
cm or in men with a flaccid length of less than 4
cm . Recently a significant and growing number of
men with normal penile dimensions demand peni -
le enhancement surgery, mostly performed by
plastic and reconstructive surgeons [16].
There are no data available from peer-reviewed
journals that contain evidence to support the effi -
cacy of penile enhancement. On the other hand
there is a growing number of reports on compli -
cations and deformities resulting from this kind
of surgery [4, 16-17]. The chief complaints were
poor cosmetic appearance and retraction of the
penis. Also postoperative sexual dysfunction and
numbness of the glans was reported. Most of these
patients needed re-operations for relief of their
complaints. From the scientific literature only one
392
recent report by Gary J. Alter could be found,
which defines actual recommendations on operati-
ve techniques in detail [11].
The author considers a 1-inch gain of penile leng-
th in the flaccid state as postoperative success,
without giving data on success-rates in his patient
material. He claims that this kind of length gain
may only be reached by a complete operative leng-
thening procedure followed by the application of
penile weights of at least 10-pounds, several times
a day for a period of months.
Operative penile lengthening should include an
infrapubic double-Z-plasty , release of the suspen-
sory ligament and incision of restraining bands of
Scarpa’s fascia on both sides. Infra- or suprapubic
liposuction may be seen as an optional procedure.
In order to prevent reattachment of the corpora and
the pubis, the space is filled with a pedicled regio-
nal fat flap.
If girth enhancement of the penis is also desired by
the patient, Alter recommends the interposition of
extended de-epithelialised dermal fat grafts bet-
ween Dartos‘ and Buck’s fascia of the penis. This
procedure shall not be combined with lengthening
procedures. If penile lengthening and girth enhan-
cement is desired, several months should separate
both interventions. There are no reliable data in
the literature on the results after such extended
procedures. Autologous fat injections , which pre-
viously had been recommended for girth enhance-
ment, should be abandoned. There are sufficient
data, that less than 50% of injected fat survives.
The results are unpredictable and severe deformi-
ties have often been reported [4,11, 16-19].
I. CONCLUSION
Penile enlargement surgery has evolved rapidly
during the past 5 years, mostly performed by
plastic and reconstructive surgeons in men
without genital deformities and pathologies.
Peer-reviewed reports on postoperative results
and complications are lacking. Patients must be
informed that these procedures are investigatio-
nal [11]. Penile lengthening oradvancement pro-
cedures in patients with deformities as concealed
or webbed penises, epispadia or exstrophy and
penile fibrosis or scarring may have therapeutic
sense, even if sufficient quantitative data on
postoperative outcome are lacking [2-3, 5, 9, 20].
 SUMMARY & RECOMMENDATIONS

I. MECHANICAL DEVICES 2. PENILE DRUG DELIVERY IMPLANTS

1. VACUUM DEVICES
The use of vacuum devices as part of the conser-
vative management of erectile dysfunction is not
common-place.
Vacuum devices work by creating a negative pres-
sure which increases the blood flow into the cor-
pora cavernosa. The erection is maintained by
trapping the blood in the penis by use of a
constriction ring at the base, cutting off the venous
outflow.
a) Complications
Petechiae skin bruising, especially at the site of
the ring
Pain at the site of the ring.
Ejaculatory changes, including pain on ejaculation
Numbness during erection
Pivoting at the base
b) Satisfaction rate
These implants consist of a cannula which is inser-
ted into the corpus cavernosum and a combined
scrotal reservoir and pump, containing a vaso-acti-
ve drug. Compression of the reservoir pump gives
a bolus of the vaso-active drug into the penile tis-
sue to stimulate an erection. Only few implants
were performed since 1986. It was developed as
an alternative to the self-injection therapy, howe-
ver there is still room for refinements and this pro-
cedure should be considered investigational.
II. VASCULAR SURGERY
Impressive progress in understanding and treat-
ment of impotence occured in the last two
decades. Although most erectile dysfunctions
respond to vacuum device, prostaglandine E1and
sildenafil, vascular surgery is an effective therapy
in selected cases.
It may offer an advantage in men failing in conser-
vative therapy for those not desiring a penile
implant.

Satisfaction rate, both short and long term, varies 1. SURGERY FOR ARTERIAL PATHOLOGY
considerably from as low as 27% to 68% short- The Michal procedure is performed using the
term, to as high as 69% with 2 year follow-up. The inferior epigastric artery. An end-to-side anasto-
reasons for dissatisfaction mainly are : mosis is done between the epigastric artery and the
Inability to maintain proximal part of the dorsal penile artery..In the
full erection 12% DDVA procedure, the epigastric artery is anasto-
mosed end-to-side to the proximal part of the deep
pain 4% dorsal vein. Hauri uses the inferior epigastric arte-
inconvenience/awareness 4% ry, which is anastomosed to one of the dorsal peni-
le arteries and the deep dorsal vein.The results are
marital problems 5%
discussed controversly, ranging between 38% and
partner dissatisfaction with: 79%, showing decline of success with time. Wide-
performance 11% ly used is the VIRAG V procedure, anastomosing
penile temperature 7% the inferior epigastric artery end-to-side to the
deep dorsal vein in combination with ligature of
appearance 13%
the proximal and distal vein and the emissary col-
laterales and the formation of a fistula between
c) Safety
the dorsal vein and the corpus cavernosum,
The devices are safe, as long as the ring applica-
tion is limited to 30 minutes. 2. SURGERY FOR VENOUS PATHOLOGY
The treatment of patients with caverno-venous
insufficiency is based mainly on the reduction of

393
venous outflow during erection. Embolization of IV. PENILE INJURIES: THE ROLE
the deep venous network with detachable balloons OF EARLY SURGICAL INTERVEN-
and coils and surgery are an alternative, but are
TION IN PREVENTING ERECTILE
discussed controversially. The surgical approach
addresses ectopic veins, deep dorsal veins and/or
DYSFUNCTION
cavernous or crural veins. Spongiolysis or peri- The mechanism of injury allows a general classi-
cavernoplasty with or without insertion of a pros- fication of urogenital trauma causing erectile dys-
thetic venous tourniquet has also been proposed. function:
The different surgical procedures described do not
Penile fracture, a unique injury of the tunica
invade the corpora cavernosa and are restricted to
albuginea which occurs only with full penile rigi-
the veins. For this reason, the immediate results are
dity; Penetrating trauma to the corpora caverno-
satisfactory but relapse can be observed a few
sa, commonly associated with urethral and other
months later. Patient selection is also important, and
genital injuries; Penile Amputation; and Blunt
those with arterial disease must be excluded. If the
penile, perineal, or pelvic trauma, which may
arterial inflow is severely reduced, ligation of the
lead to arterial injury, neuropathic dysfunction,
veins does not lead to adequate penile tumescence
and high flow priapism.
for an erection. Such patients might benefit from
deep dorsal vein arterialization if they are younger Acute injuries to the tunica albuginea, regardless
than 55 years but the results are not completely of the mechanism of injury, are best managed by
satisfactory. immediate repair. Failure to treat such injuries
may lead to angulation and erectile dysfunction
It appears that potency remains stable if the effect
due to site specific venous leakage Thus penile
of the surgical treatment persists beyond 6 months.
fracture as well as penetrating injures do not need
Venous surgery should not be restricted solely to
extensive diagnostic testing; the morbidity of a
the veins seen to be opacified on cavernosography
non-operative approach appears to be greater than
but it must be extended to the 3 main drainage
the operation itself. Expeditious repair significant-
routes of the corpora: the deep dorsal vein, the
ly reduces the likelihood of deformity and erectile
cavernous veins and the crural veins (see Algorith
dysfunction. The major problem in non-repaired
for vascular surgery).
cases is erectile deformity due to plaques.
Microvascular arterial bypass- and venous liga-
Penile amputation, while catastrophic, if reatta-
tion surgery may achieve the goal of increasing
ched within 24 hours, has remarkably good out-
arterial inflow and improving veno-occlusion.
comes both cosmetically and functionally. Even if
Certain young patients may be candidates for sur-
the organ cannot be cooled and microsurgical rea-
gical cure or improvement of ED. These patients
nastomosis is not possible, corporal reattachment
must be evaluated by specialized testing and
should preserve erectile function. Finally, blunt
should be treated at centers capable of providing
injuries to the penis, perineum, and pelvis repre-
both longitudinal followup, if possible within
sent a divergent group of clinical entities which do
research protocols.
not benefit from early surgical intervention.
Efforts at prevention, and a better understanding
III. PENILE IMPLANTS of the pathophysiology leading to erectile dys-
function, may improve outcomes for these youn-
Principally, 2 different types of implants are avai- ger men. Table 4 summarizes the correlation bet-
lable today: the malleable and inflatable penile ween traumatic injury and erectile dysfunction
devices, the devices available 1999 are (Fig. 29):
Complications are seen in 16 %, the overall suc- V. PENILE RECONSTRUCTION
cess rate is between 70 and 98%. Penile implats
are the last resort of treatment despite the fact that
The field of penile reconstruction is ample and not
with this type of surgery, still the best outcome
well defined. It may cover topics like penile res-
might be expected, However, only +/- 10% of all
tauration after traumatic lesions, penile neoforma-
patients with erectile dysfunction finally will
tion in intersex abnormalities, neophallus-
receive an alloplastic implant.

394
Table 4: Traumatic injuries associated with erectile dysfunction

MECHANISM LIKELIHOODE OFED ETIOLOGY OFED MANAGEMENT

PENILE FRACTURE 0-2% Pseudoaneurysm AV Exploration and Repair

Fistula
Site-specific CVOD1

PENETRATING PENILE Variable Arterial injury Exploration and repair

INJURIES Site-specific CVOD

PENILE AMPUTATION Very low Lack of sensation penile Immediate replantation

loss

PELVIC FRACTURE 19- 56% [64] Neurogenic Delayed evaluation of

Arteriogenic ED
Site-specfic CVOD

BLUNT INJURYTO anknown but potentially Arterial injury Delayed evaluation of

PERINEUM OR FLACCID important cause Site-specific CVOD ED
PENIS Post-embolization for priapism

1. CVOD: Corporal veno-occlusive dysfunction.

construction in transsexual patients and penile
enlargement or elongation in patients with micro-
penises up to esthetic surgical procedures like
uncircumcision. In many of these fields it will not
be possible to define future guide-lines for indica-
tions and therapeutic regiments without close
cooperation with leading experts in psychiatry,
pediatrics, plastic- and reconstructive surgery or
gynecology and endocrinology. The use of free
flaps seems to be the method of choice for penile
reconstruction. The restauration of tactile sensibi-
lity can best be fulfilled by selective microsurgi-
cal nerve anastomoses to the clitoral or dorsal
penile nerves. Reoccurence of tactile or even ero-
genous sensibility to the neophallus can be expec-
ted in up to 80 % of the cases. Most experience in
phalloplasty using free flaps has been gained by
using the radial or ulnar forearm flap . The major
drawback of this flap is the visible extended scar
formation in the donor area. Usually motor func-
tion of the arm and hand is fully restored 3 months
after flap transplantation. Longterm reduction of
grip strength or cold intolerance has not to be
expected, as could be shown in a large series of
radial donor site defects. Nevertheless other free
flap donor sites to be used for phalloplasty should
be sought. Up to now no other standard free flap
seems superior to free forearm flaps in penile
reconstruction. On the other hand it should be
noted, that pedicle flaps still remain a valuable
option in phalloplasty, if patients refrain from
complicated free flap transfer and only desire par-
tial aspects of esthetic and functional penile
reconstruction.
Penile reconstruction by free flap phalloplasty can
be done in a one-session or multiple-session pro-
cedure. If all goals of ideal phalloplasty should be
obtained multiple sessions seem inevitable in the
vast majority of patients. Penile prosthesis implan-
tation should not be undertaken before urethral
healing is complete and sensibility of the neophal-
lus has returned.
VI. PENILE ENLARGEMENT
SURGERY
Penile enlargement surgery has evolved rapidly
during the past 5 years, mostly performed by plas-
tic and reconstructive surgeons in men without
genital deformities and pathologies. Peer-reviewed
reports on postoperative results and complications
are lacking. Patients must be informed that these
procedures are investigational. Penile lengthening
or advancement procedures in patients with defor-
mities as concealed or webbed penisses, epispadia
or exstrophy and penile fibrosis or scarring may
have therapeutic sense, even if sufficient quantitati-
ve data on postoperative outcome are lacking.

395
 SUMMARY
Vacuum devices, although not in widespread use
have advantages that they are re-usable, satisfacto-
ry for many patients and safe. They should be kept
available for use and improving design will make
them more userfriendly
Vascular Surgery Microvascular arterial bypass-
and venous ligation surgery may achieve the goal
of increasing arterial inflow and improving veno-
occlusion. Certain young patients may be candi-
dates for surgical cure or improvement of ED.
These patients must be evaluated by specialized
testing and should be treated at centers capable of
providing both longitudinal followup, if possible
within research protocols.
Penile implants are the last resort of treatment
despite the fact, that with this type of surgery, still
the best outcome might be expected. However,
only +/-10% of all patients with erectile dysfunc-
tion finally will receive an alloplastic implant
Penile Injuries: Acute injuries to the tunica albu-
ginea are best managed by immediate repair. Peni-
le fracture and penetrating injuries do not need
extensive testing. The morbitidy of surgery is less
then in conservative treatment. Penile amputation,
if reattached < 24 hours has remarkably good out-
comes. Blunt injuries not necessarily benefit from
early surgical intervention
Penile Reconstruction: The use of free flaps is
the method of choice, mainly using the radial- or
ulnar forearm flap. Microsurgical nerve anasto-
moses assure the sensibility in the neophallus in
up to 80 %. Penile implants should not be perfor-
med before urethral healing and sensitivity are
accomplished.
Penile enlargement surgery has evolved rapidly
in the past 5 years (plastic- and reconstructive
surgeons) in absence of genital pathologies! Peer-
reviewed reports and p.o.results are lacking, infor-
mation on the investigational character of this pro-
cedure is mandatory ! Penile lenghtening in defor-
mities ( e.g.webbed penis, epispadia, penile fibro-
sis) is justified, even if sufficiant good data are still
not available.
396
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29. HAGE JJ, DE GRAAF FH, VAN DEN HOEK J,
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male transsexuals using a lateral upper arm sensate
free flap and a bladder mucosa graft Annals of Plast
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30. SADOVE RC, SENGEZER M, et al: One-stage total
penile reconstruction with a free sensate osteocuta-
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flap: case report J Reconstr Microsurgery, 1989;
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32. UPTON J, MUTIMER KL, LOUGHLIN K, RIT-
CHIE J: Penile reconstruction using the lateral arm
flap J Royal College of Surg of Edinburgh, 1987;
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33. ROHRICH RJ, ALLEN T, LESTER F et al: Simulta-
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403
intraoperative penile skin expansion Plast and
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34. HAGE JJ, DE GRAAF, F: Addressing the ideal
requirements by free flap phalloplasty: some reflec-
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1993;14: 592-598
35. BAKKER A, VAN KESTEREN PJM, GOOREN
LJG, et al: The prevalence of transsexualism in the
Netherlands Acta Psychiatr Scand 1993; 87: 237-
238
36. LEVINE STB, BROWN G, COLEMAN E, et al: The
standards of care for gender identity disorders: Revi-
sion by committee, Draft Nine B2, June 15, 1998
Harry Benjamin International Gender Dysphoria
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edu/nlhome/m201/ colem001/hbigda/
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38. FANG RH, LIN JT, MA S: Phalloplasty for female
transsexuals with sensate free forearm flap Micro-
surgery, 1994; 15: 349-352
39. HAGE JJ: Metaidoioplasty: An alternative phallo-
plasty technique in transsexuals Plast and Recons-
truct Surg, 1996; 97:161-167
40. LEVINE LA, ELTERMAN L: Urethroplasty follo-
wing total phallic reconstruction J Urol, 1998;
160:378-382
41. CHENG KX, ZHANG RH, et al: Cheng’s method
for reconstruction of a functionally sensitive penis
Plast and Reconstr Surg, 1995; 99: 87-92
42. BYUN JS, CHO BC, BAIK BS: Results of one-stage
penile reconstructions using an innervated radial
osteocutaneous flap Journ of Reconstr Microsurge-
ry, 1994; 10 : 321-331
43. GILBERT DA, JORDAN GH, et al: Microsurgical
forearm “Cricket Bat-Transformer” Phalloplasty
Plast and Reconstr Surg , 1992; 90: 711-716
44. HAGE JJ : Discussion : Cheng KX: Analysis of 136
Cases of Reconstructed Penis Using Va r i o u s
Methods; Plast and Reconstruct Surgery 1995 ;
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45. SOHN M, PEEK A, et al: The reconstruction of a
functional , sensible neopenis in female-to-male
transsexualism Eur J Urol Suppl 2, 1999 ; 35: 155
46. JORDAN GH, ALTER GJ, GILBERT A, et al: Peni-
le prosthesis implantation in total phalloplasty J
Urol, 1994;152: 410-414
47. JAROW JP: Risk factors for penile prosthetic infec-
tion J Urol, 1996;156: 402-404
48. GILBERT DA, et al: Phallic reinnervation via the
pudendal nerve J Urol, 1988;140 : 295-299
49. KOSHIMA I, TAI T, YAMASAKI M: One-stage
reconstruction of the penis using an innervated radial
forearm osteocutaneous flap J Reconstr. Microsur-
gery , 1986; 3: 25-26
50. HAGE JJ, DE GRAAF FH, VAN DEN HOEK J,
Bloem JAM: Phallic construction in female-to-male
transsexuals using a lateral upper arm sensate free
flap and a bladder mucosa graftAnnals of Plast Surg,
1993; 31: 275-280
51. SWANSON E, BOYD JB, MANKTELOW RT: The
radial forearm flap: reconstructive applications and
donor-site defects in 35 consecutive Patients Plast and
Reconstr Surg, 1990; 85: 258-266
52. SOHN M: Umwandlungsoperation bei Transsexuellen
– von Mann-zu-Frau und von Frau-zu-Mann Plas-
tisch-Rekonstruktive Chirurgie in der Urologie , eds:
Schreiter-Bartsch; Thieme-Verlag ;1999 : 388-396
53. PEROVIC S: Phalloplasty in children and adolscents
using the extended pedicle island groin flap J Urol,
1995; 154: 848-853
54. GILBERT DA, JORDAN GH, DEVINE CHJ, et al:
Phallic construction in prepubertal and adolescent
boys J Urol, 1993; 149: 1521-1526
55. GLÜER S, FUCHS J, MILDENBERGER H: Diagno-
sis and current management of penile agenesis J
Pediatric Surg, 1998; 4 : 628-631
56. CHEN LE, SEABER AV , URBANIAK JR: Micro-
vascular anastomoses in growing vessels: a long-term
evaluation of nonabsorbable suture materials J
Reconstr Microsurgery, 1993; 9:183-189
57. HAGE JJ, BLOEM JJAM: Review of the Literature
on Construction of a Neourethra in female-to-male
transsexuals Annals of Plast Surg , 1993; 30 : 278-286
58. YOO JJ, LEE I, ATALA A: Cartilage rods as a poten-
tial material for penile reconstruction J Urol, 1998;
160: 1164-1168
59. ATALA A: Tissue engineering in the genitourinary
system. In: Tissue Engineering, Edited by A.Atala
and D.Mooney. Boston: Birkhauser 1997; 149-164
60. HAGE JJ, BLOEM JJAM, BOUMAN F.: Obtaining
rigidity in the neophallus of female-to-male trans-
sexuals: A review of the literature Annals of Plast Surg
, 1993; 30 : 327-333
61. HAGE JJ: Dynaflex prosthesis in total phalloplasty
Plast and Reconstr Surg , 1995; 99 : 479-485
62. LEVINE LA, ZACHARY LS, GOTTLIEB, LJ: Pros-
thesis placement after total phallic reconstruction J
Urol, 1993; 149: 593-598
63. FISCH M, WAMMACK R, AHLERS J ,et al: Osseous
fixation of a penile prosthesis after transsexual phallo-
plasty: A case report J Urol, 1993; 149: 122-125
64 FANG RH, KAO YS, MA S et al: Phalloplasty in
female-to-male transsexuals using free radial osteocu-
taneous flaps: a series of 22 cases . Brit J Urol, 1999;
52: 217-222
F. PENILE ENLARGEMENT SURGERY
1. DEVINE : Eingegrabener Penis , In: Atlas urologi-
scher Operationen , ed.; Hinmann F, Enke-Verlag,
Stuttgart 1994; 66-68
2. KABALIN JN, ROSEN J, PERKASH I: Penile
404
advancement and lengthening in spinal cord injury
patients with retracted phallus who have failed peni-
le prosthesis placement alone. J Urol 1990;144 : 316-
318
3. KNOLL D, FISHER J, BENSON R, et al: Treatment
of penile fibrosis with prosthetic implantation and
flap advancement with tissue debulking. J Urol
1996;156: 394-397
4. ALTER GJ: Augmentation phalloplasty. Urol Clin N
America 1995; 22: 887-902
5. DONATUCCI CF, RITTER EF: Management of the
buried penis in adults. J Urol 1998; 159: 420-424
6. KELLEY JH, ERAKLIS AJ: A procedure for leng-
thening the phallus in boys with extrophy of the
bladder. J Pedriatr Surg, 1971; 6 : 645-649
7. JOHNSTON JH: Lengthening of the congenital or
acquired short penis. Br J Urol 1974; 46 : 685-688
8. MAIZELS M, et al: Surgical correction of the buried
penis: Description of a classification system and a
technique to correct this disorder. J Urol 1968;
136:268
9. BOMERS TML, DE JONg TPVM : The surgical cor-
rection of buried penis: a new technique. J Urol
1995; 154: 550-552
10. BAKA-JAKUBIAK M : Genital reconstruction. Cur-
rent Opinion in Urology 1998; 8: 501-504
11. ALTER, GJ: Penile enlargement surgery. Techniques
in Urol 1998; 4 : 70-76
12. WESSELLS H, LUE TF, MCANINCH JW: Penile
length in the flaccid and erect states: Guidelines for
penile augmentation. J Urol 1996; 156 : 995-997
13. SCHONFELD WA, BEEBE GW: Normal growth
and variation in the male genitalia from birth to
maturity. J Urol 1942; 48: 759 - 761
14. DA ROS, TELOKEN C, et al: Caucasian penis: What
is normal size? J Urol 1994; 151: 323 A
15. LIGHT JK, Editorial: Potpourri. J Urol 1996; 156
:998 – 1000
16. WESSELLS H, LUE TF, MC.ANINCH JW: Com-
plications of penile lengthening and augmentation
seen at 1 refferal center. J Urol 1996; 155 :1617-1620
17. ALTER GJ: Reconstruction of deformities resulting
from penile enlargement surgery. J Urol 1997; 158:
2153-2157
18. NIECHAJEV I, SEVCUK´ O: Long-term results of
fat transplantation : Clinical and histologic studies.
Plast and Reconst Surg 1994; 94 : 496-506
19. ERSEK RA; Transplantation of purified autologous
fat: a 3-year follow-up is disappointing. Plast and
Reconstr Surg 1990; 87: 219-228
20. PRYOR JP, HILL JT: Abnormalities of the Suspen-
sory Ligament of the Penis as a Cause for Erectile
Dysfunction. Brit J Urol 1979; 51: 402-403
______________________
 Committee 11

Psychological Issues in Diagnosis

and Treatment

Chairman
A. M ELMAN

Members
S. LEVINE,
B. SACHS,
T. SEGRAVES,
M.F. VAN DRIEL

405
 CONTENTS

SUMMARY STATEMENT D. QUESTIONNAIRE ASSESS-

MENT OF PATIENTS WITH
ERECTILE DYSFUNCTION
A. PSYCHOGENIC ERECTILE
DYSFUNCTION
I. MAJOR SEXUAL FUNCTION IN-
STRUMENTS IN CURRENT USAGE

B. ERECTILE FUNCTION AND

DYSFUNCTION: II. GENERAL PSYCHIATRIC
A CONTEXTUAL VIEW EVALUATION

ABSTRACT - SUMMARY
III. RECOMMENDATIONS

I. INTRODUCTION
REFERENCES
II. THE DISTINCTION BETWEEN
“REFLEXIVE” AND
“PSYCHO-GENIC” ERECTION E. PRACTICAL GUIDELINES
FOR GENERAL UROLOGICAL
III. THE PHYSIOLOGY OF EREC- PRACTICE
TION VARIES WITH CONTEXT

IV. THE DISTINCTION BETWEEN
“ORGANIC” AND “PSYCHOGENIC”
ERECTILE DYSFUNCTION
ANNEXES
I. INTERNATIONAL INDEX OF EREC-
TILE FUNCTION QUESTIONNAIRE

II. THE C-MASH

C. PSYCHOLOGICAL ISSUES
IN DIAGNOSIS AND III. ARIZONA SEXUAL EXPERIENCES
TREATMENT OF ERECTILE SCALE ( ASEX ) -MALE
DYSFUNCTION (ED) IV. MARITAL-ADJUSTMENT TEST

V. THE F.E.A.R.
REFERENCES

406
 Psychological Issues in Diagnosis
and Treatment
A. MELMAN
S. LEVINE, B. SACHS, T. SEGRAVES, M.F. VAN DRIEL
SUMMARY STATEMENT
Urologists who treat patients with erectile dys-
function should be sensitive to the emotional mea-
nings patients unconsciously attach to that pro-
blem. In addition, because intercourse involves
two people it is important, if possible, to include
both the patient and his sexual partner in both the
diagnosis and the planned treatment. The treating
physician should try to get the partner involved
early in the process of diagnosis and treatment.
That participation enhances communication,
enhances reliability of the history, and can reduce
stress and anxiety for all involved. Education of
the couple is important. One should explain in
detail, verbally and with educational tools, the
mechanism of erection and the multicausal nature
of erectile dysfunction. Any myths concerning
penile erection should be dispelled. It should be
emphasized that almost everyone has a psycholo-
gical reaction to erectile dysfunction even when
the cause is primarily a physical one. A variety of
self-report questionnaires are available for the
assessment of patients with erection dysfunction
and there is some overlap between questions asked
in different questionnaires. These questionnaires
can be assessed by consideration of their psycho-
metric properties, the availability of validated in-
struments in various languages, the brevity of the
instrument, whether the instrument has been
shown to demonstrate effects of pharmacological
interventions, and the purpose the clinician or
investigator has for the use of the instrument An-
other purpose for which an instrument could be
407
utilized would be to assist the clinician in the
assessment of patients with sexual dysfunction. In
these cases, the instrument might be used to guide
the clinical interview to problem areas and to help
identify problem areas that the clinician might
otherwise overlook. In such cases, brevity of the
instrument and its formal psychometric properties
might be of less importance as the clinician would
not necessarily be using the instrument as the pri-
mary assessment intervention. It used be emphasi-
zed that attempts to use psychometric instruments
to establish psychological characteristics of men
with psychogenic erection problems have gene-
rally be unsuccessful. Structured interviews focu-
sing on presenting symptoms have shown promise
as generalized screening instruments indicating
when further organic assessment is indicated or
when a psychological etiology can be safely assu-
med.
A problem facing the non-psychiatric physician in
the evaluation of patients with erectile disorder is
the co-morbidity of sexual disorders with certain
psychiatric syndromes. Although, various treat-
ment approaches may reverse erectile failure in
psychiatric patients, the clinician would not want
to miss an underlying treatable and possibly fatal
psychiatric disease such as major depressive disor-
der and panic disorder. Both of these disorders
have high suicide rates. A number of studies have
repeatedly demonstrated that general physicians
under diagnose psychiatric disorders such as
depression and anxiety disorders. The primary
conditions which the physician needs to screen are
depression and anxiety disorders. A variety of
general surveys for the measurement of depression
anxiety are available but are too long to be easily
incorporated in a practice setting. Recent research
suggests that two questions are sufficient for brief
screening of depression. These could be incorpo-
rated into a questionnaire format.
The questions are:
1) During the past month, have you often been
bothered by feeling down, depressed or hope -
less?
2) During the past month, have you often been
bothered by little interest or pleasure doing
things?
Anxiety can be rapidly screened by using the
Fear, a rapid screening instrument for anxiety
consisting of four questions. Two other issues
that the urologist might want to address are
dependent on the cultural context. If the primary
sexual partner is the spouse and if considerable
marital discord is present, the urologist might
want to consider referral for counseling as well as
correcting the erectile problem. A reasonably
rapid tool for screening for the presence of mari-
tal discord is the Locke Wallace Marital Adjust-
ment Test, a 15 item questionnaire requiring
minimal time to complete.
The advantage of a standardized questionnaire is
that it may pick up information that the clinician or
investigator might otherwise overlook. For
example, it is not uncommon for a man to com-
plain of impotence when it is not the primary pro-
blem. Some men may complain of impotence
when the major problem is premature ejaculation
for which alternative treatments are available.
Also, men with decreased libido may complain of
impotence when the problem is primarily decrea-
sed libido. In such cases, the clinician would prob-
ably want to consider endocrinological etiologies
of the problem. Also some men will complain of
impotence because of unrealistic performance
expectations.
Each of the treatment options, including sex and
marital theraapy, and their risks should be discus-
sed and made available the patient and couple. It
is very important to let the patient know that if one
treatment fails that other therapies can be used and
that penile implant surgery is available as the ulti-
mate choice if less invasive choices fail.
408
A. PSYCHOGENIC ERECTILE
DYSFUNCTION
PSYCHOGENIC ERECTILE DYSFUNCTION FALLS
INTO TWO BROAD NATURAL VARIETIES:
Lifelong and Acquired.
Lifelong Psychogenic Erectile Dysfunction has a
lower prevalence, a far more complicated patho-
genesis, and a lower treatment response rate than
acquired varieties. Lifelong patterns among hete-
rosexuals are generally associated with hidden
unconventional sexual identity patterns—such as
transvestism, gender identity disorder, homo-
sexual orientation, paraphilia—profound fear of
closeness to women because of egregious difficul-
ties as a child with parents, or extreme religious
orthodoxy associated with obsessive-compulsive
disorder. Lifelong Psychogenic Erectile Dysfunc-
tion is often best dealt with directly by a mental
health professional, but even with these professio-
nals the underlying disorder often proves to be
incompletely reversible.
The use of the diagnosis of Acquired Psychogenic
Erectile Dysfunction implies that the patient has
at some period in his adulthood been capable of
adequate erectile function with a woman. Men
develop Acquired Psychogenic Erectile Dysfunc-
tion in response to an array of precipitating cir-
cumstances: job loss, relationship deterioration,
divorce, loss of physical or mental health, loss of
partner’s health, personal or partner infidelity,
panic about sexual decline, guilt over hidden
addiction, failure to overcome another sexual dys-
function, etc. As performance anxiety is a final
common pathway in most forms of ED, and parti-
cularly psychogenic ED, the precipitating cause is
typically not the only contribution to the pathoge-
nesis of the problem. Mental health interventions
can often be effective in restoring men with Acqui-
red Psychogenic Erectile Dysfunction, but psy-
chotherapy cannot be expected to erase the impact
of the forces that created the problem in the first
place, particularly if the therapy consists only of a
few sessions. Often in pursuing the reversal of
Acquired Psychogenic Erectile Dysfunction, the
therapy focuses for a while on marital problems,
improving mood, coping with guilt and disap-
pointment, supporting a man through a job search
that is, the therapy focuses on nonsexual matters.
For all practical purposes, the diagnosis of psycho-
genic ED is made most often in men <50 years old
and some significant organic contribution is assu-
med in those>50 years of age. This overly simple
clinical distinction reflects the more basic fact that
there is a widespread sexual physiological decline
that occurs in healthy men during their 50s. ED is
most strongly correlated with age in both physi-
cally healthy men and patients with various forms
of cardiovascular disease. This makes it difficult
to assign with certainty an etiology to many men
with ED in their late 50s and beyond. Much ED is
probably a mixed etiology of aging, disease, medi-
cation, psychological, and interpersonal factors.
Clinicians should consider using the term «pres-
byrectia» to describe the patient in his late 50s or
older who complains of recent steadily declining
potency who lacks any apparent dramatic organic
or psychogenic cause for his ED. This diagnosis
recognizes that as men age they often lose reliable
erectile function associated with a subtle decline
of sexual drive. They are entering an era of less
efficient sexual functioning. Presbyrectia implies
that aging is the cause—not vascular disease, dia-
betes, spinal cord trauma, prostatectomy, etc.
Presbyrectia can coexist with cardiovascular
disease without implying, for instance, that the
patient’s remote inferior wall myocardial infarc-
tion is part of the same process that creates erecti-
le dysfunction.
B. ERECTILE FUNCTION AND
DYSFUNCTION:
A CONTEXTUAL VIEW
ABSTRACT - SUMMARY
There is increasing recognition that the traditional
distinction between reflexive and psychogenic
erection is based on false assumptions and has litt-
le utility. This distinction in fact identifies only
1) whether tactile or nontactile stimulation is
involved,
2) which peripheral afferent nerves mediate the
erection, and
409
3) whether the lumbosacral spinal cord is suffi-
cient to maintain that class of erection or whether
the brain is also involved. Inherent in the original
distinction was the idea that different stimuli pro-
mote erection through different physiological sys-
tems. This view has not been confirmed for the
classic example, the differential role of the hypo-
gastric nerve. However, there is compelling evi-
dence that the neural, endocrine, and neurochemi-
cal mediation of erection varies with the context in
which erection occurs.
If the psychogenic-reflexive distinction is flawed,
so too is the one between psychogenic and organic
erectile dysfunction (PED and OED). Because it is
axiomatic that all mental processes have an orga-
nic basis, PED means little more than OED of
unknown brain origin. The diagnosis of PED is
often arrived at by subtraction (no identifiable
organic dysfunction) and by evidence that erection
is present in some contexts (e.g., sleep), but not in
others. Therefore, “situational erectile dysfunc-
tion” (SED) is recommended as a more descripti-
ve alternative to PED. By implication, another
term should replace OED.
Some pharmacological treatments may be no less
effective in treating SED than OED, and their dif-
ferential efficacy may promote an understanding
of the organic origins of SED. Conversely, effec-
tive psychotherapeutic approaches to SED may act
in part by modifying brain chemistry.
I. INTRODUCTION
Among the traditional distinctions made by profes-
sionals concerned with the process of erection are
those between “reflexive” and “psychogenic” erec-
tion and between “organic” and “psychogenic”
erectile dysfunction. Each of these distinctions is
flawed and probably counterproductive in gaining
understanding of the processes underlying erectile
function and dysfunction. Closer attention to the
context, or situation, in which erection occurs or
fails to occur offers an alternative to the traditional
distinctions, an approach that furthers research
into the underlying mechanisms.
This approach may also offer a useful alternative
terminology.

II. THE DISTINCTION BETWEEN
“REFLEXIVE” AND
“PSYCHOGENIC” ERECTION
The utility of the terms “reflexive” and “psycho -
genic” erection is questionable, as is the interpre-
tation of the evidence that gave rise to the distinc-
tion between them [1]. Erections in response to
perigenital touch were termed reflexive because
these erections only require an intact lumbosacral
spinal cord; higher central nervous system lesions
facilitate these erections or have no effect. As spi-
nally mediated responses, it was assumed that
reflexive erections were simpler than psychogenic
erections, whose processing requires the cranial
nerves and the brain. However, there is no eviden-
ce that touch-based erections necessarily (1) have
shorter latencies than erections in response to non-
tactile stimuli, or (2) have fewer synapses between
stimulus and response, or (3) have less complex
interactions among excitatory and inhibitory sys-
tems, or (4) are less affected by cognitive pro-
cesses, all of which are implied by the term
“reflex.” In fact, the reflexive-psychogenic dis-
tinction is simply a statement that different sense
modalities mediate the respective erections, and
that there is a resultant difference in the afferent
nerves and relevant portions of the central nervous
system.
Despite these problems, there may be a useful ker-
nel to take from this distinction, namely that the
physiology of erection varies from one context to
another, and may do so in ways more fundamental
than the particularity of the afferent nerves car-
rying the proerectile stimuli or whether the spinal
cord can mediate erection when separated from
the brain. Some examples may prove useful.
III. THE PHYSIOLOGY OF EREC-
TION VARIES WITH CONTEXT
The idea that the physiology of erection varies
from context to context is not new; indeed, its
foundations were laid at least 50 years ago. Howe-
ver, recent research has cast doubt on some of
those foundations, while providing substantial
new evidence. Because the principle of context-
410
dependent regulation of erection was first develo-
ped with regard to the peripheral nerves, it seems
reasonable to start by revisiting some of this evi-
dence.
1. PERIPHERAL NEURAL REGULATION
There is a widespread view that the primarily para-
sympathetic pelvic nerves mediates touch-based
(reflexive) erection, whereas the primarily sympa-
thetic hypogastric nerves (HgN) mediate nontacti-
le (psychogenic) erections. This hypothesis is
mainly based on research in which electrical sti-
mulation of HgN led to penile tumescence in dogs,
cats, and rabbits. (For reviews see [2,3]). Reports
on erectile function in paraplegic men were also
used to support the idea that there are at least two
proerectile pathways which, depending on
context, are differentially involved in erection [4].
Recent evidence, however, indicates that the HgN
does not serve a proerectile function in any
context, at least in rats. Stimulation of the HgN of
intact males does not result in erection in this spe-
cies [5], and HgN transection does not impair
erections resulting from hypothalamic stimulation
[6]. Also, transection of rat HgN does not affect
erection in response to remote cues from females
[7], a context analogous to psychogenic erection
[8].
At present, there is no good evidence that the
HgN has a normal proerectile function in intact
males of any species, or that the pelvic and hypo-
gastric nerves differentially mediate erection in
different contexts. It is doubtful – but not incon-
ceivable – that there is a species difference be-
tween rats and other tested mammals regarding the
erectile role of the HgN. Nonetheless, in view of
the evidence from rats, the burden of proof is now
on demonstrating a proerectile function for the
HgN in normal, intact males.
2. ENDOCRINE REGULATION
In contrast with the weak case for context depen-
dency in the peripheral efferent nerves mediating
erection, there is strong evidence for differential
endocrine regulation. It is widely understood that
normal penile erection depends on androgenic ste-
roids, especially testosterone (T), and castration of
adult males impairs erection [3]. However, there is
ample evidence of erectile function surviving the
absence of gonadal androgen. Even when T is pre-
sent, the effective metabolite of this hormone may
vary with the erectile context: either dihydrotes-
tosterone (DHT) or estradiol (E2) can support
penile erection.
Prepubertal boys provide an obvious example of
erection in the absence of androgen. From soon
after birth to near the onset of puberty, plasma T in
boys is very low and indistinguishable from that of
girls [9], but throughout these years the penis exhi-
bits sleep-related and touch-based erection
[10,11]. Another clear example of androgen-inde-
pendent erection is the ability of castrated male
rats to continue to copulate indefinitely if they are
treated with large doses of E2. Despite atrophy of
the penis and other androgen-dependent struc-
tures, the males nonetheless gain intromission at
about the same rate as intact males [12]. Even
female rats treated with E2 can exhibit the motor
patterns of intromission and ejaculation, though of
course there is no ejaculate [13].
As noted above, rats exhibit behavior analogous
to “psychogenic” erection, in that they have erec -
tions when exposed to remote cues from estrous
females [8]. Recently, we asked which steroids
would support these noncontact erections (NCEs)
[14]. No males had NCEs after castration, even in
the first test three days after surgery. Males recei-
ving treatment T or DHT two weeks after castra-
tion resumed NCEs within 3-6 days, whereas
males receiving E2 or no hormone had no NCEs.
Clearly, NCE and touch-based erections are
androgen-dependent erectile contexts for rats,
whereas erection during copulation is indepen -
dent of androgen.
3. CENTRAL NEURAL REGULATION
Medial preoptic area (mPOA). Male copulatory
behavior in all vertebrates is critically dependent
on an intact mPOA, where lesions prevent males
from mounting receptive females [3]. But as
important as the mPOA is for copulation, it
appears to be superfluous for penile erection.
The inference that the mPOA has some role in
erection has been based on research in which
direct stimulation of the mPOA has resulted in
penile tumescence [e.g., 6,15]. However, the stim-
ulation in those experiments may have acted indi-
rectly via other brain areas, since all the connec-
tions of the mPOA with other brain areas were
411
intact. Doubt about an erectile function for the
mPOA stems from lesion experiments that have
demonstrated that the rat mPOAis dispensable for
touch-based erection [16] and for NCE [17]. To be
sure, these studies do not rule out a role for the
mPOAin the normal mediation of erection; rather,
the mPOAmay be a redundant part of two or more
parallel proerectile pathways.
Medial amygdala (mAm). Lesions of the mAm
impair copulatory behavior. Sexually inexperien-
ced male rats with such lesions may not copulate
at all [18], and sexually experienced rats are less
likely to achieve ejaculation [19,20]. Is the mAm,
like the mPOA, superfluous to erection? The ans-
wer depends on the erectile context. Lesions of
mAm do not reduce erectile competence during
copulation, at least as measured by the percentage
of mount attempts that result in intromission
[19,20]. Touch-based erections are also unaffected
by mAm lesions, but NCEs are dramatically
impaired [20]. In brief, some areas of the brain
may be considered to be organs of erection in
some contexts but not in others.
4. NEUROCHEMICAL MEDIATION
Dopamine is one of the most frequently studied of
the neurotransmitters that regulate sexual activity,
but its role in sexual behavior is incompletely
understood, especially in relation to penile erec-
tion and ejaculation. The general view that dopa-
mine facilitates erection comes from drug-injec-
tion studies and from research showing that brain
dopamine increases during sexual activity or even
exposure of males to sexual stimuli [3,21,22]. At
issue is which specific dopamine receptors media-
te the erectile response. Dopaminergic agents such
as apomorphine that bind to both D1 and D2
receptors clearly increase the probability of erec-
tion in rats and humans [23]. However, conflicting
views have emerged from research using drugs
that act more specifically on D1 or D2 receptors.
Some investigators view stimulation of D1 recep-
tors as excitatory for erection, and activation of D2
receptors as inhibitory [21,24]. Others have come
to exactly the opposite conclusion [25]. These
conflicting conclusions have emerged from re-
search in different laboratories in which opposite
effects have been observed in rats after treatment
with the same or similar drugs. Naturally, many
procedural differences distinguish the research in
these laboratories, but especially noteworthy are
differences in the context in which erection was
observed. Those who attribute proerectile function
primarily to D2 receptors [25] have observed free-
ly moving solitary rats (i.e., drug-induced erection
with no sexual context). Those who ascribe pro-
rectile influence primarily to D1 receptors have
studied either copulation and touch-based erection
in rats [21], or have observed rhesus monkeys
during noncontact erection tests [24]. It may well
be that the competing hypotheses of dopamine-
receptor function are not mutually exclusive.
Rather, the relative dependence of erection on D1
and D2 receptors may depend on the context in
which erection is evoked.
In summary, there is ample evidence for context-
dependent variation in the physiological systems
that mediate erectile function. A skewed picture
of the erectile role of any given system can be
avoided only by testing males in multiple
contexts, rather than overgeneralizing from tests
in one or two contexts.
IV. THE DISTINCTION BETWEEN
“ORGANIC” AND “PSYCHOGENIC”
ERECTILE DYSFUNCTION
If the physiology of erectile function varies signi -
ficantly from one context to another, then it fol -
lows that the physiology of erectile dysfunction
(ED) may also vary from context to context. This
principle is implicitly recognized in some tests
used by clinicians to determine whether instances
of ED are due to “organic” or “psychogenic”
causes (OED and PED respectively). Too often,
however, this differential diagnosis is made by
subtraction, i.e., in the absence of evidence for
organic dysfunction, PED is assumed. For
decades, sleep-related erection (also called noctur-
nal penile tumescence) has been the primary test
for this differential diagnosis [26]. If men had nor-
mal sleep-related erection, then the erectile phy-
siology was assumed to be functioning normally,
and ED with a sexual partner was assumed to be
psychogenic. However, the occurrence of normal
sleep-related erection only demonstrates normal
function of the penile corpora and the related
blood vessels, peripheral nerves and spinal cord.
412
In view of the evidence reviewed above, it now
seems clear that there can be organic dysfunction
in various areas of the brain that could affect erec-
tion in some contexts while leaving sleep-related
erection undisturbed.
Certain origins of ED are unambiguously organic
in origin, e.g., neural pathology due to spinal cord
injury or vascular problems due to diabetes. But in
many cases the diagnosis of PED neglects the rich-
ness of our understanding of physiological psy-
chology and the true implication of the term “psy-
chosomatic.” Simply put, it is axiomatic that all
mental processes have an organic basis. It fol -
lows that there can be no psychogenic dysfunc -
tion that does not have an organic origin. Para-
doxically, by current terminology, research into
the physiology of PED translates into the search
for the organic basis of a nonorganic disorder.
The problem, in any case, is to identify the organic
basis of PED in light of our very limited knowled-
ge of central mechanisms of erection, but some
first steps are promising. It is increasingly unders-
tood that erection and detumescence reflect an
algebraic summation of neural pro- and anti-erec-
tile influences [e.g., 3,6,10]. Failure to achieve
erection in the presence of adequate excitatory
influences can result from an excess of inhibitory
influences, which may include such normal factors
as postejaculatory refractoriness and side effects
from drugs (e.g., beta-adrenergic blockers).
However, a net inhibition of erection can also
result from “psychogenic” factors arising from the
sexual situation: a too-public place, a concern
about disease or pregnancy, or performance anxie-
ty (e.g., about erectile function or rapid ejacula-
tion). In extreme cases, masturbation may be the
only waking context in which the net of excitation
over inhibition is sufficient to achieve and main-
tain erection. But it bears repeating that in all such
cases of “psychogenic” ED there are, axiomati -
cally, physiological mechanisms underlying this
dysfunction. These mechanisms may well be
imperfectly understood or even awaiting discove-
ry, but they are no less organic than the effects of
diabetes or prostate surgery, and no more “all in
your mind” than such centrally acting conditions
as hypogonadism or hyperprolactinemia, which
also impair erection. It should also be noted that
because a man’s concern about his sexual perfor-
mance is likely to increase with each episode of
erectile inadequacy, performance anxiety is proba-
bly a major aggravating factor even when the ini-
tial cause of ED is clear organic pathology of proe-
rectile systems. (It has been said that “fear” is the
first time a man can’t do it twice; “panic” is the
second time he can’t do it once.)
If “psychogenic erectile dysfunction” means
nothing more than that the problem has its origin
in undetermined brain dysfunction, then the term
should be changed to reflect that meaning.
Because of the indeterminate causes of PED,
“idiopathic erectile dysfunction” may be a sui -
table term. However, because the diagnosis of
this condition depends so much on determining
the contexts in which dysfunction occurs, I
recommend the adoption of the term “situational
erectile dysfunction” (SED).
Diagnosis and treatment of SED clearly presents a
major challenge, but even when an organic cause
for a sexual problem is not identifiable, that does
not mean that there is not an organic cure for it.
For example, acetylsalycilic acid (aspirin) treated
pain effectively long before its action on prosta-
glandin was understood. For a more relevant
example, consider developments in the treatment
of another common sexual dysfunction, namely
rapid ejaculation. (The former term, “premature
ejaculation,” is considered pejorative.) This pro-
blem has usually been assumed to be “psychoge-
nic,” and men have commonly been referred for
psychotherapy to treat the condition [27]. Howe-
ver, it seems quite plausible that men who routine-
ly ejaculate rapidly are outside of the normal male
range with respect to the brain chemistry that regu-
lates ejaculation. It should not surprise us, then,
that serotonergic and anti-adrenergic drugs offer
help in most such cases [28,29].
SED may similarly reflect abnormal brain neuro-
chemistry. And again, even without understanding
the physiology of SED, pharmacological treat-
ments are increasingly available to change the
balance of the excitation-inhibition equation. At
present these drugs (e.g., alprostadil, sildenafil)
are thought to act primarily on peripheral tissues,
but agents presumed to act on the central nervous
system (e.g., apomorphine) are under investiga-
tion. Drugs have proliferated for the treatment of
several neurochemical dysfunctions of the brain
413
(e.g., depression, obsessive-compulsive disorder)
that are commonly called “mental” disorders. So
too it seems likely that as we gain greater unders -
tanding of the neurochemistry of erection, drug
treatments will increasingly become available to
treat SED. Furthermore, the differential efficacy
of these treatments (e.g., via action on particular
receptors) may promote our understanding of the
organic origins of SED. However, the advent of
effective medical treatments for SED should not
be interpreted as denying the utility of various
psychotherapeutic approaches. Just as psychothe-
rapy for other “mental disorders” can normalize
the brain physiology that characterizes such disor-
ders [30], so too it is reasonable to infer that effec-
tive psychotherapy for ED [27] acts by increasing
the balance of excitation over inhibition.
If it is conceded that “psychogenic erectile dysfunc-
tion” means little more than “organic erectile dys-
function of unknown brain origin,” then it follows
that all ED is of organic origin, and an alternative to
the term “organic erectile dysfunction” is desirable.
One option is to classify ED by the tissue(s) thought
to be primarily responsible for the disorder, e.g.,
neuropathology, vascular disorder, penile mecha-
nics, neuroendocrine function, and so on.
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_____________________

C. PSYCHOLOGICAL ISSUES
IN DIAGNOSIS AND
TREATMENT OF ERECTILE
DYSFUNCTION (ED)
A 55 year old man is seen in the office because of
a sexual problem. A careful, focused medical his-
tory reveals that he has hypertension treated with
a beta-blocker, recent onset adult onset diabetes
controlled by diet and recently married to a
woman 12 years younger than he. He says he is
not able to achieve and maintain an erection suffi-
ciently hard to have coitus and wants to be treated.
His states that his wife not complaining about his
inadequate erections but he feels that he is letting
her down sexually. By the way,” he says, “he is
somewhat disappointed with her because since his
marriage she has had breast implants removed and
not replaced without asking his advice.” That
vignette is an actual history. The complexities of
the story typify the dilemma that physicians who
treat the problem of erectile dysfunction must deal
with. ED in most cases is a couple’s problem and
its evaluation and treatment should be thought of
in that way by both the patient and the physician.
At the present time, the availability, effectiveness
and ease of administration of oral medication as
first line therapy for the treatment of ED has for
many diminished the need to diagnose the cause of
the problem. Moreover, Viagra, the only oral agent
approved by the United States Food and Drug
Administration for treating erectile dysfunction is
particularly successful in treating men with psy-
chological, i.e., normal endorgan, causes of the
ED. The issue of treatment without evaluation is
further compounded by the cost (of diagnostic
tests, physician charges, time lost from work) and
time (multiple visits to the office) needed to esta-
blish an accurate diagnosis. During an era of
increased pressure by government agencies insu-
rance payers, or the simple absence of resources in
developing countries, to limit medical costs there
are further demands to offer a “goal directed” (i.e,
limited, rapid and cheap) approach to treatment.
Thus, the question is what evaluation, if any, is
either needed or necessary to establish the case for
a psychological cause of erectile dysfunction in a
man seeking treatment for the problem when the
415
end result of current available therapies to create
an erection are so successful.
The search for the answer is contingent on several
factors that are independent of the physician’s the-
rapeutic ability to create penile rigidity. Both LoPic-
colo [1] and Mohr and Beutler [2] have emphasized
that formulation of the best treatment plan is the
primary purpose of the diagnostic assessment. The
prognosis of the effects of therapy as determined by
assessment of the patient and sexual partner is of
paramount importance in the specific recommenda-
tion for therapy. That raises the question how can
one assess the prognostic application of a therapy in
goal directed treatments if absolutely no assessment
is done of the patient and sexual partner. Further-
more, as many as 25% of men who present them-
selves to the Urologist’s office only want informa-
tion and not therapy for their problem. They will not
use therapy of any type offered to them. Those men
will drop from the therapy program and will be
incorrectly viewed as treatment failures if follow-up
questioning is done.
The interaction of conscious and unconscious sti-
muli from the brain, i.e., the psychological effect,
on erection and 2) the patient (and partner’s) need
for treatment, preference of treatment, and satis-
faction with the treatment must be taken into
consideration. In addition, there is the issue of the
physician’s obligation to offer the patient the most
appropriate (and successful) treatment particularly
if the condition is reversible as is true with psy-
chogenic ED.
We are presently in an era when there is great
emphasis on penile failure as a cause of ED. There
are several recently published studies that docu-
ment the high incidence of erectile dysfunction that
occur with aging in the general population. These
studies, which emphasize the physical nature of the
problem, are in contrast to the psychological predo-
minance of diagnoses of only two or three decades
ago. Despite the swing of the medical pendulum to
the physical nature of ED, the importance of the
effect of the brain on erectile mechanisms in heal-
thy and aging men cannot be overlooked. Reports in
this section by Sachs, highlight the effect of central
inhibitory stimuli on penile erection. Those inhibi-
tory signals from the erectile center of the brain
translate into increased release of contractile neuro-
transmitters by nerve fibers in the penis that cause
smooth muscle contraction. In the penile corpora
contraction results in a flaccid penis and if the tone
is sufficiently high, ED is the outcome. Functional
antagonism in the penis is a concept developed in
our laboratory (see Lerner et al. [3]), shown in figu-
re 1, that describes the effect of diverse mechanisms
on the physiology of erection.
This figure highlights the interplay of contractile
and relaxant forces on the penile smooth muscle
and what might happen when aging, disease, or an
overabundance of contractile agonists impacts
upon those muscle fibers.
This concept is further documented in a paper by
Taub et al. [4] In that report strips of erectile tis-
sue obtained at surgery from two types of patients
were studied in an organ bath (figure 2). One
patient (triangles) had normal erectile activity the
other (closed circles) had ED caused by diabetes.
Both tissues were maximally contracted with the
α-agonist phenylephrine and then made to relax
with the addition of the nitric oxide donor nitro-
glycerine to the organ bath. At every level of prior
contraction the corporal tissue from the man with
ED relaxed less that the tissue from the control
patient in response to the same relaxation stimu-
lus. Moreover, even the normal tissue could not be
relaxed more than 60% of its maximal response in
the presence of the maximal contractile stimulus.
This in vitro study demonstrates the in vivo res-
ponse of the smooth muscle fibers of the corpora
FUNCTIONAL ANTAGONISM
In the normal state smooth muscle relaxation allows
erection to occur
ERECTION
ERECTION
DYSFUNCTIONAL ANTAGONISM
Two little relaxation or augmented contraction causes
erectile dysfunction
Incomplete
relaxation
ED
Heightened
contraction
Figure 1: Functional Antagonism
416
favors contraction over relaxation. The clinical
correlate is the patient with performance anxiety.
The high outflow of the catecholamines norepine-
phrine and epinephrine, that are present in the
fight or flight anxiety state, causes the penis to
remain contracted even in presence of the most
intense sexual stimuli. ED is the visible result.
In an important study by Lo Piccolo [5] he deter-
mined the etiology of erectile failure in 63 men
independently evaluated for the degree of psycho-
logical and organic impairment. That evaluation
followed complete psychological, vascular, hor-
monal, neurological, and NPT determinations.
Three clinicians separately reviewed the clinical
and psychological data and each arrived at a score
ranging from 0 (purely psychological) to 4 (pure-
ly organic). The results showed that the vast majo-
rity of men had combinations of problems of orga-
nic and psychological etiology. In fact in that
group only 10 of the men were diagnosed with
pure psychogenic and 3 with a purely organic etio-
logy. In a similar study in which the patients were
referred to a Urologist’s office the breakdown in
diagnosis was pure organic (28.8%, pure psycho-
genic 39.7%, mixed 25.1% and unknown 6.4%.
The implication is that even in men with clear phy-
sical causes of their erectile component there are
psychological issues that can cloud the results of
medical therapy. Lo Piccolo has emphasized that
erectile failure is a continuum with a small percent
Figure 2: Strips of Erectile Tissue Obtained at Surgery
from Two Types of Patients are Studies in an Organ Bath
of men with a pure state at the extreme ends and the
majority with mixed conditions in the center.
In a new study reported by Lee et al., from King-
ston, Ontario, Canada [6] the authors sought to
identify the number of men with psychopathology
in a group referred to the institution’s Urology
Department for ED. The prevalence of significant
psychiatric disease was as high as 33% (40/120).
37.5% of that group suffered from major depres-
sion, and 10% were schizophrenic. The report
highlights the need to identify the presence of
psychological issues during the focused history
taking. The identification of depression, schizo-
phrenia, drug and alcohol abuse require that those
problems be treated before an effort is made to
correct the ED.
Recently, the advent of self-administered tests to
categorize the presence of ED by symptom score
has come into vogue. The prominent use of the
brief sexual function inventory and the use of the
International Index of Erectile Function (IIEF) [7]
during the Viagra trials has promulgated the use of
such devices not only to test the effect of therapies
upon the erectile condition but to describe the
erectile condition based upon the patients observa-
tions of his erectile capacity. The question is whe-
ther men with psychogenic erectile dysfunction
are good observers of their erectile capacity or do
they tend to minimize their erectile capacity for a
range of reasons. That question was addressed in a
report by Davis-Joseph et al., [8] who studied the
accuracy of a formal history of sexual function and
general physical examination to establish a dia-
gnosis for the cause of ED. The study was com-
pleted in 45 men with a mean age of 57 years.
Most importantly 20% of men initially diagnosed
with organic ED because of their history were
eventually classified as having normal erectile
capacity after multidisciplinary testing. Others
have also studied this underreporting of erectile
capacity. In their recent review Ackerman and
Carey [9] note that the affect associated with ED
such as performance concerns and apprehension
can lead to interference and distraction from erotic
cues. Barlow ha shown that men with ED unde-
restimate the amount of erection response and
decreased their erection response when demands
to obtain an erection were made upon them. Bar-
low also has outlined the results on the erectile
ability of several studies of sexually functional
417
and dysfunctional men subjected to both erotic
and anxiety inducing stimuli [10].
Those results are summarized in the flow diagram
shown below.
If it is the intent of the treating physician and the
goal of the patient that therapy be as specific as
possible the results of these important studies
emphasize the importance of not relying solely on
the patient’s self-reported history to establish an
accurate diagnosis.
The presence of a psychogenic cause for the ED has
several implications. Clearly whatever treatment is
employed may have a high rate of success because
of the possibility of placebo effect and the fact that
the end organ tissues are capable of erection as a
result of the therapy because there is no end organ
disease. More important, is that the psychological
cause of the problem might be related to inner or
self-directed issues (such as lack of esteem or per-
formance anxiety) that might be overridden by an
effective medical therapy. However, the psycholo-
gical problem could also be caused by relationship
issues for which the ability to have an erection
might not have a corrective effect and thus lead to
continued dissatisfaction with sex.
The importance of interviewing the wife or sexual
partner for diagnostic and therapeutic reasons is
well documented. Ackerman and Antoni [11]
found that wives in troubled marriages were not
able to corroborate their husband’s self-reported
erectile function symptoms. There may be as
much as a 50% discrepancy in the history given by
the sexual partner of the men who are seeking the-
rapy when the interview is done as a separate, pri-
vate confidential process [12]. The major discre-
pancies noted are duration of the problem, drug,
smoking, and alcohol intake, marital issues and
satisfaction; these items are summarized in Table 1
and figure 3.
Outcome of successful treatments for ED with
vacuum devices, intracavernous injection therapy,
intraurethral therapy, and penile prosthetic
implants have shown durable responses with
enhanced satisfaction, higher levels of arousal and
frequency of intercourse in the female partners
[14,15]. However, none of the reports however
documented the response to any of the therapies
when marital dissatisfaction with the relationship
is the primary issue. There is no published data
Table 1: Specifics of patient-partner Discrepancies
1. NATURE OF SEXUAL PROBLEM 20% (8 CASES)
Patient says erectile difficulty, partner says: 3 cases
Inhibited desire 2 cases
Normal age changes 2 cases
Retarded ejaculation 1 cases
2. DURATION OF SEXUAL PROBLEM 30% (12 )
Patient’s estimate longer 3 cases
Partner’s estimate longer 9 cases
3. PATIENT’S DRUG/ALCOHOL HISTORY 8% (3 CASES)
Partner’s estimate longer 3 cases
4. MARITAL SATISFACTION 45% (18 CASES)
Patient’s estimate greater 6 cases
Partner’s estimate greater 12 cases
5. PARTNER’S SEXUAL INTEREST 25% ( 10 CASES)
Patient says partner interested/
Partner disagrees 3 cases
Patient says partner not interested/
Partner disagrees 7 cases
6. OTHER
Discrepant medical history 4 cases
Discrepancy in additional sexual problems 8 cases
Discrepancy in adequacy of current function 2 cases
Discrepancy in recount of previous sex therapy 3 cases

Figure 3: Types of Discrepancy Between Patients and Partners . (adapted from Tiefer, L., and Melman, A. Sexuality and Dis-
ability 3/4167-175,1983. [13])

418
FUNCTIONALS DYSFUNCTIONALS
(Positive Feedback loop) (Negative Feedback Loop)

Explicit or Implicit Demands for

Sexual performance (e.g., a responsive
Partner or other contexts) leading to
Public expectation of performance
(erection)

Positive affect and expectancies, Negative affect and

Accurate reporting of APPROACH AVOIDANCE expectancies, inaccurate
Erections, perception of control underreporting of erection,
Perceived lack of control

Attenional focus on erotic cues Attenional focus on public

Consequences of not
Performing or other non-
erotic issues

Increased autonomic arousal Increased autonomic arousal

Increasingly efficient Increasingly efficient

Attentional focus on erotic Attentional focus on
clues Consequences of not Performing

Functional performance dysfunctional performance

419
available as yet for long term satisfaction in the Immigration, religion, ethnic background
sexual partners of men on Viagra therapy. Medical and psychiatric history
The knowledge of what one is seeking when ques- - Current levels of fatigue, pain
tioning patients or patient sexual partners for psy- - Current medications, smoking, alcohol,
chological issues is necessary to be as accurate as drugs
possible. An excellent summary of the Psycholo- • Sexual history
gical causes of sexual dysfunction by Hawton
Childhood and adolescent sexual learning
[16] and the topics to be covered in a psychosexual
and activities
interview were recently outlined by reviewed by
Tiefer and Scheutz-Mueller [17]. Masturbatory history, specific practices
Interpersonal sexual activity history
PYSCHOLOGIC CAUSES OF SEXUAL DYSFUNCTION
Breadth and flexibility of sexual script with
• Predisposing factors all partners
Restrictive upbringing
• Current sexual function
Disturbed family relationships
Current Masturbatory and interpersonal
Inadequate sexual information
sexual activities (with all partners)
Traumatic early sexual Experiences
Nature of problem ,onset, course, frequency,
Early insecurity in psychosexual role (with all partners)
• Precipitants Spontaneous sexual experiences (e.g.,
Childbirth morning erections)
Unreasonable expectations • Relationship harmony, communication,
Dysfunction in the partner partner’s health
Ransom failure Current/recent life stresses, losses
Discord in the general relationship Expectations and goals for evaluation and
Reaction to organic factors treatment
Depression and anxiety Until 30 years ago the only therapy available for
Traumatic sexual experience any type of sexual dysfunction was psychotherapy.
Aging, infidelity Behavioral modification techniques have been
employed most frequently in the past 25 years.
• Maintaining factors Long-term, controlled, comparative outcome of
Performance anxiety that therapy is scant. The good prognostic indica-
Guilt tors for successful outcome of psychotherapy has
Inadequate sexual information been recently reviewed by LoPiccolo [1]. The
Psychiatric disorder positive factors include:
Discord in the general relationship 1. The presence of lack of adequate sexual stimu-
Loss of attraction between partners lation of the man by his partner;
Fear of intimacy 2. the wife’s sexual satisfaction is dependent enti-
Impaired self-image rely on of knowledge of the couple of age-rela-
ted changes in male sexuality;
Restricted foreplay
4. unrealistic expectations of the male’s sexual
Sexual myths
capability,
Poor communication
5. relationship issues that give positive reinforce-
TOPICS COVERED IN PSYCHOSOCIAL INTERVIEW ment to the man’s continued erectile failure.
• Background variables Hawton, has also noted that a good general rela-
tionship of the couple, a motivation for therapy,
Age, marital history, children
the quality of the sexual relationship despite the
Current living arrangement
presence of the sexual problem and early enga-
Educational level (social class assessment), gement in home-work assignments led to a bet-
occupation ter outcome [ 18].

420
Negative prognostic factors listed by LoPiccolo
include:
1. An unwillingness on the part of either the man
or his wife to reconsider male sex-role demands;
2. the presence of pedophilia or transvestism;
3. extreme, deep seated religious beliefs;
4. clinical depression. In an unpublished fol-
low-up study at our institution we observed that
the majority of men who were thought to have a
predominant psychological etiology of their erec-
tile problem, who were referred for sex therapy
refused the treatment. The men who came to the
office seeking a physical cause of the problem
did not want to believe that the problem was “in
their head.” Most had no treatment of any type.
They simply ignored the recommendation.
Today the availability of Viagra ® will allow the
internist or general practitioner to treat those
patients prior to referall to a specialist. However,
the relapse rate in those men in whom the basic
problems that caused the ED in the first place
will not be resolved. Hawton has emphasized
that one of the most important outcomes of
couples sex therapy is the teaching of the couple
how to cope with relapse.
In summary, in the awake male the brain and the
penis function as a symbiotic unit. The physician
who is trying to treat men with erectile dysfunc-
tion, be it of central nervous system or end organ
origin must begin his evaluation with a detailed,
structured interview of the patient and, if pos-
sible, his sexual partner. A thorough physical
examination accompanied by physical and labo-
ratory testing should be done that is consistent
with the goals of the physician and patient. That
triad history, examination, and testing will be
help plan for appropriate successful and long las-
ting therapy.
REFERENCES
1. LOPICCOLO J: Psychological assessment of erectile
dysfunction. Isis Medical Media Ltd. (eds): ATextbook
of Erectile Dysfunction, Oxford: OS1 1ST, UK
2. MOHR D, BEUTLER, L: Erectile Dysfunction: A
Review of Diagnostic and Treatment Procedures. Clin
Psychol Rev. 1990;10:123- 150.
3. LERNER SE, MELMAN A, Christ GJ.Areview of erec-
421
tile dysfunction:new insights and more questions. J.
Urology 149;1993:1246-1255.
4. TAUB HC, LERNER SE, MELMAN A, CHRIST GJ:
Relationship between contraction and relaxation
in human and rabbit corpus cavernosum. Urology 1993;
42:698-703.
5. LOPICCOLO J: Post modern sex therapy for erectile
failure. In: Rosen RC, Leiblum SR (eds):Erectile disor-
der:assessment and treatment. New York:Wiley Liss,
1992.
6. LEE JC,SURRIDGE D,MORALES A, HEATON JPW.
The prevalence and influence of significant psychiatric
abnormalites in men undergoing comprehensive mana-
gement of organic erectile dysfunction. IJIR (in press)
7. ROSEN R, RILEYA, WAGNER G,et al. An interna-
tional index of erectile dysfunction (IIEF);a multidi-
mensional scale for assessment of erectile dysfunction.
Urology 1997:49:822-830.
8. DAVIS-JOSEPH, B, TIEFER, L, MELMAN, A. Accu-
racy if the initial history and physical examination to
establish the etiology of erectile dysfunction. Urology
1995;45:498-502.
9. ACKERMAN MD, CAREY MP: Psychology’s role in
the assessment of erectile dysfrunction:Hoistorical Pre-
cendents, current t knowledge, and Methods. J Consul-
ting and Clinical Psychology 1995;63:862-876.
10. BARLOW D: Causes of Sexual Dysfunction: The Role
of Anxiety and Cognitive Interference. J Consult Clin
Psychol. 1986;54:140-148.
11. ACKERMAN MD, ANTONI MH: Unhappy wives do
not corroborate details of their husband’s erectile diffi-
culties: Disparities in attribution of symptoms. Citation
presented at the 15th annual scientific session of the
Society of Behavioral Medicine. Boston ,1994.
12. TIEFER, L., AND MELMAN, A., Inteview of wives: A
necessary adjunct in the evaluation of impotence.
Sexuality and Disability 1983: 6:167-175.
13. COOKSON MS, NADIG P. Long -term results with
vacuum constiction device. J. Urology 1993;149:290.
14. TURNER LA, ALTHOF SE, LEVINE,SB, BODNER
DR, KURSH ED AND RESNICK MI. Twelve-month
comparison of two treatments for erectile dysfunction:
self injection versus external vacuum devices. Urology
1992;39:139 –144.
15 PEDERSEN, B., TIEFER L., RUIZ, M. AND MEL-
MAN, A.: Evaluation of Patients and Partner One to
four years following penile prosthesis surgery. J. Uro-
logy, 1988;139:956-958.
16 HAWTON K. Sex Therapy: practical guide . New York
Oxford University Press. 1985 p 57.
17. TIEFER L. SCHEUTZ-MUELLER D. Pyschological
issues in Diagnosis and Treatment of Erectile Disorders
Urol Clin North America 1995:22:767-774.
18. HAWTON K AND CATALAN J. Prognostic factors in
sex therapy. Behaviour Research and Therapy 1986;
24:377-385.
___________________

D. QUESTIONNAIRE ASSESS-
MENT OF PATIENTS WITH
ERECTILE DYSFUNCTION
A variety of self-report questionnaires are avai-
lable for the assessment of patients with erection
dysfunction and there is some overlap between
questions asked in different questionnaires. Each
instrument has a slightly different focus, primari-
ly reflecting the purpose for which the instrument
was developed. These questionnaires can be
assessed by consideration of their psychometric
properties, the availability of validated instru-
ments in various languages, the brevity of the
instrument, whether the instrument has been
shown to demonstrate effects of pharmacological
interventions, and the purpose the clinician or
investigator has for the use of the instrument. An
instrument utilized in pharmacological trials
might be valued more for brevity, demonstrable
ability to pick up changes in function with phar-
macotherapy, and its psychometric properties.
Another purpose for which an instrument could
be utilized would be to assist the clinician in the
assessment of patients with sexual dysfunction.
In these cases, the instrument might be used to
guide the clinical interview to problem areas and
to help identify problem areas that the clinician
might otherwise overlook. In such cases, brevity
of the instrument and its formal psychometric
properties might be of less importance as the cli-
nician would not necessarily be using the instru-
ment as the primary assessment intervention. It
used be emphasized that attempts to use psycho-
metric instruments to establish psychological
characteristics of men with psychogenic erection
problems have generally be unsuccessful.
(Segraves [24], 1981). Structured interviews
focusing on presenting symptoms have shown
promise as generalized screening instruments
indicating when further organic assessment is
indicated or when a psychological etiology can
be safely assumed.(Segraves [25], 1987; Abel
[1], 1982; Kockett [11], 1980).
The advantage of a standardized questionnaire is
that it may pick up information that the clinician
or investigator might otherwise overlook. For
example, it is not uncommon for a man to com-
422
plain of impotence when it is not the primary
problem. Some men may complain of impotence
when the major problem is premature ejaculation
for which alternative treatments are available.
Also, men with decreased libido may complain of
impotence when the problem is primarily decrea-
sed libido. In such cases, the clinician would pro-
bably want to consider endocrinological etiolo-
gies to the problem. Also some men will com-
plain of impotence because of unrealistic perfor-
mance expectations.
The purpose of this report will be to review the
major instruments in current usage with an
English language version. Numerous instru-
ments with a more specialized function will not
be reviewed. This review will also consider whe-
ther instruments which might pick up psycholo -
gical causes of erection problems should be
employed in assessment. An argument can be
made that instruments to assess marital discord
and depression should be employed in a scree-
ning battery.
I. MAJOR SEXUAL FUNCTION INS-
TRUMENTS IN CURRENT USAGE
The International Index of Erectile Function
(IIEF) is a 15 item self-report inventory was spe-
cifically designed to assess changes in erectile
function in response to pharmacological inter-
ventions (Rosen [21], 1997). It measures erectile
function, orgasmic function, libido, and satisfac-
tion. This measure has the advantage of being
available in many languages, being simple to
administer, having high reliability coefficients,
and requiring less than 15 minutes to complete. It
has been shown to detect change in sexual func-
tion with treatment. A briefer five question ins-
trument is also available (Rosen [22], 1998).The
dimensional structure of this instrument has been
confirmed by factor analysis. Norms are under
development. This instrument merits serious
consideration in any trial of the treatment of erec-
tile dysfunction. It is less clear that this instru-
ment has value as a supplement to the sexual
interview in clinical practice or that this instru-
ment is sensitive in detecting changes in orgas-
mic function or sexual desire during treatment.
The questions contained in this instrument are
listed in Annex I.
A similar instrument is the Brief Male Sexual
Function Inventory (BMSFI) developed in a uro-
logic context by O’Leary and colleagues (O’Lea-
ry,1998; O’Leary [18], 1995). This 11 question
inventory is easy to use, psychometrically sound,
and available in over one dozen languages. It
measures drive, erectile function, ejaculation,
and satisfaction. It was developed to help evalua-
te patients in clinical practice as well as to mea-
sure outcome in clinical trials. Discriminant sen-
sitivity has been demonstrated and norms are in
the process of development. Many of the items in
this instrument overlap with those in the IIEF.
There is minimal evidence to recommend use of
one of these instruments over the other except
that the IIEF was utilized extensively in sildena-
fil trials and thus is a widely accepted instrument
in numerous countries.
The Derogatis Sexual Interview for Sexual Func-
tioning was developed by Lyn Derogatis, a high-
ly respected psychometrician in the United States
(Derogatis [5] 1997, Derogatis [6] 1998). The
advantage of this instrument is that it comes both
with a self report and a semi-structured interview
format. Each contains 25 items and takes
approximately 15 minutes to administer. The
psychometric properties of both versions are
exemplary., and it has both a male and a compli-
mentary partner version. It is available in 9 lan-
guages. Domains measured include sexual fan-
tasy, sexual arousal, sexual experience, orgasm,
arousal, and sexual drive. This instrument has a
companion female version. This instrument is
perhaps longer than necessary for clinical trials
yet contains information of value to the clinician
such as measures of the patient’s sexual expe-
rience and activity. The items on sexual fantasy
can also be valuable to clinicians. As both ques-
tionnaire and structured interviews have different
advantages in different contexts, this instrument
has the advantage of being able to use sister ins-
truments in different contexts. The respect with
which this instrument is held by other psychome-
tricians can be appreciated when it is realized
that most of the other instruments mentioned in
this report used correlations with the DSFE to
validate their instruments.
423
The Golombok Rust Inventory of Sexual Satis-
faction (GRISS) was developed primarily for
research purposes although it can be used both as
an assessment instrument as well as a therapy
outcome measure ( Kuile and Golombok, 1999;
Rust and Golombok,1985). This instrument has
both a male and female form. Each form contains
28 items and can be completed in approximately
10 minutes. Partner’s aggregated scores provide
a profile of a couple’s sexual functioning within
a relationship. Twelve subscales are scored. The
scales include impotence, premature ejaculation,
female anorgasmia, vaginismus, frequency of
sexual contact, sexual noncommunication, male
and female sexual dissatisfaction, male and
female dissatisfaction, male and female nonsen-
suality, male and female sexual avoidance. The
psychometric properties of this instrument are
excellent. It was developed in Great Britain and
has been translated into Dutch It has been shown
to demonstrate sex therapy induced change. This
instrument appears to be primarily of use for the
evaluation of the efficacy of nonpharmacological
therapies. However, the impact of pharmacologi-
cal therapy on some of the indices not usually
measured in drug studies could be of theoretical
importance.
Two other scales which show promise for clinical
trials include the Center for Marital and Sexual
Health Sexual Functioning Questionnaire
(CMASH-SFQ) and the Arizona Sexual Expe-
rience Scale (ASEX). The CMASH-SFQ was
previously known as the Case Western Reserve
Sexual Functioning Questionnaire and was deve-
loped primarily by Stan Althof and his colleagues
as part of a study of the efficacy of intracorporeal
injection of vasoactive substances (Glick [7],
1997). It is a 21 item questionnaire which address
specific items from both the patient’s and the
partner’s perspective. Domains measured include
frequency of sexual activity, quality of erections,
quality of orgasm, and sexual satisfaction. The
instrument has sound psychometric properties.
One advantage of the instrument is that the ques-
tionnaires from both partners are keyed to one
another and this factor can be used to correct for
possible distortion of responses by the patient.
Another advantage of this instrument is that it
was developed by a clinician actively involved in
the psychological as well as pharmacological
treatment of sexual disorders. Norms are not
available and to this author’s knowledge, it has
not been translated into other languages. This
instrument has been shown to be sensitive to the-
rapeutically induced changes. The questions in
this instrument are listed in (annex II).
A new instrument recently developed which
shows promise because of its inherent simplicity
and ease of use if the Arizona Sexual Experiences
Scale ( ASEX) (annex III). This instrument was
developed to measure sexual dysfunction in psy-
chiatric patients (Mc Gahuey [16], 1999). It
consists of both a male and a female version.
Each version consists of 5 items only which ask
questions about desire, arousal, erection or lubri-
cation, orgasm, and satisfaction. Its psychometric
properties appear sound. Norms are not available.
It is only available in English but translation
should be relatively easy. Each question is ans-
wered on a 6 point scale. For example, sex drive
is rated from extremely strong to no sex drive.
The brevity and simplicity of this questionnaire
are intriguing. Further study will indicate how
robust it is in detecting change in clinical trials.
Two other questionnaires in development require
mention. The Brief Sexual Function Questionnai-
re was developed by the depression study group
at the University of Pittsburgh to assess erectile
function in men with depression (Reynolds [20],
1998). This brief scale has a brief companion
scale for the partner and preliminary studies indi-
cate good psychometric properties. A similar
scale was developed by Anita Clayton at the Uni-
versity of Virginia to measure antidepressant
induced sexual dysfunction (Clayton [4], 1997).
Preliminary studies indicate that this instrument
has acceptable psychometric properties. Assess-
ment of Psychiatric Status
II. GENERAL PSYCHIATRIC
EVALUATION
A problem facing the non-psychiatric physician
in the evaluation of patients with erectile disorder
is the co-morbidity of sexual disorders with cer-
tain psychiatric syndromes (Othmer and Oth-
424
mer,1987; Lindal and Stefansson, 1993).
Although, various treatment approaches may
reverse erectile failure in psychiatric patients, the
clinician would not want to miss an underlying
treatable and possibly fatal psychiatric disease
such as major depressive disorder and panic
disorder. Both of these disorders have high suici-
de rates. A number of studies have repeatedly
demonstrated that general physicians under di-
agnose psychiatric disorders such as depression
and anxiety disorders (Hirshfield [9], 1997;
Lecrubier, 1998; Kessler [10], 1999; Weiler [29],
1998). Omnibus psychometric instruments such
as the MMPI are too comprehensive to be useful
as a screening instrument. The clinician has
several options. One is to use a brief instrument,
which screens several psychiatric conditions
such as Primary Care Evaluation of Mental
Disorders (PRIME-MD). However, this instru-
ment covers some disorders of peripheral interest
to the treatment of erectile disorder. (Spitzer [28],
1994). The primary conditions which the physi-
cian needs to screen are depression and anxiety
disorders. A variety of general surveys for the
measurement of depression such as the Beck
Depression Inventory (Beck [3], 1961, [2] 1979)
and anxiety (e.g. Spielberger State-trait Anxiety
Inventory, Spielberger [27], 1970, Whooley [31],
1997) are available but are too long to be easily
incorporated in a practice setting. Recent resear-
ch suggests that two questions are sufficient for
brief screening of depression. These could be
incorporated into a question-naire format. The
questions are:
1) During the past month, have you often been
bothered by feeling down, depressed or hope -
less?
2) During the past month, have you often been
bothered by little interest or pleasure doing
things?
Anxiety can be rapidly screened by using the
Fear, a rapid screening instrument for anxiety
consisting of four questions. (Krasuchi [12],
1999;Willchen [30], 1998).Two other issues that
the urologist might want to address are dependent
on the cultural context. If the primary sexual
partner is the spouse and if considerable marital
discord is present, the urologist might want to
consider referral for counseling as well as correc-
ting the erectile problem. A reasonably rapid tool
for screening for the presence of marital discord
is the Locke Wallace Marital Adjustment Test
(annex IV), a 15 item questionnaire requiring
minimal time to complete. Alonger instrument in
common use is the Dyadic Adjustment Scale
(Spanier, 1976). Another issue which may be dif-
ferent in different cultures is whether the urolo-
gists wishes to assess the sexual function of the
usual sexual partner prior to correcting erectile
function in the male. If a man has erectile func-
tion restored, his spouse may or may be pleased.
If his partner is postmenopausal without hormo-
ne replacement and has dyspareunia, a unilateral
approach to the couple’s sex life may create dif-
ficulties for the relationship, which might be
avoided by recognition of the spouse’s difficulty
and referral of the spouse to a gynecologist.
III. RECOMMENDATIONS
In the ideal setting, a clinician skilled in sexual
interviewing would assess the patient, deter-
mine the precise nature of his problem, deter-
mine whether it is secondary to treatable psy-
chiatric disease, whether it secondary to rela-
tionship discord, and assess the impact of res-
tored function on the relationship. The inter-
viewer would also interview the partner. This
is important as many men seeking therapy for
erectile dysfunction are in their late 50’s, an
age during which their partners may be post-
menopausal. In most contexts, such an ideal
situation is impossible to obtain. Many men
refuse to involve their partners in treatment
and cultural tradition may render this impos-
425
sible in some settings. In some locations, there
may be a scarcity of clinicians with clinical
skills in sexual interviewing. In these settings,
the use of questionnaires may serve to aug-
ment the clinician in his or her diagnostic and
treatment decisions. Although any of the ins-
truments mentioned above would suffice, the
IIEF has the advantage of being brief and
being available in many different languages.
The two questions about depression could be
combined with the Fear anxiety scale provi-
ding a quick screen of anxiety and depression.
The physician can always question the man
about his relationship with the partner and
about his partner’s health.
In clinical trials, a standardized questionnai-
re offers the advantage of ratings, which are
independent of clinician skill and bias. Again,
the IIEF is an excellent instrument, which can
detect changes in arousal , ejaculation, and
libido. It should be combined with instru-
ments to detect anxiety, depression, and mari-
tal discord.
ANNEXES
I. INTERNATIONAL INDEX OF ERECTILE FUNCTION
II. THE C-MASH
III. ASEX
IV. L OCKE-WALLACE MARITAL ADJUSTMENT
TEST
V. THE FEAR

REFERENCES
1 ABEL GG, BECKER JU, CUNNINGHAMATHER J,
MITTELMAN M, & PRIMACK M. Differential diagno-
sis of impotence in diabetics. Neuro Urodynamics, 1982,
1,57-69.
2. BECK AT, RUCH AJ, SHAW BF, EMERY G. Cognitive
therapy of depression. New York, Guilford, 1979.
3 BECK A, WARD C, MENDELSON M. An inventory for
measuring depression. Arch Gen Psychiatry, 1961, 4, 53-
63.
4 CLAYTON AH, MCGARVEY EL,CLAVET GJ, PIAZ-
ZA, L. Comparison of sexual functioning in clinical and
nonclinical populations using the Changes in Sexual
Functioning Questionnaire (CSFQ). Psychopharmaco
Bull, 1997,33,747 53.
5 DEROGATIS LR . The Derogatis Interview for Sexual
Functioning ( DISF/DISF-SR ):an introductory report. J
of Sex Marit Ther, 1997,23,291-304.
6 DEROGATIS LR. , LABAN MP. Psychological assess-
ment measures of human sexual functioning in clinical
trials. Int Impot Res, 1998,10,Suppl 2, S13-20.
7 GLICK HA, MCCARRON TJ., ALTHOF SE, CORTY
EW, WILLKE RJ. Construction of scales for the center
for marital and sexual health ( CMASH ) sexual functio-
ning questionnaire. J Sex Marit Ther, 1997,23,103-117.
8 HAMILTON M. A rating scale for depression. J Neurol
Neurosurg Psychiatry, 1960,22,56-62.
9 HIRSCHFIELD RMA, KELLER MD. PANICO S. The
national depressive and manic-depressive association
consensus statement on the undertreatment of depression.
JAMA, 1997, 275,233-340.
10 KESSLER D,LLOYD K, LEWIS G, GRAY DP. Cross
sectional study of symptom attribution and recognition of
depression and anxiety in primary care. BMJ,
1999,318,436-440.
11 KOCKETT G, FEIL W, REVENSTORF D, ALDEN-
HOFF J, BESINGER U. Symptomatology and [psycho-
logical aspects of male sexual inadequacy:results of an
experimental study. Arch Sex Behav,1980,9,457-475.
12 KRASUCKI C, RYAN P, ERTAN T, HOWARD R, LIN-
DESAY J, MANN, A. The FEAR:a rapid screening ins-
trument for generalized anxiety in elderly primary care
attenders. Frequency of anxiety, enduring nature of
anxiety, alcohol or sedative ,restlessness of fidgeting. Int
J Geriatr Psychiatry,1999,1,60-68.
13 KUILE MMT., LANKVELD JJMV, KALKHOVEN P,
EGMOND MV. The Golombok Rust Inventroy of Sexual
Satisfaction ( GRISS ) :Psychometric Properties within a
Dutch Population. J Sex and Marital Ther, 1999,25,59-
71.
14 LECRUBIER Y. Is depression under-recognized and
undertreated? Int Clin Psychopharmacol, 1998, suppl5,
S3-6.
15 LINDAL E, STEFANSSON JG. The lifetime prevalence
of psychosexual dysfunction among 55 to 57-year olds in
Iceland. Soc Psychiatr Epidemiol, 1993, 2,91-95
16 MCGAHUEY CA, GELENBERG AJ, LAUKES CA,
426
MCKNIGHT KM, MANBER R, MORENO FA, DEL-
GADO PL. The Arizona Sexual Experience Scale
(ASEX): reliability and validity. J Sex Marit Ther, 1999
(In Press )
17 OTHMER E & OTHMER SC. Evaluation of sexual dys-
function. J Clin Psychiat,1987,48,191-193
18 O’LEARY M.P. Clinical trials in sexual dysfunction. Int
J Impot Res, 1998,10,suppl2,S7-12.
19 O’LEARY MP ,FOWLER FJ, LENDERKING WR,
BARBER B, SAGNIER PP,GUESS HA, BARRY MJ. A
brief male sexual function inventory for urology. Urolo-
gy,1995, 46, 697-706.
20 REYNOLDS CF, FRANK E, THASE ME, PATRICIA
R, HOUCK J, JENNINGS R, HOWELL JR, LILIEN-
FIELD SO, KUPFER DJ. Assessment of sexual function
in depressed, impotent, and healthy men: factor analysis
of a brief sexual function questionnaire for men, Psych
Res,1998,24,231-250.
21 ROSEN R, RILEY A.,WAGNER G.,OSTERLOH IH,
KIRKPATRICK J,MISHRA A.. The index of erectile
dysfunction: a multidimensional scale for assessment of
male erectile dysfunction. J Urol, 1996,155,466A.
22 ROSEN R., CAPPWLLERI J.C.,SMITH MD, LIPSKY
J,PEFIA BM. Constructing and evaluating the sexual
health inventory for men:IIEF-5 as a diagnostic tool for
erectile dysfunction. Int J Impot Res, 1998,10,S35.
23 RUST, J, GOLOMBOK S. The Golombok Rust Invento-
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chol,1985,24,63-64.
24 SEGRAVES RT, SCHOENBERG HW, ZARINS CK,
KNOPF, J & CAMIC P. Discrimination of organic versus
psychogenic impotence with the SDFI: a failure to repli-
cate. J Sex Marit Ther, 1981,7,230-238.
25 SEGRAVES KA, SEGRAVES RT, SCHOENBERG HW.
Use of sexual history to differentiate organic from psy-
chogenic impotence. Arch Sex Behav, 1987,16,125-137.
26 SPANIER BG. Measuring dyadic adjustment:new sclaes
for assessing the quality of mariage and similar dyads. J
Marr Family,1976,24,15-26.
27 SPIELBERGER CD, GORSUCH ZRL, LUSHENE RE.
STAI Manual. Palo Alto,Consuting Psychology Press,
1970.
28 SPITZER RL, WILLIAMS JB, KROENKE K, LINZER
M, DEGRUY FV, HAHN SR, BRODY D, JOHNSON
JG. Utility of a new procedure for diagnosing mental
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JAMA, 1994,272,1749-1756.
29 WEILLER E, BISSERBE JC, MAIER W, LECRUBIE-
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30 WITTCHEN HU, BOYER P. Screening for anxiety
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31 WHOOLEY MA, AVINS AL, MIRANDA J, BROW-
NER WS. Case finding instruments for depression. Two
questions are as good as many. J Gen Intern Med, 1997,
12, 439-445.

E. PRACTICAL GUIDELINES
FOR GENERAL UROLOGICAL
PRACTICE
To be able to offer men with erectile dysfunction
the best possible help, urologists will have to be
prepared to continue to work with qualified psy-
chologists or sexologists.
If a case presents itself, general practitioners
should refer patients primarily to sexologists or
urologists trained in sexology, who closely work
together, not competitve.
Urologists treating patients with erectile dysfunc-
tion should be sensitive to the emotional meanings
patients unconsciously attach to this sexual dys-
function. These meanings are often extremely
important, self-evident, unquestionable truths to
the patient and his partner, based on long-held
beliefs about sexual dysfunction, but are not
necessarily self-evident to the urologists.
Our first task is to try to understand the
patient’/partner’s beliefs, and to offer the best
understanding of the likely causes of the erectile
dysfunction. The challenge is to help patients
approach their sexual problem as they do other
health problems: to understand what might be
contributing to it, to evaluate the treatment
options, and to proceed with the treatment that
best meets their physical and emotional needs.
If erectile dysfunction and other sexual com-
plaints, such as premature ejaculation, are viewed
purely as physical abnormalities, then we run the
risk of medicalising sexuality too much. In addi-
tion, there is the risk of further standard isation,
perfectionism, mechanisation and dehumanisation
of sexual relationships.
A ‘mechanical’approach is the biggest turn-off for
a woman. She will feel that she is being treated
like a machine or a doll: no emotional communi-
cation, no fun, just pure calculation to get the job
done as effectively as possible.
Some psychologists and sexologists, not surprisin-
gly, are sickened by the fact that today so much
attention is paid to the phallus. Despite all the
shortcomings of sex therapy, it does at least lay
427
some degree of emphasis on mutual pleasure,
communication and creativity; and both men and
women are invited to participate. Neither the man
nor the woman is excluded, nor kept in the dark.
Obviously some women will find more enjoyment
in harder and more long-lasting erections; and
some women will benefit more if their partner is
no longer weighed down by fear of failure and has
regained sufficient self confidence to be able to
have sex
Hard and long-lasting erections are not automati-
cally a blessing for mankind! Many women will
probably not be pleased with the idea of frequent
confrontations with a rigid penis when they are in
their seventies or eighties. Female sexologists
have very good reason to point out carefully that
the vagina of a post-menopausal woman does not
usually become very well-lubricated, in other
words, is no longer meant to be penetrated.
Growing older means an unpleasant physical
decline. That will never change. However, many
of us live in western society in which a healthy,
vigorous, ‘young’, beautiful and potent body has
been elevated to measuring-rod status. In fact, the
ideal view of the body as ‘a machine that must
function well for ever and ever’ is based on sup-
pression, not only by present-day Young-One cul-
ture, but also by ourselves. Suppression of the
undeniable reality that every single one of us lives
in a body that is mortal, that can let us break down,
that becomes ill, and that one day day will die.
Patients as well as their partners may have serious
emotional reactions (anxiety, depression and even
fear for death) to what they believe erectile dys-
function represents. These reactions are not neces-
sarily relieved by an oral drug, an intra-urethral
prostaglandine, an intracavernous injection, a
vacu-pump, or a penile prosthesis.
Unsuccessful treatments are often due to one or
more of the following elements:
unrealistic expectations on the part of the patients,
unclear communication, misunderstandings on the
part of the partner, and/or unresolved conflicts in
the relationship which the restoration of erectile
functioning does not resolve.
In many cases, the fundamental problem is not so
much erectile dysfunction, as the sexual relation-
ship. In this situation we must be careful that erec- • Emphasize that almost everyone has a psycho-
tion and coitus do not become the ultimate goals of logical reaction to erectile dysfunction even if
urological treatments. its cause is primarily physical.
Our main goal must be to restore both a healthy • Discuss all the current (symptomatic) treatment
physical and emotional outlook to the patient and options including thier risks.
his partner and therefore to improve their ultimate
• Help the couple to take responsibility for their
satisfaction with our treatments [1].
choice(s) including the unknown outcomes.
In order to achieve this the following recomman -
• Support a couple with counseling in adjusting
dations can be given:
to the new situation (‘the rigid penis’) and re-
• Realize that when a man has an erection pro- evaluate them in case of difficulties.
blem, the couple has a sexual problem. • Let them know that failure of one treatment
• Try to get the partner involved early in the pro- does not mean they need to give up!
cess of diagnosis and treatment. Such partici-
pation enhances communication and can redu-
ce stress and anxiety for everyone.
REFERENCE
• Educate the couple: explain in detail the
mechanism of erection and the multicausal
nature of erectile dysfunction; dispel any myths
that they have concerninq penile 1. BERGER RE, BERGER DM, HAPPE-HARTSELL,
HEIMAN JR. Couples: The art of solving impotence
• Learn each partner’s reaction to the erection problems. AUA Update Series, Lesson 20, Volume VII,
problem, no matter what its cause(s), and help 1988.
the couple to understand her reaction. The part-
ner in a couple with erectile dysfunction may ________________________
need as much or even more help than your
‘patient’.

428
 ANNEX I.
INTERNATIONAL INDEX OF ERECTILE FUNCTION QUESTIONNAIRE
Please answer the following questions as honestly and clearly as possible.
In answering these questions the following definitions apply:
• Sexual activity included intercourse, caressing, foreplay and masturbation.
• Sexual intercourse is defined as vaginal penetration of the partner ( you entered your partner )
• Sexual stimulation includes situations like foreplay with a partner, looking at erotic pictures, etc
• Ejaculation is defined as the ejection of semen from the penis ( or the feeling of this )
Please answer the following questions for the past -------weeks by checking one box per question.

1. How often were you able to get an erection during sexual activity?
• No sexual activity
• Almost never/never
• A few times (much less than half the time)
• Sometimes (about half the time)
• Most times (much more than half the time)
• Almost always/always

2. When you had erections with sexual stimulation, how often were your erections hard enough for
penetration?
• No sexual activity
• Almost never/never
• A few times ( much less than half the time )
• Sometimes ( about half the time )
• Most times ( much more than half the time )
• Almost always/always

3. When you attempted sexual intercourse, how often were you able to penetrate (enter) your
partner?
• Did not attempt intercourse
• Almost never/never
• A few times (much less than half the time)
• Sometimes (about half the time)
• Most times (much more than half the time)
• Almost always/always

4. During sexual intercourse, how often were you able to maintain your erection after you had
penetrated ( entered) your partner?
• Did not attempt intercourse
• Almost never/never
• A few times (much less than half the time)
• Sometimes (about half the time)
• Most times ( much more than half the time )
• Almost always/always

429
5. During sexual intercourse, how difficult was it to maintain your erection to completion of
intercourse?
• Did not attempt intercourse
• Extremely difficult
• Very difficult
• Difficult
• Slightly difficult
• Not difficult

6. How many times have you attempted sexual intercourse?

• No attempts
• One to two attempts
• Three to four attempts
• Five to six attempts
• Seven to ten attempts
• Eleven + attempts

7. When you attempted sexual intercourse, how often was it satisfactory for you?
• Did not attempt intercourse
• Almost never/never
• A few times ( much less than half the time )
• Sometimes ( about half the time )
• Most times ( much more than half the time )
• Almost always/always

8. How much have you enjoyed sexual intercourse?

• No intercourse
• No enjoyment
• Not very enjoyable
• Fairly enjoyable
• Highly enjoyable
• Very highly enjoyable

9. When you had stimulation or intercourse, how often did you ejaculate?
• No sexual stimulation/intercourse
• Almost never/never
• A few times ( much less than half the time )
• Sometimes ( about half the time )
• Most times ( much more than half the time )
• Almost always/always

430
10. When you had sexual stimulation or intercourse, how often did you have the feeling of orgasm
or climax?
• No sexual stimulation/intercourse
• Almost never/never
• A few times ( much less than half the time )
• Sometimes ( about half the time )
• Most times ( much more than half the time )
• Almost always/always
The next two questions ask about sexual desire. Let’s define sexual desire as a feeling that may include
wanting to have a sexual experience ( for example, masturbation or intercourse ), thinking about having
sex, or feeling frustrated due to lack of sex.

11. How often have you felt sexual desire?

• Almost never/never
• A few times ( much less than half the time )
• Sometimes ( about half the time )
• Most times ( much more than half the time )
• Almost always/always

12. How WOULD You rate your level of sexual desire?

• Very low/none at all
• Low
• Moderate
• High
• Very high
13. How satisfied are you with your overall sex life?
• Dissatisfied
• About equally satisfied and dissatisfied
• Very dissatisfied
• Moderately satisfied
• Very satisfied
14. How satisfied have you been with your sexual relationship with your partner?
• Dissatisfied
• About equally satisfied and dissatisfied
• Very dissatisfied
• Moderately satisfied
• Very satisfied
15. How do you rate your confidence that you could get and keep an erection?
• Very low
• Low
• Moderate
• High
• Very high
REPRODUCED WITH PERMISSION OF THE AUTHOR.

431
 ANNEX II.
THE C-MASH

1. Have you had any difficulties obtaining a firm hard, long-lasting erection?
YES NO

2. Are you currently having any difficulties obtaining a firm, hard, long-lasting erection?
YES NO

2A. HOW LONG AGO DID THIS CURRENT ERECTILE PROBLEM BEGIN? _____________________
3. THE FOLLOWING QUESTIONS ASK YOU TO THINK ABOUT YOUR SEXUAL DRIVE DURING THE PAST 30 DAYS.
3A. HOW MANY TIMES IN THE PAST 30 DAYS DID YOU FEEL SEXUAL DESIRE ( HORNEY,
THE DESIRE TO HAVE SEX? ____________________

3B.HOW MANY TIMES IN THE PAST 30 DAYS DID YOU ENGAGE OR ATTEMPT TO ENGAGE
IN INTERCOURSE? _____________________

3C. HOW MANY TIMES DID YOU AND YOUR PARTNER ENGAGE IN OTHER SEXUAL ACTIVITY
IN THE PAST 30 DAYS? _____________________

3D. HOW MANY TIMES DID YOU MASTURBATE IN THE PAST 30 DAYS? _____________________

4. These next questions ask you to judge the quality of your erections under different circumstances
during the past 30 days.
• Each rating scale goes from 0 to 8 ( no erection to full erection )
• Please circle the number ( 0 to 8) on each scale that best reflects the quality of your erection under
each of the following circumstances.
• If you have not engaged in that particular activity, circle NA ( not applicable )
Please rate the quality of your erections during the past 30 days.
4a. Quality of erection during the night or upon awakening
NO ERECTION SEMI-FIRM FULL
0 1 2 3 4 5 6 7 8
4b. Quality of erections spontaneously or when reading about. Looking at, or thinking
about something sexy
NO ERECTION SEMI-FIRM FULL
0 1 2 3 4 5 6 7 8
4c. If you have engaged in masturbation during the past 30 days, rate quality of erection
during masturbation.
NO ERECTION SEMI-FIRM FULL
0 1 2 3 4 5 6 7 8
4d. If you have engaged in foreplay in the past 30 days, rate quality of erection during foreplay.
NO ERECTION SEMI-FIRM FULL
0 1 2 3 4 5 6 7 8
4e. If you have engaged in intercourse during the past 30 days, rate quality of erection during
intercourse
NO ERECTION SEMI-FIRM FULL
0 1 2 3 4 5 6 7 8
432
5. Now think back over the past 3 months.
The following questions concern your experience with orgasm ( ejaculation or “coming”) during this
time period.
• Please circle the number (0-8) on each scale that best reflects how often you have reached orgasm
under each of the following circumstances.
• If you have not engaged in a particular activity during the past 3 months, circle NA (not applicable for
that activity.

5a. How often in the past 3 months have you had an orgasm during intercourse?
ALMOST SOMETIMES ABOUT HALF MOST OF ALMOST
NEVER OF THE TIME THE TIME ALWAYS
NA 0 1 2 3 4 5 6 7 8

5b. How often have you had an orgasm during masturbation in the past 3 months?
ALMOST SOMETIMES ABOUT HALF MOST OF ALMOST
NEVER OF THE TIME THE TIME ALWAYS
NA 0 1 2 3 4 5 6 7 8

5c. How often did you ejaculate (come ) more quickly than you would like during intercourse
in the past 3 months?
ALMOST SOMETIMES ABOUT HALF MOST OF ALMOST
NEVER OF THE TIME THE TIME ALWAYS
NA 0 1 2 3 4 5 6 7 8

5d. How often did it take you longer than you’d like to reach orgasm during intercourse in
the past 3 months?
ALMOST SOMETIMES ABOUT HALF MOST OF ALMOST
NEVER OF THE TIME THE TIME ALWAYS
NA 0 1 2 3 4 5 6 7 8

6. The final two questions concern your overall satisfaction with your sexual life during the
past 3 months.
• Please circle the number ( 0-5) on each scale which best reflects your degree of satisfaction.
• If you have not engaged in any type of sexual activity in the past 3 months, circle NA.
6a.How satisfied have you felt after a typical sexual encounter in the past 3 months?

EXTREMELY MODERATELY MILDLY MILDLY MODERATELY EXTREMELY

UNSATISFIED UNSATISFIED UNSATISFIED SATISFIED SATISFIED SATISFIED
NA 0 1 2 3 4 5

6b. How satisfied do you think your partner has felt after a typical sexual interaction during
this time period?

EXTREMELY MODERATELY MILDLY MILDLY MODERATELY EXTREMELY

UNSATISFIED UNSATISFIED UNSATISFIED SATISFIED SATISFIED SATISFIED
NA 0 1 2 3 4 5

REPRODUCED WITH PERMISSION OF THE AUTHOR.

433
 ANNEX III.
ARIZONA SEXUAL EXPERIENCES SCALE ( ASEX ) -MALE

For each item, please indicate your overall level during the past week including today.

1. How strong is your sex drive?

1 2 3 4 5 6
extremely very somewhat somewhat very no sex
strong strong strong weak weak drive

2. How easily are you sexually aroused ( turned on ) ?

1 2 3 4 5 6
extremely very somewhat somewhat very never
easily easily easily difficult difficult aroused

3. Can you easily get and keep an erection?

1 2 3 4 5 6
extremely very somewhat somewhat very never
easily easily easily difficult difficult

4. How easily can you reach an orgasm?

1 2 3 4 5 6
extremely very somewhat somewhat very never
easily easily easily difficult difficult reach
orgasm

5. Are your orgasms satisfying?

1 2 3 4 5 6
extremely very somewhat somewhat very can’t
satisfying satisfying satisfying unsatisfying unsatisfying reach
orgasm

ARIZONA BOARD OF REGENTS, COPYRIGHTED 1997, REPRINTED WITH PERMISSION.

434
 ANNEX IV.
MARITAL-ADJUSTMENT TEST
1. Check the dot on the scale line below which best describes the degree of happiness, everything conside-
red, of your present marriage. The middle point, "happy", represents the degree of happiness which most
people get from marriage, and the scale gradually ranges on one side to those few who are very unhappy
in marriage, and on the other, to those few who experience extreme joy or felicity in marriage.

VERY HAPPY PERFECTLY

UNHAPPY HAPPY
State the approximate extent of agreement or disagreement between you and your mate on the following
items. Please check each column.

Almost Almost
Always Always Occasionally Frequently Always Always
Agree Agree Disagree Disagree Disagree Disagree
2. Handling family finances
3. Matters of recreation
4. Demonstrations of affection
5. Friends
6. Sex relations
7. Conventionality (right, good,
of proper conduct)
8. Philosophy of life
9. Ways of dealing with in-laws

For the questions below please check the most appropriate answer.

10. When disagreements arise, they usually result in:

Husband giving in ( ) Wife giving in ( ) Agreement by mutual give and take ( )

11. Do you and your mate engage in outside interests together?

All of them ( ) Some of them ( ) Very few of them ( ) None of them ( )

12. In leisure time do you generally prefer:

To be "on the go" ( ) To stay at home ( )
Does your mate generally prefer:
To be "on the go" ( ) To stay at home ( )

13. Do you ever wish you had not married?

Frequently ( ) Occasionally ( ) Rarely ( ) Never ( )

14. If you ever had your life to live over, do you think you would:
Marry the same person ( ) Marry a different person ( ) Not marry at all ( )

15. Do you confide in your mate:

Almost never ( ) Rarely ( ) In most things ( ) In everything ( )

435
 ANNEX V.
THE F.E.A.R.

1. IN THE PAST MONTH HAVE YOU FELT

SO FIDGETY OR RESTLESS THAT YOU
COULDN'T SIT STILL?

IF YES : DO YOU KNOW WHAT BROUGHT IT ON? Please circle or tick your
Responses in this column
WAS IT DUE TO WORRY, FEAR,
OR SOMETHING ELSE? Restlessness due to
Worry/fear/anxiety

No 0
Yes 1

2. HOW OFTEN, IF AT ALL, HAVE YOU

WORRIED IN THE PAST MONTH?
Never 0
Some Days 0
Most Days 0
All the time 1

3. IN GENERAL, WOULD YOU DESCRIBE

YOURSELFAS A WORRIER?
No 0
Yes 1

4. DO YOU TAKE ANYTHING TO HELP Sedative tablets No 0

YOU RELAX? Or alcohol to relax Yes 1

WHAT ABOUT SEDATIVE TABLETS OR

ALCOHOL?

*REPRODUCED WITH PERMISSION BY THE INSTITUTE OF PSYCHIATRY, DENMARK HILL, LONDON

436
 Committee 12

Peyronie’s Disease

Chairman
T.F. LUE

Members
M.K. GELBARD,
G.GUEGLIO,
G.H. JORDAN,
L. A. L EVINE,
R. MORELAND,
J. PRYOR,
D. R ALPH,
D. YACHIA

437
 CONTENTS

I. INTRODUCTION VIII. CLINICAL FEATURES

II. INCIDENCE IX. MEDICAL MANAGEMENT

III. ETIOLOGY X. SURGICAL TREATMENT

IV. PATHOLOGY XI. PENILE ANOMALIES THAT

MAY CAUSE ERECTILE
DYSFUNCTION
V. MOLECULAR BASIS OF
PEYRONIE’S DISEASE
XII. CONCLUSION

VI. NATURAL HISTORY XIII. RECOMMENDATIONS

VII. PSYCHOLOGICAL ISSUES REFERENCES

438
 Peyronie’s Disease
T.F. LUE
M.K. GELBARD, G.G UEGLIO, G.H. J ORDAN, L. A. L EVINE, R. M ORELAND, J. P RYOR,
D. R ALPH, D. YACHIA-
I. INTRODUCTION
Peyronie's disease was first reported by Fallopius
in 1561 and popularized in 1743 by Francois
Gigot de la Peyronie, surgeon to King Louis XVof
France, a disease that has since born his name.
Peyronie’s disease (indurato penis plastica) is a
condition which is characterized by the formation
of fibrous nodules within the tunica albuginea.
These plaques impede tunical expansion during
erection resulting in penile bending. In some
extreme cases, these plaques may induce a collar-
like or an hourglass-like appearance in the erect
penis.
Peyronie's disease has a colorful history, a volumi-
nous literature, but not, unfortunately, a cure.
However, most patients benefit from medical
attention. For some, reassurance is sufficient. For
others, medical therapy may promote stabilization
or improvement. A minority of patients, afflicted
with disabling deformity, may find palliation in
surgical procedures. That somewhat negative-
sounding opening statement summarizes the clini-
cal management of this disorder. Fortunately,
ignorance of origin and cure does not translate into
therapeutic nihilism. To tell patients that nothing
can be done is to misinform them; to offer surgery
indiscriminately is worse. The physician’s challen-
ge is to steer a course between these two extremes,
providing a combination of counseling, guidance,
supportive therapy, and when necessary, surgery
uniquely tailored to each individual.
439
II. INCIDENCE
Peyronie’s disease has been reported to occur in
association with Dupuytren’s contractures, plantar
fascial contractures, tympanosclerosis as well as
trauma, urethral instrumentation, diabetes, gout,
pagets disease, and the use of beta blockers [1].
This condition can occur in a familial pattern [2].
There is a 10 to 40% chance that the descendent of
a patient with Dupuytrens contracture will develop
that problem, and a 15% chance that a man so
afflicted will develop Peyronie’s disease. Dupuy-
tren’s contracture is a genetic disorder known to be
transmitted in an autosomal dominant pattern.[2],
[3].
One university-based survey placed the incidence
of Peyronie’s disease at approximately one in a
hundred [4]. A thirty-five year retrospective study
in Rochester, Minnesota is notable. In this study,
comprised primarily of Caucasian men, the avera-
ge age of onset was 53 years old, with a prevalen-
ce of 388.6/ 100,000 (0.4%) [5]. Further, over a
thirty-five year period, both total Peyronie’s disea-
se and Peyronie’s disease associated with pain and
impotence increased. This may be an actual
increase in disease occurrence or due to heighte-
ned patient awareness and seeking of medical
attention. Interestingly, rheumatoid arthritis (p <
0.0001) and hypertension (p < 0.01) were the most
commonly associated conditions reported in this
group of Peyronie’s disease patients. It should be
noted that the study described above probably
underestimates the true prevalence of Peyronie’s
disease as indicated by autopsy studies. In a study
of 100 men who had no known Peyronie’s disease,
22/100 has asymptomatic, fibrotic lesions of the
tunica albuginea [6]. This suggests that in the
natural course of aging and sexual activity, these
asymptomatic lesions may develop. The prevalen-
ce of Peyronie’s disease probably is much higher
than 0.4% if one includes subclinical and asymp-
tomatic cases [4].
Disease incidence peaks in the mid-fifties coinci-
ding with a more generalized age-related loss of
tissue elasticity. While there is no evidence to sug-
gest the epidemiology of this disease is changing,
some believe the clinical incidence is increasing.
This may be less a consequence of pathobiology
than of the increasing number of men using medi-
cations for erectile dysfunction. Patients previous-
ly sexually inactive may resurrect themselves with
drugs only to discover a bent penis.
III. ETIOLOGY
Contemporary thinking suggests Peyronie’s disea-
se represents a localized abberation of the wound
healing process. Pathologically, Peyronie’s
plaques begin with fibrin deposition and end up
looking like scars. A number of factors may contri-
bute to the initiation of this process. Intermediary
steps on route to scar maturation have long been
sought as pharmacological entry points for the
modification or abrogation of this ubiquitous pro-
cess. Drug based modification of scarring has been
more of a theoretical goal than a practical reality to
date, though research in connective tissue biology
has expanded the knowledge base in this field
considerably.
Clinical data, anatomical pathology, and bioengi-
neering analysis all implicate trauma as an initia-
tion factor in Peyronie’s disease [7]. A survey
among 732 patients demonstrated an association
between penile trauma and both Peyronie’s disea-
se and erectile dysfunction [8]. Peyronie’s disease
is most prevalent after the fifth decade, when col-
lagenous connective tissue has begun to loose its
protective elasticity. Documented by studies of
elastic fiber fragmentation in Peyronie’s disease,
this change renders the tunica more vulnerable to
440
the effects of repeat tensile stress. Fibrin deposi-
tion is recognized as one of the initial conse-
quences of microvascular injury, and it may be the
precursor to Peyronie’s plaque formation [9].
Force-deformation analysis of tunica albugenea
during erection reveals the dorsal midline region
experiences internal destructive stress, and is sur-
rounded by a region of shear stress. These regions
both predispose to delamination, and are located
anatomically where the disease usually develops
[7, 8]. The observed pattern of plaque location
may be closely approximated by utilizing the
known relationship between tensile stress and
fibrosis, then mapping this according to the parti-
cular stress distribution found throughout the tuni-
ca during erection [10].
Genetics and Occurrence. The search for a gene-
tic link for Peyronie’s disease has yet to identify a
genetically predisposed population. However,
there are reports associating this condition and
Paget’s disease of the bone [11], Dupuytren’s
contracture (2)and specific HLA subtypes [2, 3,
12]. In all of these studies, patients reporting one
of the traits (Paget disease of the bone, Dupuy-
tren’s contracture or specific HLA subtypes) did
not always report symptoms of Peyronie’s disease.
Studies of Peyronie’s patients have implicated an
auto-immune component. It has been reported that
Peyronie’s disease patients had at least one abnor-
mal immunologic test (75.8%), alterations in cell-
mediated immunity (48.5%) and in markers of
auto-immune disease (37.9%) [13]. Another study
found higher than normal levels of anti-elastin
antibodies in the serum of patients with Peyronie’s
disease, suggesting an autoimmune etiology[14].
It is likely that a certain proportion of men in this
age group respond to mechanical tunical stress and
microvascular trauma[15] [7, 8] with an aberrant
or hyperactive wound healing response [16]. Thus,
there may be a subpopulation whose genetic back-
ground is such that response to wound healing pre-
disposes development of Peyronie’s plaques.
IV. PATHOLOGY
Perivascular round cell infiltration can be found
adjacent to the tunica albuginea in association
with Peyronie’s disease, though this is not a
constant feature of the disease [17]. It may repre-
sent no more than a response to trauma, as one
study turned up this histologic finding in 23% of
cadavers without evidence of Peyronie’s disease.
[6] Fibrin deposition, presumably from microvas-
cular injury, has been found in relation to Peyro-
nie’s plaques, but not in normal or scarred tunica
from individuals without Peyronie’s disease. [9]
Centrally, plaques consist of dense collagenous
connective tissue. Elastic fibers are reduced in
number, and often display fragmentation. Cartila-
ginous metaplasia can occur, and in about one
third of patients, radiologically demonstrable dys-
trophic calcifications is present [18]. The scar tis-
sue of Peyronie’s disease contains excessive
amounts of type III collagen, which renders it par-
ticularly responsive to the wound contraction pro-
cess [19]
The microscopic anatomy of the tunica albugi -
nea and its impact on Peyronie’s disease plaques.
The tunica albuginea is a multilayered structure of
inner circular and outer longitudinal layers of
connective tissue encompassing the pair of corpo-
ra cavernosa [20] [21]. An incomplete septum
separates the two corpora cavernosa and anchors
into the circular inner layer. In the distal, pendu-
lous penis, intracavernous pillars anchor the tuni-
ca across the corpora cavernosa at the two and six
o’clock positions with minor struts branching off
of these pillars at the five and seven o’clock posi-
tions. It has been demonstrated that tunical thick-
ness varies from 1.5 to 3mm thick depending on
the circular position around the tunica[20] [21].
The longitudinal outer layer which provides
strength to the tunica albuginea is absent at the six
o’clock position where the corpus spongiosum fits
in the indentation between the two corpora caver-
nosa [21]. It has been proposed that this design
allows unrestricted expansion of the corpus spon-
giosum such that ejaculation is unimpeded during
penile erection [21]. The longitudinal layer is also
thinnest at the three and nine o’clock positions;
consistent with the greatest number of traumatic
penile fractures in those positions [20]. Patients
with Peyronie’s disease most often show plaque
formation on the dorsal side of the penis [22] [10]
[23]. There may be two possible reasons for this
observation. First, the dorsal aspect is opposite the
portion of the tunica lacking longitudinal fibers
and thus upper bending during erection is possible
[3]. Further, the joining of the septum into the cir-
441
cular inner layers of the tunica may be particular-
ly susceptible to microvascular trauma and tunical
delamination [15] [8] [7]. The tunica albuginea is
composed of fibrillar (mainly type I but also type
III) collagen in organized arrays interlaced with
elastin fibers [21]. Peyronie’s plaques are also
composed almost entirely of types I and III colla-
gen [24]. While collagen has a greater tensile
strength than steel, it is unyielding. In contrast,
elastin can be stretched up to one hundred fifty
percent of its length [21]. It is the elastin content
that allows the compliance of the tunica albuginea
and helps to determine stretched penile length
[25]. Disorganization of the circular or longitudi-
nal layers in the tunica as well as disruption of
elastin or a decrease in elastin content has been
reported in Peyronie’s disease and can result in
penile deformities during erection as well as erec-
tile dysfunction [26].
V. MOLECULAR BASIS OF
PEYRONIE’S DISEASE
1. TUNICAL MECHANICAL STRESS AND
MICROVASCULAR TRAUMA
One of the most likely causes of Peyronie’s disea-
se may be repeated tunical mechanical stress and
microvascular trauma. Excessive bending during
erection or blunt trauma to the erect penis may
result in bleeding into the subtunical spaces or
tunical delamination at the point where the septum
integrates into the inner circular layer of the tuni-
ca albuginea [15] [8] [7]. Such microvascular trau-
ma may come from sexual intercourse; either with
the woman on top (torque to the penis with an
upward twist applying pressure to the septum tuni-
ca junction) or an accident during penetration
where the man misses the vagina and fractures the
penis. Microvascular trauma or subtunical blee-
ding can result in fluid and fibrinogen in the sub-
tunical layers. The resulting fibrin deposits may be
key in the initiation of a wound healing response
which encompasses pain, hematoma and subse-
quent inflammatory response with recruitment of
macrophages and neutrophils [16] [27] [9].These
cells, in response to clot formation, release a varie-
ty of cytokines, autocoids and vasoactive factors
which may precipitate a fibrotic reaction (see
below). The unique anatomy of the tunica albugi-
nea with its multiple subleyers of dense fibrous tis-
sue and hypovascularity may "trap" the inflamma-
tory reaction, prolonged the process to months or
years and therefore foster the formation of Peyro-
nie's plaque.
In order to better understand the molecular patho-
logy of Peyronie’s disease, it is helpful to review
the events in a normal wound healing response
[16] [27] [9]. Microvascular trauma leads to extra-
vascular leakage of blood, with thrombus forma-
tion. Platelets release their contents including
serotonin, platelet derived growth factors (PDGF-
A and PDGF-B) as well as transforming growth
factor-b1 (TGF-b1). Thrombus formation leads to
deposition of fibronectin, which binds a variety of
growth factors, localizing them to the wound site.
Fibrinogen leakage results in fibrin deposits.
Fibrin forms a meshwork of fibers which will be
the sites of attachment for inflammatory cells and
fibroblasts later in the healing process [27] [9].
The combination of these factors attracts a variety
of inflammatory cells to the wound site including
macrophages, neutrophils and mast cells. Neutro-
phils, the predominant inflammatory cells in the
site in the first 24 hours, function to remove bac-
teria and debris from the site [16]. Macrophages
become the predominant cell type by 48 hours and
in addition to removal of cell and foreign debris
from the wound, release a variety of growth fac-
tors including TGF-b1. Fibroblasts migrate into
the site attracted by growth factors and autocoids
released by platelets and macrophages and begin
to proliferate as a result of PDGF. These cells pro-
bably provide the bulk of the connective tissue
synthesis during tissue repair. The myofibroblast
is a mesenchymal cell type which has characteris-
tics of both smooth muscle (contractile) and fibro-
blast (synthesis of connective tissue) [16]. There
has yet to be a detailed examination of this cell
type in the pathology of Peyronie’s disease. Trans-
forming growth factor-b1 has a pleotropic effect
on fibroblast function by increasing transcription
and synthesis of collagen, proteoglycans and
fibronectin while also increasing synthesis of tis-
sue inhibitors of collagenase which prevents
connective tissue breakdown. The collagen and
connective tissue repair damage while in dermal
wounds, re-epithelialization takes place. Finally,
in the later stages of healing, the connective tissue
is remodeled by specific collagenases and pro-
442
teases [16]. In Peyronie’s disease, defects in over-
production of collagen and other tissue remode-
ling mechanisms result in an inability to resolve
the injury and in plaque formation.
2. MOLECULAR MECHANISMS:
• Involvement of TGF-b1.
Fibrosis is defined as the over accumulation of
connective tissue or the replacement of normal
cellular material with connective tissue [16].
Transforming growth factor-b1 has been implica-
ted in a number of soft tissue fibroses [28, 29] as
well as erectile dysfunction [30]. The pathology
observed in these conditions is worthy of conside-
ration here before discussing Peyronie’s disease.
Transforming growth factor-b1 is synthesized as
an inactive, latent peptide by a variety of cell types
including platelets, macrophages and fibroblasts
[28, 29]. Upon activation, TGF-b1 binds to speci-
fic cell surface receptors and through a signal
transduction cascade, results in an increased syn-
thesis of connective tissue and an inhibition of col-
lagenases. It also can induce its own synthesis as
well as that of its receptors [28, 29, 30]. This auto-
up regulation can set into motion a chain of events
that results in continued connective tissue accu-
mulation and what has been termed “the dark side
of fibrosis” [28]. The negative regulators of this
process are not well characterized. However, in
the lung and in the corpus cavernosum, a role for
prostaglandin E has been proposed [28]. PGE inhi-
bits TGF-b1-induced collagen synthesis both in
lung fibroblasts and in corpus cavernosum smooth
muscle via cAMP dependent pathways [30]. Des-
pite these initial clues, a number of autocoids,
vasoactive substances and cytokines can regulate
connective tissue metabolism so that these two
factors may be involved but not exclusive to the
process.
A role for TGF-b1 has been proposed in the patho-
genesis of Peyronie’s disease [31, 32, 33]. Peyro-
nie’s disease plaques and tunica albuginea biop-
sies were examined for the presence of expression
and compared to specimens from non-Peyronie’s
disease patients. In thirty Peyronie’s disease
patients, increased protein expression of TGF-b1
(26/30), TGF-b2 (7/30) or TGF-b3 (5/30) were
noted as compared to only 1/6 in the non-Peyro-
nie’s disease group [31]. This single patient in the
control group had a localized tunical fibrotic reac-
tion. In all of the Peyronie’s disease patients with
 A B

Figure 1: Micrographs of normal tunica albuginea and Peyronie’s disease.

A) is a 40 micron thick section of the tunica albuginea from a man with ED stained with Hart elastic fiber stain, the irregu-
lar elastic network onto which the collagen component rests is seen.
B) is from a patient with Peyronie’s disease, elastic fibers appear broken, shortened and irregularly displaced by nodularly
arranged collagen fibers.

Blood clot fibrin Emissary vein Circumflex vein

ELASTASE Inflammatory
cells

Outer
longitu-
dinal
TGF-ß layer Tunica
Elastic albuginea
fibers
Inner
circular
Fibroblast layer
Superoxide

Collagen
(triple helix structure)

Figure 2: Molecular pathogenesis of Peyronie’s disease.

A minor injury to the tunica albuginea may rupture an emissary vein and cause bleeding within the densely packed sublayers
of the tunica albuginea. The ensuing fibrin deposition and accumulation of inflammatory cells may cause obstruction of the
draining veins and resulting in a “trapped” inflammatory process. The inflammatory cells produce a number of cytokins,
metalloproteinases and reactive oxygen radicals. Among them, the superoxide and TGF-beta can stimulate the adjacent fibro-
blasts to produce collagen fibers. TGF-beta can also stimulate the inflammatory cells to produce more TGF-beta and forming
a vicious cycle. The elastase can destroy the elastic fiber network and impair the elasticity. Together, these processes produce
the typical symptoms of Peyronie’s disease: pain, plaque and deformity.

443
increased TGF-b1 expression, fibrotic changes in
tunica albuginea biopsies were reported [31]. If
increased expression of TGF-b1 is causal in Pey-
ronie’s disease, one would like to validate this
mechanism in a cell culture or animal model
where the progression of disease can be followed.
As described above, wound healing processes
involve a number of different cell types including
neutrophils, macrophages and fibroblasts. These
cell types can modulate each other and themselves
via complex autocrine and paracrine mechanisms.
Further, the collagenous connective tissue matrix
plays a poorly understood role, as neutrophils,
macrophages and fibroblasts must migrate through
this diffuse connective tissue to the wounding site.
Thus, while Peyronie’s disease fibroblasts may be
cultured and grown in confluent monolayers, this
cell culture model may be of little use in the study
of the progression of Peyronie’s disease. A rat
model of Peyronie’s disease has been developed
using subtunical injections of a synthetic hepta-
peptide, cytomodulin, which induces increased
TGF-b1 expression and/or inflammatory cell
recruitment [32, 33]. Six weeks after cytomodulin
injection 15/18 rats exhibited tunical thickening
and plaque formation as well as increased TGF-b1
mRNA and protein expression [32]. No increases
were observed in either TGF-b2 or TGF-b3
mRNA or protein expression [32]. Finally, elec-
tron microscopy revealed the infiltration of
inflammatory cells as well as disorganized colla-
gen fibrils [33]. This model is indeed a significant
advance as it allows following the progression of
disease as well as a system for the evaluation of
pharmacotherapeutics for Peyronie’s disease.
VI. NATURAL HISTORY
Palpable nodularity and scarring to the Tunica
Albuginea in Peyronie’s disease develops over
time, and seems to correspond to a pattern that is
at least somewhat predictable. This tendency for
the disease process to evolve over time, in the
absence of therapy, has been the subject of several
studies. In most cases, onset is associated with an
active phase, consisting of painful erections, and a
changing configuration of plaque and or bending.
Up to a third of patients with Peyronie’s disease
present with painless curvature, however. Whether
444
the onset of deformity associated with the active
phase is gradual or sudden, pain resolves and the
pathologic process itself seems to stabilize after 12
to 18 months. A relatively quiescent secondary
phase follows, which is characterized clinically by
painless stable deformity, and pathologically by
mature scar. Earlier series characterized Peyro-
nie’s disease as a process of gradual spontaneous
resolution. More recent data does not bear this out.
Out of 97 patients with Peyronie’s disease of 1 to
5 years duration polled at UCLA, 14% called their
disorder resolving, 40% termed it progressive and
47% felt it to be unchanging [34]. Erectile pain
almost always resolves with time; penile deformi-
ty usually does not. Features associated with a lack
of spontaneous resolution include long-standing
duration at presentation (greater than 2 years), the
presence of Dupuytren’s contractures or plaque
calcification, and bending in excess of 45%.
VII. PSYCHOLOGICAL ISSUES
The relationship of erectile dysfunction to Peyro-
nie's disease is a very difficult one to ascertain.
Discussions of erectile dysfunction after surgery
begin with the first report of surgery for Peyronie's
disease using excision and grafting by Lowsley in
the 1940s [35]. In that series, postoperative erecti-
le dysfunction was a major source of failure. In
that series, patients with ventral curvature were
singled out as a particularly at risk group. That
series, however, was not stratified preoperatively
for erectile function, and erectile function post-
operatively was based on patients complaints and
not testing.
In 1970, Williams and Thomas [36] described a
group of 25 patients and followed their natural his-
tory. Of those 15 patients, 4 were described as
being "impotent". Again, there was no testing in
that series, and the plea of that series was to avoid
surgical correction. Gelbard in 1990 [Gelbard,
1990 #414] again attempted to describe the natural
history of Peyronie's disease. In his manuscript, he
describes "impotence" as an end point, an inade-
quate one. He did, however, describe in that series
a large number of patients who discussed poor
erections/ erectile dysfunction. In that analysis,
almost 80% of the patients complained of "psy-
chological effects" due to Peyronie's disease. Over
time, of those 80%, about 70% complained that
their psychological complaints did not improve.
The problem with trying to separate out the func-
tional issues from organic issues is that in the lite-
rature seldom are they stratified in that fashion,
and the existence of erectile dysfunction soley on
the basis of functional aspects is mentioned only
in passing in many articles.
Since Brock and Lue’s analysis of 1993 [37]
approximately 8-9 papers have been published
that deal with stratification preoperatively with
functional testing. In those papers, there is a wide
variance of opinion concerning erectile dysfunc-
tion coexisting with Peyronie's disease, with Jor-
dan and Angermier's paper [38] showing erectile
dysfunction in almost 100% of patients, and Jar-
row's analysis reporting 76 of 95 patients who by
testing were "impotent"[8]. Further review, howe-
ver, showed only abnormalities of vascular erecti-
le parameters in those patients. In Ralph's analysis
in 1992, 20 patients with ED were studied with
duplex ultrasonography and the conclusion was
that 90% of these patients had complaints of ED
because of functional aspects, and not organic
aspects [39].
The existence of functional erectile dysfunction
following surgery is mentioned in a number of
articles beginning with Melman's negative report
concerning excision with dermal graft in which
one of his failures was clearly a failure due to
emotional causes [40]. Jones' analysis of 20 men
[41] who failed to resume coitus after excision
with dermal grafting, while a different population,
comes close to the same numbers reported by
Ralph [39]. In the 20 men studied, 15 men were
found not be able to have coitus because of psy-
chogenic causes. Pryor's recent report of incision
and vein grafting also report patients who failed to
resume coitus because of psychogenic causes, and
these patients have been stratified pre and post-
operatively by duplex ultrasound examina-
tion.(unpublished data)
Unfortunately, from what is in the literature, little
is clear other than the fact that patients preoperati-
vely complain in large numbers of the psychologic
impact of their Peyronie's disease, and psycholo-
gic aspects continue to plague good surgical
results. In a review by Jones [42] dealing with the
counseling of men with sexual dysfunction, he
445
cites a number of psychologic complaints based
on an experience at the time of writing of inter-
views in over 1,500 men with Peyronie's disease.
Men discussed with him the fact that their body
image was disturbed and hampered, and the
thoughts of painful treatment being necessary was
devastating. Many agreed that their sexual dys-
function which they complained of in addition to
mechanical difficulty with coitus was due in large
part to emotional factors. Jones describes the
counseling as being much the same as counseling
a person who has suffered death in grieving. As
with death, men's grieving is complicated by a
denial, ambivalence, anxiety, depression, shame,
embarrassment, and in the case of this particular
group of patients self disgust. Many of these
patients are not good talkers. In review of patient
information from the group in Norfolk, Peyronie's
disease has been described as a disease of youthful
libido in an aging body. Peyronie's patients seem
to have intercourse more frequently and more
vigorously than aged matched adult cohorts. This
data has been criticized in that the analysis was
accomplished in the 50 and 60s, and the point has
been made that the adult population now in gene-
ral may be more sexually active and more vigo-
rously so. This new data is in the process of being
gathered. Thus, the issue of whether Peyronie's
patients are better at intercourse than perhaps ver-
bal relations with their partners remains an unk-
nown. It is safe to say from Jones' review that Pey-
ronie's patients tend not to like to talk about their
problem with their spouses and spurn counseling
in many instances.
Jones further makes the point in dealing with Pey-
ronie's patients, in order to avoid emotional fac-
tors, that patients need to hear the suggestion that
they must "keep sexual expression alive, be active
to whatever degree possible at every stage of the
progression or regression of a Peyronie's disease
course." He emphasizes that men do not hear that.
The physicians that they initially consult and
clearly the functional aspects of Peyronie's disease
are made worse by general misunderstanding of
the disease among urologists and primary care
physicians in general. Many patients have been
told that Peyronie's disease probably is the end of
their sex. It is clear from Jones' review that most
couples eventually show regret that discussion of
sexual behavior was not entered in earlier their
course of Peyronie's disease. They admit that they
cope poorly; and, because of that, sexual expres-
sion and happiness suffered. In that review, many
men said that the belief that "sex was intercourse",
thus when coitus is precluded avoid other sexual
activity, thus increasing their frustration. Most
ignored the pleas of their partners who asked for
intimacy regardless of whether or not there was
intercourse.
All of the above states that the functional aspects
are recognized but poorly categorized. In order to
better define the functional aspects, there must be
uniformity in history taking in centers that deal
with Peyronie's disease; there must be uniformity
in preoperative assessment with regards to erectile
function; and in failures of surgical therapy, where
possible, there must be uniformity in evaluation of
erectile function postoperatively.
VIII. CLINICAL FEATURES
The presenting symptoms of Peyronie’s Disease
include:
1. Penile pain.
2. Penile deformity or shortening during erection.
3. Presence of a plaque or induration.
4. Erectile dysfunction.
All the patients have either a well defined plaque
or an area of induration that is palpable on physi-
cal examination, even though 38-62% of patients
are unaware of [43, 44, 45, 46]. The plaque is
usually located on the dorsal surface of the penis
with a corresponding dorsal penile deformity.
Lateral and ventral sited plaques are not as com-
mon but result in more coital difficulties as there is
a greater deviation from the natural coital angle.
Multiple plaques located on opposite sides of the
penis or plaques appearing in the pectinate septum
may cause shortening with or without a penile cur-
vature. Penile pain may be persistent in the inflam-
matory stage of the disease but is usually only pre-
sent during erection. The pain is not usually seve-
re in nature but may interfere with sexual function
although spontaneous improvement usually occurs
as the inflammation settles.
The reported incidence of erectile dysfunction in
Peyronie’s Disease is variable. Bystrom reported
446
that 52% of 106 patients had coital difficulties and
17% had poor penile rigidity distal to the plaque
[44]. However, only 8% of patients described coi-
tal difficulties at the initial presentation suggesting
that this was probably a late feature of the disease.
Stecker and Devine found abnormal nocturnal
penile tumescence in 29% of patients with Peyro-
nie’s Disease with suspected organic impotence
although in only 5% of patients could the Peyro-
nie’s Disease plaque be the sole cause of the dys-
function [47]. Other series have reported an inci-
dence of erectile dysfunction of 19% [46]. Amin
discovered that out of 208 patients investigated
routinely by colour Doppler ultrasound for erecti-
le dysfunction, 20% had undiagnosed Peyronie’s
Disease [48]. It is clear, therefore, that erectile
dysfunction in Peyronie’s Disease is common and
is usually due to one or more of four factors [49].
1. Psychological (Performance anxiety). The phy-
sical abnormality of the penis can cause anxie-
ty which may be severe enough to interfere
with the ability to obtain or maintain an erec-
tion.
2. Deformity preventing coitus. The penile defor-
mity may be so severe that penetration is made
difficult or even impossible. This is more like-
ly to occur if the deformity is in a ventral or
lateral direction, where deviation from the nor-
mal angle of vaginal entry is maximal. The
pain that is sometimes experienced in Peyro-
nieís Disease may also interfere with the erec-
tile capacity.
3. Flail penis. There is a small group of patients
with extensive Peyronieís disease who have
circumferential plaques and a degree of caver-
nosal fibrosis. Tumescence is absent from this
segment and if extensive it may result in a
hinge effect and an unstable penis.
4. Impaired erection. It is often difficult to deci-
pher the cause of the impaired erectile capaci-
ty. It may be due to concomitant vascular disea-
se that occurs in 30% of patients with Peyro-
nie’s Disease [50] or to veno occlusive dys-
function (VOD) [51,52]. Most studies have
used both colour Doppler ultrasound and
cavernosometry to investigate the impaired
erection in Peyronie’s Disease. Lopez showed
that out of 76 patients, 36% had arterial disea-
se and 59% had VOD [53]. Others have also
suggested there is a mixture of arteriogenic and
 venogenic factors [54, 55]. It is thought that the
venous leakage may occur through the emissa-
ry veins that pass through the Peyronie’s
plaque into the dorsal vein of the penis. The
reduced compliance of the tunica albuginea of
the plaque prevents the normal compression of
these veins during rigidity and therefore does
not compress the venous channels. This site
specific VOD has also been found in 80% of 19
patients with an impaired erection secondary to
trauma, one of the suggested aetiological fac-
tors in Peyronie’s Disease [56].
The findings that there is reduced elastic fibre
content of the tunica and an increased type III col-
lagen content also supports the findings that Peyro-
nie’s Disease is associated with veno-occlusive dys-
function as these pathological abnormalities can
also be seen in patients with veno-occlusive dys-
function disease without Peyronie’s Disease [57]
[26].
Patients may present with only a flaccid distal por-
tion of the penis or a soft glans penis, the proximal
segment being normal. There is controversy as to
the mechanism of this, be it arterial, venous or
fibrotic in nature. One study has shown that this fea-
ture is likely to be of mixed pathology in that
patients are likely to have extensive cavernosal
fibrosis which impedes the distal arterial flow as
measured on colour Doppler ultrasound [39]. This
would be supported by the fact that the inflamma-
tion in the early stage of Peyronie’s Disease and the
fibrosis in the latter stages can extend into the erec-
tile tissue [58]. Patients with a soft glans only are
likely to have extensive dorsal plaques with interfe-
rence of the dorsal neurovascular bundle.
The diagnosis of Peyronie's disease is usually
apparent by the patient history and physical exa-
mination of the penis. If surgery is contemplated,
a detailed evaluation of penile vascular function in
patients with Peyronie’s disease is highly recom-
mended.
1. HISTORY
The medical history should include time and mode
of onset (sudden or gradual), course of disease
(stable or progressive), history of penile surgery,
urethral instrumentation or trauma, medication or
drug abuse and family history of Peyronie's disease
or Dupuytren's contracture. In patients complain of
ED, the risk factors for ED should also be assessed.
447
A detailed psychosexual history should also be
sought. This includes penile rigidity during erec-
tion, shortening, induration, hourglass constriction,
or pain with or without erection. Other important
information should also be determined such as abi-
lity to have intercourse, adequacy of erection (rigi-
dity and duration), frequency of intercourse, libido,
psychological impact. A photograph of patient's
erect penis to identify the extent, direction, and cha-
racter of erectile distortion is helpful.
2. PHYSICAL EXAMINATION
Examination of the penis in patients with Peyro-
nie's disease is facilitated by gentle stretching of
the penis. This will help identify the size, location
and consistence of plaques which may be helpful
in determing the stage and monitoring the pro-
gression. The patient should also be examined for
the presence of Dupuytren's or planter fascial
contractures. Further diagnostic studies should
include photography or drawing of the erect penis
after intracavernous injection or vacuum erection
device. The stretch length of the penis should also
be documented.
3. VASCULAR TESTING
Many patients have little in the way of symptoms
and reassurance, particularly that the palpable
lump is not cancer, is all that is necessary. The
majority of patients with Peyronie’s Disease may
be managed without vascular investigation.
Patients usually give an accurate description of
their deformity to within 10-20º and it is therefore
often unnecessary to obtain clinical confirmation
of this either with a photograph or an intracaver-
nosal injection of a vasoactive agent [59, 60].
However with complex deformities or where
patients cannot give an accurate description the
intracavernosal injection of a vasoactive agent is
important, particularly when planning a surgical
correction of the deformity.
When the site and size of the Peyronie’s plaque
needs to be assessed, ultrasound usually will suffi-
ce [61] and is particularly helpful in monitoring
the progress of medical treatment.
In patients who also complain of an impaired erec-
tion further evaluation is essential and this should
be either with color Doppler ultrasound or dynamic
infusion cavernsometry as arterial and/or venous
pathology may be present to account for this.
a) Color duplex ultrasonography with or without hypospadias, penile dorsal vein
High resolution sonography allows for detailed thrombosis, cavernosal fibrosis secondary to local
objective assesment of the plaque, calcification as trauma, leukemic infiltration of the corpora caver-
well as defining multiple areas of the involvement. nosa, ventral curvature secondary to urethral instru-
Sonography can also be used to follow plaque pro- mention, benign or malignant primary or seconda-
gression, after medical therapy or surgery. Therefore, ry tumors, late syphilitic lesion, penile infiltration
sonography is the most objective means of assessing with lymphogranuloma venerum.
plaque dimensions at any stage of the disease. There is no symptom score or quality of life instru-
Color duplex sonography performed before and after ment designed specifically for Peyronie’s disease.
intracavernous injection of a vasodilator allows for a The following is a proposal by the committee.
thorough assessment of the structure of the corpus
cavernosum, tunica albuginea and cavernous arterial Symptoms Scores proposed by the committee
and venous function. Furthermore, it is an excellent 1. PAIN
tool to detect collateral arterial connections between 0 = Absent
the dorsal and cavernous as well as the cavernous and 1 = Slight, during erection
spongioal arteries. In some patients the dorsal artery
may give a large branch to supplement the cavernous 2 = Slight, during sexual
intercourse
artery. Surgerical damage to this large branch during
dissection of the neurovascular bundle may results in 3 = Moderate
impotence. 4 = severe
b) Dynamic infusion cavernosometry 5 = constant
After intracavernous injection of vasodilators, infu- 2. PLAQUE SIZE (CUMULATIVE)
sion of normal saline can determine the degree of
0 = None
venous leakage. Jordan and Angermeier [38] reported
that there is a linear association between preoperative 1 = 1 cm
erectile function and postoperative results. If the 2 = 2 cm
patient is noted as having adequate erectile function, 3 = 3cm
his chance of having good results from penile straigh- 4 = 4cm
tening alone is in excess of 90%,however, if a patient
has obviously inadequate erectile function, although 5 = 5 cm or more
the penis may be straightened by surgery the lack of 3. DEFORMITY
rigidity will persist, causing difficult penetration Prefix D, L, V, S 0 = Absent
during intercourse [38].
Dorsal 1 = 15º
Whereas many treatment protocols have been sug-
Lateral 2 = 30º
gested for the management of patients with Peyro-
nieís disease these should be used as a guide only: Ventral 3 = 45°
individual patient requirements and assessment are Shortening 4 = 60°
more important in determining which patients requi- 5 = >75°
re simple reassurance, which need investigation and
which will be appropriate to treat surgically. 4. ERECTION
c) Differential diagnosis 0 = Normal
Although the diagnosis of Peyronie's disease is fair- 1 = Functional
ly straightforward, a rare sarcoma may be confused
2 = Impaired – penetration
with Peyronie's disease. This possibility must be
possible
ruled out with a biopsy, especially when the plaque
has grown rapidly. When evaluating patients with 3 = Impaired – no penetration
Peyronie’s disease, many other causes of bending 4 = Distal flaciddity
and induration of the penis must also be considered
such as, congenital curvature of the penis, chordee 5 = Absent

448

IX. MEDICAL MANAGEMENT
In spite of various treatment options, Peyronie's
disease remains a therapeutic dilemma for the
practicing urologist. Peyronie advocated use of
Barege spa water and mercurial ointments. In the
1800’s iodine, arsenic and camphor were used.
Throughout the years, different modes of energy
transfer including orthovoltage radiation, ultra-
sound, short wave diathermy, laser therapy, and
shock wave lithotripsy have been used to treat
Peyronie's disease [62, 63, 64]. None of these
methods are recommended at this time. The follo-
wing discussion will review current treatment
options based primarily upon experiences reported
in the English literature. Unfortunately, most stu-
dies are compromised by poorly characterized,
limited numbers of patients, short follow-up times,
no placebo or control groups, and little objective
measure of change. We will first review systemic
and then local or intralesional therapy for Peyro-
nie's disease.
1. ORAL AGENTS
a) Vitamine E
The use of oral agents for the treatment of Peyro-
nie's disease began in 1948. Scott and Scardino
[65] reported on treatment of 23 patients with vita -
min E, a tocopherol with antioxidant properties.
The proposed dose was 200 to 300 mg per day.
Based on changes in pain, plaque size and angula-
tion, they reported a beneficial effect in 11
patients, some improvement in 10 and no change
in 2 patients. The study did not compare the effect
of the treatment with the natural history of the
disease. Use of vitamin E continued and, over
time, became widely accepted because of its mild
side effect profile and low cost. Several studies
have claimed favorable outcomes with vitamin E,
however, the majority did not compare the out-
comes with the natural history of the disease or a
placebo controlled group. In 1990, Gelbard et al.
[34] compared the effects of the vitamin E treat-
ment and natural progression of the Peyronie's
disease. They described 27 patients who received
no treatment and 59 patients who were taking vita-
min E. They noted no significant differences bet-
ween the two groups with respect to pain, bend,
449
ability for intercourse, and over-all perception of
disease progression. At this time, vitamin E conti-
nues to be the primary mode of treatment despite
the lack of a controlled study showing its benefits.
b) Potassium aminobenzoate
In 1959, Zarafonetis [66] studied potassium ami -
nobenzoate (Potaba) as a systemic therapy agent.
This substance is classified as "possibly effective"
by the Food and Drug Administration for the treat-
ment of Peyronie's disease, scleroderma, dermato-
myositis, linear scleroderma, and pemfigus. One
of the most extensive reviews of this therapy is a
summary of 214 European urologists' experience
with 2653 patients on Potaba [67]. The treatment
was considered unsuccessful in 42.7% of the cases
and successful in 57.3%, with complete resolution
in 9.3%. The mechanism of action is not well
understood. It has been suggested that Potaba
increases utilization of oxygen by tissues and
increases activity of monoamine oxidase, which
decreases concentration of serotonin, a substance
thought to be responsible for fibrogenesis. Carson
reported a retrospective review of 32 patients trea-
ted for at least 3 months with 12 grams of Potaba
powder daily and followed for 8 to 24 months.
Subjective symptoms analysis demonstrated
improvement in penile discomfort in 8 of 18
(44%), decreased plaque size in 18 of 32 (56%)
and improvement in penile angulation in 18 of 31
(58%) patient. Complete resolution of angulation
was reported in 8 of 31 (26%) patients. Carson
suggested that a prospective, double-blind, multi-
center, study with objectives criteria was needed to
control for the natural history of spontaneous reso-
lution of Peyronie’s disease symptomatology and
to confirm the role of Potaba in the treatment of
Peyronie’s diseae as suggested in the above noted
non-controlled studies [68]. Based upon these
modest results, unsubstantiated mode of action, its
relatively high cost, and side effects including gas-
trointestinal intolerance, which often results in
noncompliance, enthusiasm for the use of Potaba
is cautiously guarded.
c) Tamoxifen
Ralph et al. described their experience with oral
tamoxifen in 1992 [69]. It has been suggested that
tamoxifen facilitates the release of transforming
growth factor-beta (TGF-b) from fibroblasts [70].
TGF-b has been shown to play a central role in
regulating immune response, inflammation and
tissue repair by deactivating macrophages and T
lymphocytes. Tamoxifen results in a reduced
inflammatory response and, therefore, diminished
angiogenesis and fibrogenesis [71]. Their prelimi -
nary study showed encouraging results in patients
with recently (less than 4 months) acquired Peyro-
nie's disease. Their regimen included 20 mg of
tamoxifen twice a day for 3 months. Eighty per-
cent of patients reported an improvement in pain,
35% showed improvement in deformity, and 34%
experienced plaque shrinkage. An unpublished
anecdotal report by Toloken of a controlled trial of
oral tamoxifen (20 mg BID) vs placebo demons-
trated no therapeutic advantage to tamoxifen and
several men reported scalp hair loss [72]. Like
many of the newer treatment options, tamoxifen is
difficult to recommend since long term results,
side effects, and larger cohorts are not available.
Yet this type of therapy is particularly interesting
in light of better understanding of scar formation.
d) Procarbazine (Natulan)
The use of procarbazine (Natulan) has brought lar-
gely disappointing results. This cytotoxic alkyla-
ting agent was commonly used for treatment of
Hodgkin's lymphoma. In spite of the initial favo-
rable reports in patients with Dupuytren's contrac-
tures, studies have not shown a benefit in men
with Peyronie's disease. Theoretically, procarbazi-
ne should inhibit proliferation of rapidly dividing
fibroblasts. Oosterlick and Renders in 1975 saw
no improvement in 9 out of 10 patients following
treatment with 100 mg of procarbazine daily for
27 to 150 days [73]. Similarly, Morgan and Pryor
[74] reported that 91% of 34 patients in their study
failed to improved or worsened. They also pointed
out several toxic side effects including intestinal
disturbances, severe headaches, skin eruptions,
alcohol intolerance and leukopenia. From this
experience, there does not appear to be any value
in the use of this toxic agent.
e) Colchicine
Oral colchicine therapy was recently reported in a
non-controlled study by Akkus et al. [75]. This
agent is known to induce collagenase activity and
decrease collagen synthesis [76, 77, 78, 79]. Col-
chicine acts in four ways. It binds to tubulin and
causes it to depolymerize, and subsequently, inhi-
bits mobility and adhesion of leukocytes. It inhi-
450
bits cell mitosis by disrupting the spindle fibers. It
also blocks the lipoxygenase pathway of arachido-
nic acid metabolism, thus diminishing chemotaxis
and inflammatory response. Lastly, it interferes
with transcellular movement of protocollagen.
Akkus et al recommended an initial dose of 0.6 to
1.2 mg daily during the first week of treatment fol-
lowed by a gradual increase to 2.4 mg over three
to five months. Although not qualified further,
penile curvature was slightly improved in 2 (11%)
and markedly improved in 5 (26%) of the 19
cases. Seven of nine patients with painful erec-
tions reported significant relief. Palpable plaque
disappeared in 2 and decreased in 10 patients. The
investigators also performed ultrasound on five
patients and described a decrease of approximate-
ly 50% in plaque size. However, the authors poin-
ted out that a double blind study is needed to bet-
ter evaluate the usefulness of this medication. The
primary reported side effect of colchicine is gas-
trointestinal upset with diarrhea reported in 33%
of subjects [74].
2. INTRALESIONAL INJECTION
a) Steroids
Based upon anti-inflammatory properties, as well
as decreased collagen synthesis by unclear mecha-
nisms, steroids have been employed as an intrale-
sional therapy for Peyronie's disease. In 1954,
Teasley [80] described the intralesional use of ste-
roids in 29 poorly characterized patients with
unclear results. Also in 1954, Bodner reported
good results of intralesional cortisone and hydro-
cortisone treatment in 17 patients [77]. In 1975,
Winter and Khanna published their results on the
use of mechanically aided injection (Dermo-Jet)
of dexamethasone [82]. They reported on 21
patients who were managed with 6 to 10 injections
of 0.4% dexamethasone solution per treatment,
repeated monthly for a total of 1 to 6 months.
Although they noticed a decrease in both plaque
size and pain during intercourse, no statistical dif-
ference was evident in comparison to the natural
history of the disease. The authors also failed to
objectively quantify the changes in plaque size
and degree of the curvature.
In 1980, Williams and Green [83] described a
prospective study on the use of intralesional
triamcinolone, a long-acting glucocorticoid with
low solubility, which theoretically produces maxi-
mal local action with minimal systemic side
effects. Forty-five patients were followed for one
year without treatment and then treated with intra-
lesional triamcinolone hexacetonide at 6-weekly
intervals for 36 weeks. During the one year obser-
vation period only three patients (6%) had sponta-
neous resolution of their symptoms. After the ini-
tiation of therapy, 33% of the patients noticed mar-
ked improvement. The mean duration of treatment
which resulted in clinical improvement was 18
weeks. Pain, when present, improved first and
most consistently, followed by plaque and then
curvature. They also identified that patients under
the age of 50 with small, firm, discrete plaques are
more likely to respond to triamcinolone treatment.
This treatment has also been shown to benefit
Dupuytren's contractures and hypertrophic scars.
[83, 84].
We now recommended that treatment of Peyro-
nie's disease with intralesional steroids be elimi -
nated or at least initiated with extreme caution
because of local side effects and the inconsistent
pattern of improvement in well-established curva-
ture. Although steroids are known to suppress
fibroblast production of collagen, this effect is
unpredictable and may result in local tissue atro-
phy. Anecdotally, in one unreported case, a patient
developed adrenal insufficiency due to excessive
use of steroid injections. In addition, steroid injec-
tions make surgery more complex due to the diffi-
culty in subsequent separation of tissue planes bet-
ween Buck's fascia and the tunica albuginea.
b) Parathyroid hormone
Other hormones used in the intralesional treatment
include parathyroid hormone (PTH). Morales and
Bruce [85] described the use of PTH in 12 patients
with a mean duration of illness prior to treatment
of 23 months. Fifty units of PTH were injected
into the plaque weekly for 8 weeks. They descri-
bed their criteria of "markedly improved" as a
reduction of a particular symptom by 50 to 90%.
After the course of therapy, seven of 12 patients
reported absence or marked improvement in
plaque, while 5 of 12 remained unchanged or
minimally improved. Six of 12 noted marked
improvement in curvature, and five out of six, who
complained of pain, were cured or markedly relie-
ved of pain. The rationale for using PTH in Peyro-
nie's patients is based upon reports of increased
451
production of a collagenolytic factor in bone by
this hormone [86]. It has been suggested that
injection of PTH into the plaque may depress col-
lagen synthesis and promote collagen degradation.
In spite of this single study, the use of PTH has not
been substantiated by further reports in the litera-
ture.
c) Collagenase
Purified clostridial collagenase was first studied
in vitro with surgically excised Peyronie's plaques
by Gelbard et al [87] in 1982. Three years later,
Gelbard et al. [88] published data on the use of a
single intralesional collagenase injection in 31
patients. The results of this study were encoura-
ging, with objective improvement in 20 patients
within 4 weeks. Only one recurrence during the
9.8 month follow-up period was noted.
In 1993, results of the only double-blind study of
any type of medical therapy for Peyronie's disease
were published [89] In this study of 49 men, a sta-
tistically significant improvement in plaque size
was found following collagenase treatment as
compared to placebo control. The patients were
stratified according to the severity of their disease
and a modified Kelâmi system was used for clas-
sification [59] Category 1 patients had a bend of
30 degrees or less, and/or a palpable plaque of less
than 2 cm. Category 2 patients displayed 30 to 60
degrees of angulation and/or a palpable plaque
between 2 and 4 cm. Category 3 patients had grea-
ter than 60 degrees penile bending and/or greater
than a 4 cm plaque. The researchers used vacuum
chamber photography to document the degree of
angulation. Patients in the category 1 received
6,000 units of purified clostridial collagenase,
patients in group 2 received 10,000 units and
patients in group 3 received 14,000 units. The
category 1 patients responded best to the treatment
( 3 of 3 (100%) who received the study drug noted
some improvement), followed by category 2
(36%), and category 3 (13%). The authors cautio-
ned, though, that maximal angular improvement
observed ranged from 15 to 20 degrees, which was
acceptable only in category 1 patients. In more
severe cases, change in curvature was detectable
but not clinically significant. No side effects were
noted by the authors. Currently, this mode of the-
rapy is a promising option for mild to moderate
degrees of Peyronie's disease and is being evalua-
ted in an FDA approved multi-center study. Fur-
ther study may demonstrate added benefit when
this drug is given as a course of several injections
resulting in a better reduction of curvature.
d) Orgotein
Orgotein, an anti-inflammatory metalloprotein
with pronounced superoxide dismutase activity,
was first studied in Europe. Gustafson et al. [90]
used this agent on 22 patients and Bartsch et al
[91] treated 23 patients. The drug was delivered
intralesionally and both investigators achieved
results in decreasing the plaque size and increa-
sing sexual function. Verges and Chateau [92]
delivered orgotein via ionophoresis. The authors
showed decrease in pain, induration, and curvatu-
re which permitted the resumption of sexual acti-
vity in over 75% of the cases. Primus [93] recent-
ly published a report of marked improvement with
intralesional orgotein use on a selected group of
patients with severe symptoms. Orgotein is not
available in the U.S. and was recently restricted
from intralesional use in Germany due to a severe
toxicity profile.
e) Verapamil
The calcium antagonist verapamil was first repor-
ted as an intralesional therapy by Levine et al in
1994 [94]. The rationale for use of verapamil
comes from the experiments by Kelly [95] who in
1985 demonstrated that exocytosis of extracellular
matrix molecules including collagen, fibronectin
and glycosaminoglycans, the primary components
of a Peyronie's plaque, is a calcium ion dependent
process. Aggler and associates demonstrated that
when fibroblasts were exposed to anti-tubular
agents and calcium antagonists in vitro a change in
cell shape was noted. This morphogenic change
resulted in an altered protein secretion phenotype,
manifested by increased extracellular matrix colla-
genase secretion as well as decreased collagen and
fibronectin synthesis and secretion [96]. Similar
changes have been seen when fibroblasts have
been exposed in vitro to other agents such as col-
chicine, tamoxifen and interferon. Lee and Ping
[97] reported in 1990 on their experiments with
cultured bovine fibroblasts exposed to increasing
concentrations of verapamil and nifedipine. They
found a dose-dependent decrease in the incorpora-
tion of radiolabelled proline and sulfate into extra-
cellular matrix collagen and glycosaminoglycans,
452
respectively, indicating decreased synthesis and
secretion of these cellular products. They also
noted that the doses necessary to inhibit extracel-
lular matrix formation are much greater than the
typical doses in systemic use of these drugs for
hypertension. Therefore, local injections of vera-
pamil were necessary to avoid systemic toxicity
and to expose fibroblasts within the plaque to an
adequate verapamil concentration.
In the first non-controlled, non-randomized study
of intralesional verapamil for Peyronie's disease,
14 men with a mean age of 51 years received this
therapy in a dose escalating fashion. [94]. The
patients had a mean duration of disease of 20
months, and 11 of the 14 had failed prior oral the-
rapy with vitamin E and/or Potaba. Prior to admi-
nistering verapamil, a penile block with xylocaine
was given. Verapamil was then injected using a
10cc syringe with a 25 gauge needle in a multiple
puncture technique (100-150 punctures per dose).
The starting concentration was 1 mM and was
doubled monthly. All patients received twelve
injections over six months with a maximum dose
of 10mg in 10 mL of solution. Ninety-one percent
of patients who had experienced pain at the initia-
tion of the study had rapid resolution of the pain
within 1-2 injections. Penile deformity, including
shaft narrowing, decreased in 100% of patients,
but curvature improved in only 42%. Fifty-eight
percent reported that their sexual performance had
improved. Objectively, a decrease in plaque volu-
me of greater than 50% was noted by ultrasound in
4 of 12 (30%) patients, but all noted plaque softe-
ning. Overall, 83% noted that the disease had
arrested or improved with no recurrence of symp-
toms or deformity within the eight month follow-
up period. In addition, 4 patients who had incom-
plete response to verapamil underwent successful
surgical repair without added difficulty caused by
the injection therapy.
More recent research has also demonstrated the
effects of verapamil to modulate extracellular
matrix metabolism by inhibiting the expression of
collagen as well as by increasing the proteolytic
activity of collagenase, thereby enhancing matrix
remodeling by human fibroblasta in burn scars and
vascular smooth muscle cells in vitro. [98, 99]. In
addition, verapamil and other calcium channel
blockers were found to affect cytokine expression
associated with early phases of wound healing and
inflammation, including platelet-derived growth
factor-BB, interleukin-6 and interleukin-8 [99,
100]. All of this work indicated the importance of
regulating the balance between matrix biosynthe-
sis and degradation by fibroblasts.
In a second published study, Levine reported on 46
Peyronie's patients who participated in a non-ran-
domized, non-placebo controlled phase II study of
verapamil [101]. Ten mg of verapamil diluted to
10 mL with saline was injected every two weeks
for six months. The maximum dose of 10 mg was
chosen because of the optimal response demons-
trated in the previous study as well as limited car-
diovascular risk following intravenous injection of
10 mg as suggested by pharmaceutical industry
safety data. The mean age and disease duration
were 51 years and 17.2 months, respectively.
Fifty-nine percent of these 46 men had failed prior
oral therapy and 61% had painful erections. Only
26% were fully potent prior to therapy and 48%
had stuffable erections. Mean plaque volume was
approximated with duplex ultrasound (DU) at 3.9
mL (range 0.8 - 11.6 mL) and mean penile curva-
ture was assessed after injection of 60 mg Papave-
rine at 50° (range 10 - 90°).
Thirty-eight men have completed the therapy.
Subjectively, 97% (26/27) had rapid resolution of
pain after a mean of 2.5 injections. Penile curvatu-
re improved in 76% (32/38), mean 38 degrees,
range 5 to 70 degrees), with improved distal rigi-
dity in 93% (25/27), reduction in hour-glass defor-
mity in 86% (19/22) and increased sexual perfor-
mance in 72% (27/38). Thirty-five men underwent
objective evaluation included pre- and post-treat-
ment duplex ultrasound, which demonstrated a
decreased curvature in 54% (19/35) with a mean
decrease of 25° (range 10 - 40°), no change in DU
parameters, and no significant change in plaque
volume.
There were no substantial differences in response
to treatment noted on duration of disease (greater
or less than 12 months), or within the 3 Kelami
classification groups as discussed before with the
intralesional collagenase studies [102].
The Rush-Presbyterian-St. Luke’s Medical Center,
Chicago experience with over 170 non-randomi-
zed patients suggests that intralesional injection of
Verapamil results in
1) rapid resolution of pain,
453
2) modest improvement of penile deformity,
3) improved rigidity and/or sexual performance in
approximately 75%, and
4) no acute or chronic side effects. the ideal candi-
date for intralesional verapamil treatment appears
to be those who present with pain, refuse surgery,
have curvature less than 90o and do not have
extensive plate-like plaque calcification
Further published studies on the use of verapamil
for Peyronie’s disease includes a report by Teloken
et al who noted no advantage to verapamil over
placebo or steroids when given in a controlled
fashion. Yet, the study agents were not injected
into the plaque; rather, they were injected around
the plaque [103]. It seems that if a change in fibro-
blast metabolism and plaque behavior is expected
a more concentrated direct distribution of drug is
necessary. Rehman et al in a randomized single-
blind trial of intralesional verapamil vs saline
reported on 14 patients in which there was a
decreased plaque volume of 57% in the verapamil
gorup vs 28% in the control group, a non-signifi-
cant improvement trend in penile curvature in the
verapamil group of 38o vs 30o in the control group
and a subjective improvement in penile narrowing
in all verapamil patients with improved quality of
erection in 43% vs none in the control group.
[104]. Of note, there was no local or systemic toxi-
city except occasional ecchymosis at the injection
site similar to the Chicago experience.
f) Interferon
The potential use of interferons as an intralesional
therapy for Peyronie's disease was demonstrated
in a 1991 study by Duncan et al. [106] in which
fibroblasts from Peyronie's plaques were cultured
in the presence of interferons alpha-2B, beta-
Ser17, and gamma. The rationale for interferon
therapy originates from studies illustrating similar
fibroblast activity in Peyronie's plaque, keloid
scars and scleroderma [107, 102]. In these cases,
fibroblasts are activated and produce excessive
amounts of extracellular matrix components,
including collagen, glycosaminoglycans, and
fibronectin. In vitro study indicates that interfe-
rons normalize the activity of fibroblasts derived
from patients with scleroderma and keloids [102,
107, 108]. In fibroblasts derived from Peyronie's
plaques, the addition of interferons decreased the
rate of proliferation in a dose dependent fashion,
decreased the production of extracellular collagen,
and increased the production of collagenase.
These in vitro results suggest the potential of inter-
ferons as an in vivo treatment for Peyronie’s disea-
se. Interestingly, interferon-gamma increased the
production of fibronectin and glycosaminogly-
cans. These in vitro results suggest the potential of
interferons as an in vivo treatment for Peyronie's
disease.
Several clinical trials of intralesional interferon for
Peyronie’s disease have been published. Wegner
and associates studied 25 men who were given 5
local injections of 1 million units of interferon-
alpah-2b on a weekly basis [109]. The condition
improved clinically in only 1 case. Side effects
including myalgia and fever, occurred in 4
pateints.
Further dose-finding studies by Wednger in 30
patients with 3 million units IFN-alpha 2b given
weekly for 3 injections demonstrted clinical
improvement in only 1 subject [110]. Three wor-
sened and 10 new plaques developed. 25% of
patients had untolerable side effects, including 74
of 90 injections causing fever > 38 degrees C.
They concluded that this agent is not useful for the
treatment of Peyronie’s disease with this regimen.
Using a different dosing regimen with IFN-alpah
2b of 1.5 million units three times a week for 3
weeks, Judge and Wisniewski reported on 10
patients again treated without a control arm. [111].
Six of ten had disappearance of pain and subjecti-
ve improvement in deformity. Objective improve -
ment in deformity was considered small with
mean improvement of 20 degrees. Patients with
small plaques (< 4 cm) were more likely to have a
better response. All patients experience brief
influenza-like side effects.
In a study of IFN-alpha-2A intralesional injection
in 15 patients was evaluated by magnetic resonan-
ce imaging. This study demonstrated plaque size
reduction only, particularly in small plaques (< 1
cm) where there was complete plaque disappea-
rance.
3. OTHER APPLICATIONS
a) Topical Beta-aminopropionitrile
Topical beta-aminopropionitrile, a potent colla-
gen cross-link inhibitor, was employed by Gelbard
et al. in 9 patients with Peyronie's disease [105]
454
Beta-aminopropionitrile irreversibly binds to lysil
oxidase, an enzyme responsible for the cross-lin-
king of collagen fibrils, and prevents normal col-
lagen fibrogenesis. A four-week course of twice a
day topical application brought only subjective
improvement in 3 patients. No changes in plaque
diameter were noted by ultrasonography or penile
deformity following intracorporal infusion.
b) Various energy modalities
Reports have also been presented at international
meetings, in the past three years, using various
energy modalities alone or in combination with
agents, including steroids, verapamil and orgotein.
In an Italian study of 68 patients receiving orgo-
tein infiltration with or without topical laser and
ultrasound therapy pain rapidly resolved, but there
was no improvement of penile bending [112].
c) Iontophoresis
Iontophoresis was examined as a means of enhan-
cing topical delivery of verapamil (10 mg) and
dexamethasone (4 mg) with a local electric field in
15 patients with Peyronie’s disease. This treatment
was given 3 sessions a weeks for three weeks for
20 minutes per session using a 3 mA current. At a
mean 5 month follow-up penile pain resolved in
66%, curvature improved in 53% and plaque size
reduced or softened in 40% of cases [113]. We are
likely to see more and hopefully better controlled
studies of topical drug enhancing technologies for
the treatment of this difficult disease.
d) Local penile lithotripsy
Local penile lithotripsy has also been proposed as
topical therapy for Peyronie’s disease with limited
numbers of patients reporting subjective results.
[63]. The rationale for this approach is not known.
4. FUTUR TRENDS
Clearly, the need for continued controlled clini -
cal trials is in order as well as basic research into
the pathophysiology of this disorder. Break-
throughs in understanding the role of cytokines
and fibroblast activity as well as their interaction
with extra-cellular matrix macromolecules, inclu-
ding collagen but likely other components, will
enhance our ability to offer reasonable and effecti-
ve non-surgical therapy.
In addition, further investigation will be necessary
to establish standards for evaluating objective
measures of plaque and deformity change. Ultra -
sound has been demonstrated to be a relatively
inexpensive, reliable and non-invasive technique
to measure plaque dimensions and calcification
[55-114]. Vacuum chamber photography [89]
was used in concert with vasoactive intracaverno-
sal injectin in an effort to obtain the optimum erect
state in study patients so that intra and inter-sub-
ject variation in the ability to measure deformity
would be minimized. Unfortunately, in this inves-
tigator’s experience it appears that due to the sub-
stantial extra-tunical penile engorgement that
occurs with vacuum chambers this may conceal
the underlying shaft deformity caused by the tuni-
ca albuginea scarring. Therefore, the key to redu-
cing variability in erectile response which is critial
to accurate measurement of deformity (curvature
and narrowing) will be complete smooth muscle
relaxation and patient confirmation of a full erec-
tion.
5. SUMMARY OF NON-SURGICAL THERAPY
(TABLE 1)
a) Oral Treatments
Vitamin E – In general a safe, inexpensive, non-
toxic therapy showing at best a modest improve-
ment in deformity (10-15 %). Most studies are
small in number, non-controlled with subjective
reporting on outcome. [Dose 800-1000 mg/day]
Potaba – A therapy which has no clear rationale
for its use. Yet, frequently employed for obscure
historical reasons. Virtually all reports with no
control and only subjective reporting of outcome.
Recent placebo-controlled trial with one year fol-
low-up showed statistically significant improve-
ment in plaque size but no significant change in
deformity. This drug is also relatively expensive
with significant gastrointestinal intolerance [Dose
12gm/day].
Colchicine – The newest oral therapy : again limi-
ted published studies and no controlled trials. The
rational for its use is sensible with respect to chan-
ge in fibroblast function, yet getting adequate tissue
levels into the tunica has not been demonstrated.
Objective measures of improvement in deformity
reported in 30-40 % of patients primarily with early
stage disease (< 3 month duration). Significant gas-
trointestinal intolerance 30-50 %. Not recommen-
455
ded for longer than 3 months due to possible bone
marrow suppression [Dose 0.6 mg TID].
Tamoxifen – Several small, short-term reports
suggest moderate benefit based upon response
seen with idiopathic retroperitoneal fibrosis.
Usually well tolerated but gastrointestinal distress
and alopecia reported. No significant difference
reported in deformity improvement in single
controlled trial [ Dose 20 mg BID].
b) Intralesional Injection
Orgotein – Mechanism unclear may be due to
change in superoxide dismutase activity. No
controlled studies found. Subjective reported
benefits high at 80-90 %, yet significant toxicity.
Not available in US and taken off market in seve-
ral European countries.
Steroids – Several short-term non-controlled sub-
jective reports on response using various steroids
and doses with mean reported benefit in deformi-
ty around 60 %. Risk with this therapy outweigh
benefits and include tissue atrophy, skin thinning
and making surgical repair more difficult due to
loss of tissue plane between Buck’s fascia and
tunica. Not recommended for use.
Verapamil – Several studies reported, two control-
led trials, one showing benefit in all objective
measures, the other showing no statistical benefit
over saline control. Its action is based on change in
fibroblast behavior and cytokine inhibition. Goals
of this treatment are to stabilize disease process
and in responders reactivate a more “normal”
remodelling process, yielding gradual improve-
ment in deformity. This is why multiple doses over
time given. Reported side-effect primarily ecchy-
mosis with objective measures of deformity
improvement in 50-60 % of patients treated. [Dose
10 mg verapamil in total of 10cc volume injected
every 2-4 weeks x 12].
Interferon – Several small non-controlled studies
with short follow-up. Mechanism may be similar
to verapamil by affecting fibroblast function and
acute reactive cytokine activity. Yet improvement
in deformity limited 4-60 %. This mediation is
expensive with a high rate of flu-like symptom
side-effects. Await further controlled trials.
Collagenase – Not yet available but several publi-
shed reports including one controlled trial sho-
wing benefit for deformity less than 30 %. Mecha-
nism to alter collagen content of plaque. Toxicity
profile low. Further study ongoing.
Overall, therapeutic advances in Peyronie's disea-
se have not resulted in a reliable cure. This appears
primarily due to an incomplete understanding of
the basic pathophysiology of this disease and the
lack of an animal model for study. Recent
advances in the understanding of disorders of
wound healing have allowed forward strides in the
understanding of this disease and may offer new
therapies, such as the injection of calcium antago-
nists. The similar response of cultured fibroblasts
to colchicine, vinblastine, interferons, and the cal-
cium antagonists, verapamil and nifedipine, sug-
gests that through medical therapy some common
primary cellular metabolic events may be altered
in Peyronie's plaques. Whether this is at the cyto-
kine level such as TGF-b will require further
investigation. Ultimately, a multi-modality thera-
py such as verapamil with collagenase and pos-
sible oral therapy, may be indicated as a non-ope-
rative approach. This may allow stabilization or
improvement of the Peyronie's deformity. In addi-
tion, in advanced cases, which do not respond to
conservative therapy, surgery may offer conside-
rable relief.
X. SURGICAL TREATMENT
The replacement of diseased tunica albuginea in
Peyronie’s disease was largely unsuccessful until
the introduction of a dermis graft. Numerous ope-
rations have been described subsequently and it is
only now that there is an element of consensus as
to the choice of operation. This is because deci-
sions have been based largely on personal expe-
rience, and bias, and due to the paucity of good
data with regard to outcome - and in particular cli-
nical trials. In looking at outcome it would be rea -
sonable to only review those series consisting of
more than 50 patients who preferably had the same
operation and where the indications are given and
there is some statement as to the means of asses-
sing outcome.
1. INDICATIONS FOR OPERATION
• These fall into two categories:
a) Deformity
456
There is considerable variation in the deformity
that makes penetration difficult. In young men
particularly with congenital deformities the bend
causes more psychological distress than physical
disability and it may be necessary to correct defor-
mities as little as 20-30 degrees. In contrast, a man
who is in a stable relationship and with a partner
who has had several children is able to cope with
a much more severe deformity. It should however
be noted that a ventral deformity causes more dif-
ficulty than a dorsal or lateral one.
b) Erectile dysfunction
Unless the dysfunction is for psychological rea-
sons, the patients may be better served by the
implantation of a penile prosthesis if non-surgical
ED treatment is not satisfactory. Some improve-
ment of function may occur postoperatively by
reducing the volume of the corpora [115] or by
ligating a prominent dorsal penile vein.
2. PREOPERATIVE ASSESSMENT
The surgeon should be convinced that there is ade-
quate erectile function (natural or in response to
non-surgical ED therapy) before embarking on an
operation to correct the deformity and document if
there is an organic impairment of erection before
implanting a prosthesis. Informed patient consent
is essential.
An operation to correct a penile deformity should
be delayed until the disease process has stabilized.
This is usually taken to be a year after the onset of
the disease, pain on erection is no longer usually a
feature, and the bend has been stable for three
months. In older men with a vasculogenic ED not
responding to non-surgical therapy there is no
necessity to delay implanting a penile prosthesis.
• Relative contraindications
Reconstructive surgery is not recommended in the
acute phase of the disease. Patients with unrealis-
tic expectations will not be satisfied with any out-
come and are not good candidates for surgery.
Although many penile implants have been perfor-
med in patients with normal penile rigidity in the
past, we feel that penile implant should be reser-
ved for Peyronie's patients who also have erectile
dysfunction and do not respond to non-surgical
therapies such as sildenafil, vacuum device, trans-
urethral or intracavernous injection.
• Anaesthetic and Incision
The fitness of the patient to undergo surgery is
rarely a consideration as the operations may be
performed under local or general anaesthesia and
as outpatients or inpatients. Outpatient surgery
requires more expertise and better patient selec-
tion. A degloving circumglandular incision would
seem to be the most popular and consideration
should be given whether or not to circumcise the
man in order to reduce postoperative complica-
tions. In a Nesbit type operation for dorsal curva-
ture, a longitudinal skin incision over the apex of
the convex curve is a better approach.
3. SURGICAL TREATMENT
a) Plication or wedge resection
Reed Nesbit [116] described the correction of
erectile deformities due to congenital abnormali-
ties by shortening the opposite side of the penis
using a plication technique or by the excision of an
ellipse of tunica albuginea. The results of correc-
tion of congenital deformities have been excellent.
Although Nesbit described the plication technique
it was not until two decades later that plication was
rediscovered [117, 118]. In addition to the plica-
tion technique a variety of corporoplasties have
been described [119, 120, 121, 122, 123, 124,
125]. The plication techniques are simpler but the
outcome is less reliable.
The Nesbit technique was introduced for Peyro-
nie’s disease in 1979 [126] and in 359 men opera-
ted upon between 1977 and 1992, 295 (82%) had
good results and were able to have intercourse.
[127]. A literature review confirmed the favorable
results [128].
In considering the outcome of the Nesbit procedu-
re it is apparent that the prognosis is worse than in
patients with congenital deformities. It is also
apparent that with increasing time since the opera-
tion there is a decrease in the satisfaction rate
although this is usually a change from excellent
results to satisfactory results. The overall results of
the Nesbit procedure improved in the operations
performed after 1985. It was by that stage that
pharmaco-testing for erectile function had become
a routine and this eliminated many of the patients
having an operation with impaired erectile func-
tion due to vasculogenic causes [127].
Porst also noted that the outcome of the Nesbit
457
procedure was good in 94% of 65 patients with
normal preoperative erectile function but only
satisfactory in 77% of 53 patients with preoperati-
ve impairment of erectile function [129].
The complications from the Nesbit procedure are
relatively minor [127] and the main drawback is
the question of penile shortening. A feature of Pey-
ronie’s disease is the formation of scar tissue and
penile shortening is always more than is suggested
by the deformity alone. The width of the ellipse
excised to correct Peyronie’s disease was found to
average 7 mm in width and the average of defor-
mity was 68 degrees. [127] (Figure 3). In reality
the shortening of the Nesbit operation is rarely
troublesome and was only of more than 2 cm in 17
of 359 men and intercourse was possible in 15 of
these [127]. Several modified approaches such as
the Yachia procedure have also been reported to
have excellent results (Figure 4).
Incision or wedge resection of the tunica requires
dissection of the neurovascular bundle or the cor-
pus spongiosum and placement of sutures to shor-
tened the longer side of the tunica. A simplified
approach is to perform plication on an erect penis
produced by intracavernous injection of papaveri-
ne or alprostadil. For ventral curvature, 2-3 pairs
of non-absorbable sutures (2-0 Ticron or Tevdex)
are placed between the deep dorsal vein and the
dorsal arteries. For dorsal curvature, same sutures
are placed in the paraurethral ridges. No dissection
of the neurovascular bundle or corpus spongiosum
is necessary. Because the procedure is performed
on an erect penis and the sutures are tied partially
until the penis is straight, this procedure is less
invasive and equally successful (Figure 5).
b) Excision or incision of tunica and grafting
Plaque excision was general unsuccessful until a
dermal graft replacement of the tunica albuginea
was described by Bystrom et al [130] in Scandina-
via and by Devine and Horton [131] in the United
States (Figure 6). Bystrom et al (1982) reported
that despite good early results the later results
were disappointing with only 6 of 17 men having
a good result after 10 years. A review of the litera-
ture [128] showed that there was great variability
in the outcome of plaque excision and dermal graft
and in a recent large series of 418 men [132] it was
found that 17% of patients required further surge-
ry for curvature and 20% of patients had signifi-
cant impairment of erection.
458
459
460
461
A B

C D

E F

Figure 3: Nesbit's wedge resection.

(A), Penile curvature is assessed by an artificial erection. The incision line is marked. (B), The tunica albuginea is exposed
after incising the Buck's fascia. (C). The ellipse of tunica to be removed is marked. (D), The tunica is excised. (E,) The edges
are approximated. (F), The penis is straight as assessed by artificial erection.

462
A B C

Figure 4: Yachia procedure for correction of curvature.

(A), Buck's fascia is reflected exposing the tunica albuginea. (B), Longitudinal incisions are created at the area of maximal
curvature as demonstrated by artificial erection. (C), The longitudinal closures are closed transversely, with artificial erec -
tion demonstrating straightening of the penis.

Figure 5: Plication procedures performed on an erect penis (after intracavernous injection of papaverine) (Donatucci and
Lue,1992) [146]. The location of paired non-absorbable plication sutures is shown: (A), perispongiosal for dorsal curvature.
(B), between dorsal vein and dorsal arteries for ventral curvature.

463
 B C
A

D E F

Figure 6: Plaque excision and dermal grafting (Devine's technique)

(A), An artificial erection demonstrates the dorsal curvature of the penis. The incision is made in the scar of the previous cir -
cumcision. (B), The skin is de-gloved to the base of the penis. An incision in the deep dorsal midline of Buck's fascia exposes
the deep dorsal vein. (C), The deep dorsal vein is mobilized and (D), resected. (E), The neurovascular bundle is freed from the
plaque. (F,) An artificial erection demonstrates the curvature caused by the inelastic plaque. Stellate releasing incisions have
been marked.

464
G H I

J K

(G), Prolene sutures have been placed distal and proximal to the plaque and at the tip of each of the releasing incisions. An
incision has been made outlining the plaque, and the plaque is excised. (H), The plaque has been excised. This defect must
now be filled with a dermal graft. (I )The dermal graft has been obtained and inlaid in the defect. An artificial erection shows
the penis to be straight. If there is a leak in a suture line, it is oversewn. (J), Buck's fascia is loosely re-approximated in the
midline with interrupted sutures. One or two small suction drains are left in the space superficial to Buck's fascia. (K), The
skin is closed with interrupted sutures

465
Erectile dysfunction following plaque excision is
due to a combination of factors ranging from Neurovascular
damage to the underlying erectile tissue adherent bundle
to the plaque, loss of compliance of the dermal
graft, new venous channels forming to give veno
occlusive dysfunction [133] and deterioration of
the underlying aetiological factors which are gene-
rally thought to be ischaemic or vasculogenic in
origin. It is now recognized that the histological Midline plaquie
changes of Peyronie’s disease are not confined to
the plaque but may also be seen in the normal tuni-
ca albuginea excised during the Nesbit procedure A
[134,135]. In some instances the plaque extends
into the erectile tissue [136].
Jordan and Angermeier [38] showed that the out-
come of plaque excision and grafting was related penis
to the preoperative findings on dynamic caverno- stretched
sometry. All four men with normal preoperative
function had an excellent outcome whereas 9 of
the 12 men with some impairment had a satisfac-
tory outcome and only 1 of 4 with poor perfusion 3 Relaxing incision
in tunica
characteristics was potent postoperatively. In view
of the relatively poor outcome of plaque excision
and dermal grafting great care is required in B
patient selection for this procedure.
Subsequently, many autologous tissue (dermis,
temporalis fascia, dura mater, tunica vaginalis and
dorsal or saphenous vein) and synthetic material
(Dacron and Goretex) have been used with diffe-
rent results. Excision of the plaque has been the
standard approach. However, it is now known that Middle relaxing inci-
the pathologic process of Peyronie's diease sion darted at apex
extends far beyond the plaque and removing a
large area of tunica albuginea may impair erectile C
function. In 1991, Gelbard and Hayden [137] pro-
posed plaque incision and grafting rather than
excision and this has becoming a more popular
technique (Figure 7).
So far there is no graft material that is perfect for
replacing the diseased tunica albuginea. The syn-
thetic material, dura and fascia may provide a
strong covering for the tunica but they don't stret- Gaps filled with
ch as the normal tunica and curvature may recur tailored grafts of
after the graft is fixed to the surrounding tissue. temporalis fascia
Synthetic material also has some risks of foreign D
body reaction and infection. Dermis is a good sub-
stitute and plentiful but it tends to contract after Figure 7: Plaque incision and temporalis grafting (Gel -
bard's procedure) (A). Dissection of the neurovascular
several months and cause recurrence unless a lar- bundles. (B) Effect of multiple relaxing incisions in tunica
ger graft (1/3 larger than the defect) is placed to albugeniea--plaque completely divided in three locations.
allow contraction. Recently some proposed saphe- (C) Relaxing incision darted. (D). Relaxing incisions graf -
nous vein graft because ted with temporalis fascia free grafts.

466
1) it regains blood supply within minutes,
2) the endothelium limit permeation of blood and
therefore will not cause hematoma at the graft site
and
3) its smooth muscle coat reacts to high pressure in
the penis and becomes thicker and stronger in
about 3 months. There is experimental evidence to
suggest that a vein patch is superior to dermal flap
or synthetic tissue [138] and in the only large
series using the Lue technique [139, 140] (Figure
6) follow-up was possible in 112 of 145 men. Of
these, 95% reported that the penis was straighte-
ned but 17% complained of penile shortening and
13% of preop potent patients reported decreased
penile rigidity after surgery [140].
c) Implantation of a Penile Prosthesis with or
without grafting
This is the treatment of choice for those men with
Peyronie’s disease and erectile dysfunction not
responding to non-surgical ED treatment. Literatu-
re review [128] showed excellent results provided
men had realistic expectations. Although there
may be some intrusion on the corporal bodies, this
does not usually cause any difficulty in the
implantation. In the past, if a patient has both
penile deformity and erectile dysfunction, he is
automatically recommended for insertion of peni-
le prosthesis. However, this indication has been
modified since the less invasive treatments (oral
sildenafil, intracavernous injection, intraurethral
medication and vacuum constriction device) has
now replaced penile prosthesis as the initial treat-
ment options for erectile dysfunction.
In most patients with mild to moderate deformity,
insertion of a penile prosthesis tends to straighten
the penis and no additional procedure is necessary.
However, if severe deformity still persists after
prosthesis is inflated, one can perform an incision
of the plaque and cover the defect with synthetic
material such as Goretex. The use of operative
molding of the penis over the prosthesis may give
good correction of the deformity [141].
A malleable prosthesis usually corrects the defor-
mity but gives less overall functional satisfaction.
If inflatable penile prosthesis is used in Peyronie's
disease, it is recommended not to use the distally
expanding prosthesis (such as Ultrex, from Ameri-
can Medical Systems [AMS]) because when the
device lengthens it also tends to bend the penis.
The girth expansion-only devices (such as CX
467
from AMS and Alpha 1 from Mentor) are better
choices in patient with penile curvature [142]. The
satisfactory outcome of inflatable prostheses was
also found in publications of Knoll et al. (1990)
[143], Eigner et al (1991), [144] and Carson
(1998) [145].
In the surgical management of Peyronieís disease,
patient selection and attention to surgical detail are
both important. For the less experienced surgeon it
is probably better to rely upon the tried combination
of the Nesbit technique to correct the deformity and
the implantation of a penile prosthesis in those
patients with additional vasculogenic erectile dys-
function. In a patient with normal potency there is
still a place for plaque excision/incision and dermal
grafting. In the light of current experience, and par-
ticularly in the short stubby penis, plaque incision
and the insertion of a vein patch is well worth consi-
dering for the experienced surgeon.
XI. PENILE ANOMALIES THAT
MAY CAUSE ERECTILE
DYSFUNCTION
Most congenital anatomical penile abnormalities
do not cause erectile dysfunction. Usually the
patients are fully able to reach a rigid erection.
However in some cases the shape or size of the
penis makes penetration difficult or may cause dis-
comfort or even pain to the partner, as a result of
the anomaly a sexual dysfunction starts to deve-
lop. This later can become a psychosexual dys-
function which may result in erectile dysfunction.
The effect of acquired penile abnormalities to the
patients erectile ability is variable. While in some
patients the erectile ability does not change as the
result of the disease, the change in the shape of the
penis may cause severe sexual dysfunction to the
patient or the couple. In others the disease has a
direct effect on the erectile ability.
What has not been objectively evaluated is the
impact of the various penile deformities to the
sexual well being of the patients or the couples.
Such evaluation can be done using a symptom
score for the patient and a quality of life index,
which can be divided into 2 parts: for the patient
himself and of the couple.
Table 2 comprises the congenital and acquired
penile abnormalities which may have an effect on
erectile or sexual dysfunction.
Table 2: Penile abnormalities that may cause erectile and/or sexual dysfunction

CONGENITAL ERECTILE PSYCHO-SEXUAL

DYSFUNCTION DYSFUNCTION
PENIS
Curvature N S
Micropenis: Y Y
- Endocrinic N Y
- non-endocrinic
Concealed N Y
Hypospadias N S
Epispadias N Y
Shaft rotation N S
PREPUTIUM:
Phymosis N S
Paraphymosis N S
Short Frenulum S S
ACQUIRED ERECTILE PSYCHO-SEXUAL
DYSFUNCTION DYSFUNCTION
PEYRONIE’S DISEASE S S
URETHRAL
Iatrogenic:
Hypospadias Cripples S Y
Extrophy/epispadias cripples S Y
Kelami Sydrome N S
Traumatic:
URETHRAL:
Self induced (Kelami Syndrome) N S
CORPORAL:
Accidental (T. albuginea tears) S S/N
Self induced (T. albuginea tears) S S
Iatrogenic
- After hypospadias repair N S
- After curvature repair N S
- ICI induced Y Y
- Penile prothesis erosion Y Y
NEURO-VASCULAR:
Pelvic fractures S S
PENILE:
Retraction (after surgery or circumcision) N Y
Amputations:
Self induced Y Y
Accidental (circumcision) Y Y
Medical (penile tumors) Y Y
Disease:
Ca of penis S Y
Penile lymphedema N Y
Penile condyloma N S/N
Skin inflammations N S
Foreign bodies (Self implanted) N S
Y = yes, N = no, S = sometimes

468
A B

C
D

Figure 8 : H-incision and saphenous vein grafting (Lue et al, 1998).

(A). dissection of neurovascular bundles (medial to lateral) with tenatomy scissors under 3x or 5x magnification loupes. (B),
H-shaped transverse relaxing incision in center of plaque for correction of penile curvature and longitudinal incisions for
hourglass deformity. (C). The tunical defect is measured by stretching the penis longitudinally and transversely. (D). A seg -
ment of saphenous vein is resected, opened, cut into several pieces and stapled together with vascular clips. The vein graft is
then sutured to the tunical defect with the endothelial surface facing the inside of the corpus cavernosum.

469
 • Medical
HISTORY • Sexual
• Family

PHYSICAL EXAMINATION
PLAGUE SIZE, LOCATION
DUPUYTREN’S
STRETCHED PENILE LENGTH

BLOOD TESTS ASSESS : FINDINGS Penile sonography

FOR EDUCATE : PATHOPHYSIOLOGY if necessary (Duplex
PATIENT WITH ED COUNSEL : OPTIONS sonography optional)

SHARED
mild or
DECISION ASSURANCE, VITAMIN E (±)
asymptomatic
MAKING

long standing
moderate or
peyronies with
severe symptons
severe
deformity
(more Non-surgical therapy
than one for 3-6 months
year) ORAL - colchicine
potaba
Tamoxifen
Intralesional - Verapamil

Mild or no Persistent pain > 1 year

deformity Moderate or
severe deformity

CONTINUE NON- DOCUMENT: - deformity LOW DOSE RADIATION (±]

SURGICAL THERAPY - penile
- length OR
OR WITH - photograph
- drawing
- vacuum SURGERY (±]
WATCHFUL WAITING device
with ED without ED

Poor response to Severe deformity

non-prosthetic ED hour glass deformity
therapy Gool response Moderate hinged penis short
to non-prosthetic deformity penis
ED therapy vascular
Nesbit Wedge testing
PENILE or Modified Duplex or GRAFTING
PROSTHESIS Nesbit DICC PROCEDURE
or plication
Procedure
Figure 9 : Algorithm for the management of Peyronie’s disease

470

XII. CONCLUSION
Peyronie's disease is one of the most puzzling
diseases in urology: the pathogenesis is still not
certain, the medical treatments are unpredic-
table and effective in less than 50 % of patients,
and controversies still exist regarding surgical
approach. A recommended algorithm for the
management of Peyronie’s disease is shown in
Figure 7. New research on the etiology and
pathogenesis is urgently needed which hopeful-
ly will improve our understanding and mana-
gement for patient with this frustrating disease.
XIII. RECOMMENDATIONS
In dealing with Peyronie’s disease, a detailed
medical and psychosexual history followed by a
focused examination of the penis to assess the
location, size, number, and consistency of the
plaque is essential in planning the management
strategy. Because Peyronie’s disease is not a life-
threatening condition, the treatment can be tailo-
red to patient’s treatment goal (a goal-directed
approach). Education of the pathogenesis, natural
history and treatment options of the disease will
help the patient and his partner make an informed
choice.
Reassurance and watchful waiting may suffice if
the condition is painless, the deformity is minimal
and erectile function is satisfactory.
In symptomatic Peyronie’s disease, several treat -
ments are recommended by the committee based
on literature review: vitamin E, potaba, tamoxifen,
colchicine and intralesional verapamil.
Patients with erectile dysfunction in addition to
penile deformity or pain may also benefit from
using one of the non-surgical treatement for ED.
Reconstructive surgery should be reserved for
potent patients with disabling deformity for more
than 12 months duration (and stable for more than
3 months). ED patients who respond well to non-
surgical ED treatment can also be candidates. For
less experienced surgeon, the Nesbit wedge resec-
tion, plication surgery or one of the modifications
471
offers the best overall results. Grafting procedures
should be performed by more experienced sur-
geons because more advanced skills are required
in dissection of neurovascular bundles and graf-
ting.
In those with disabling penile deformity and ED
not satisfied with non-surgical treatment, penile
prosthesis implantation gives the best outcome.
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___________________
476
 Committee 13

Male Orgasmic and Ejaculatory

Disorders

Chairman
W.F. HENDRY

Members
S.E. ALTHOF,
G.S. B ENSON,
S.M. HAENSEL,
E.M. HULL,
K. KIHARA,
R.J. OPSOMER

477
 CONTENTS

DEFINITIONS
I. PHYSIOLOGY OF NORMAL
EJACULATION
1. PRODUCTION OF SEMEN
2. PROPULSION OF EJACULATE
3. O RGASM
II. NERVOUS PATHWAYS AND
AREA CONTROLLING
EJACULATION AND ORGASM
1. SENSORY RECEPTORS AND AREAS
2. AFFERENT PATHWAYS
3. CEREBRAL RECEPTOR AREAS
4. SPINAL MOTOR CENTERS
5. EFFERENT PATHWAYS
III. ELECTROPHYSIOLOGICAL
EVALUATION OF THE NERVOUS
PATHWAYS CONTROLLING
EJACULATION
1. PUDENDAL SOMATOSENSORY EVOKED
POTENTIALS (PUDENDAL SEPS)
2. PUDENDAL MOTOR EVOKED POTENTIALS
(PUDENDAL MEPS)
4. NEUROGICAL DISORDERS
5. THE EFFECTS OF DRUGS ON ORGASM AND
EJACULATION
6. FUNCTIONAL DISORDERS
V. INVESTIGATION
1. EVALUATION OF PATIENTS WITH RAPID/
PREMATURE EJACULATION
2. ASSESSMENT OF DELAYED RETARDED
EJACULATION
3. HAEMOSPERMIA
4. ASSESSMENT OF SMALL VOLUME
EJACULATE
5. ASSESSMENT OF EJACULATORY DUCT
OBSTRUCTION ON IMAGING
VI. TREATMENT
1. PSYCHOLOGICAL TREATMENT FOR RAPID
EJACULATION
2. PSYCHOLOGICAL TREATMENT FOR
DELAYED EJACULATION
3. DRUG TREATMENT FOR RAPID EJACULATION
4. SPINAL INJURIES
5. LOSS OF EJACULATION AFTER RETROPERI-
TONEAL LYMPH NODE DISSECTION

3. SACRAL REFLEX ARC TESTING: 6. SURGICAL TREATMENT OF EJACULATORY

THE SOMATIC-SOMATIC REFLEX ARC DUCT OBSTRUCTION
4. S YMPATHETIC SKIN RESPONSES (SSRS)
VII. CONCLUSIONS
IV. PATHOPHYSIOLOGY OF
EJACULATORY DISORDERS
VIII. RECOMMENDATIONS
1. EMBRYOLOGY AND CONGENITAL
ANOMALIES
2. TRAUMATIC DAMAGE
REFERENCES
3. INFECTIVE DISORDERS

478
 Male Orgasmic and Ejaculatory
Disorders
W.F. HENDRY
S.E. ALTHOF, G.S. B ENSON, S.M. H AENSEL, E.M. H ULL, K. K IHARA , R.J. O PSOMER
Orgasm and ejaculation constitute the final phase
of the sexual response cycle. Although erection
and ejaculation are co-ordinated, the mechanisms
that produce them are different. We must, therefo-
re, commence by defining our terms, before consi-
dering the physiology of normal ejaculation.
Disorders of male sexual function affect erection
and ejaculation quite differently.
DEFINITIONS
Orgasm: A pleasurable feeling (a cerebral event)
usually associated with emission and/or ejacula-
tion.
Emission: deposition of seminal fluid components
from the ampullary parts of the vasa deferentia,
seminal vesicles, and prostate gland into the pos-
terior urethra.
Ejaculation: passage of seminal fluid through the
urethra and its expulsion from the urethral meatus.
Rapid or premature ejaculation: Inability to
delay ejaculation sufficiently to enjoy lovemaking.
Persistent or recurrent occurrence of ejaculation
with minimal sexual stimulation before, on, or
shortly after penetration and before the person
wishes it.
Delayed ejaculation: undue delay in reaching a
climax during sexual activity
Anorgasmia: Inability to achieve an orgasm
during conscious sexual activity, although noctur-
nal emission may occur.
Anejaculation: Absence of ejaculation during
orgasm.
479
Retrograde ejaculation: Backward passage of
semen into the bladder after emission usually due
to failure of closure of the bladder neck mecha-
nism, demonstrated by presence of spermatozoa in
the urine after orgasm.
I. PHYSIOLOGY OF NORMAL
EJACULATION
1. PRODUCTION OF SEMEN
The spermatozoa are stored in the tails of the epi-
didymides and the ampullary parts of the vasa, and
they normally constitute less than 0.1 % of the
semen volume. The ejaculate is produced by com-
bining the secretions of the prostate with the
contents of the ampullary parts of the vasa defe-
rentia, followed by their expulsion from the ure-
thra washed out by fluid from the seminal vesicles
[1]. The normal ejaculate can be split into four to
six fractions [2]. Serial biochemical analysis indi-
cates that the first part contains the maximum
number of spermatozoa, and subsequent fractions
contain sequentially less. Acid phosphatase, citric
acid and zinc, emanating from the prostate, are in
highest concentration in the first part of the ejacu-
late, whereas fructose, coming from the seminal
vesicles, increases in concentration towards the
end of the ejaculatory process. Alteration of the
pH values in successive parts of the split ejaculate
indicates how the acid component provided by the
prostate is serially mixed with the more alkaline
contribution of the fructose rich fluid from the
seminal vesicles. Approximately 15 - 30% of the
entire ejaculate is contributed by the prostate, and
50 - 80% by the seminal vesicular secretion; there
is, in addition, a small contribution to the first part
of the ejaculate from the bulbo-urethral (Cow-
per’s) glands which is rich in enzymes and plas-
minogen activator [3].
2. PROPULSION OF EJACULATE
Propulsion of the ejaculate is obtained by contrac-
tion of the containing chamber (proximal urethra)
combined with proximal closure of the bladder
neck to prevent retrograde flow and distal urethral
patency. Expulsion is achieved by rhythmic
contractions of the bulbospongiosus and bulboca-
vernosus muscles, which forces the contents
through the distal urethra. Intermittent contraction
of the urethral sphincter prevents retrograde flow
into the proximal urethra [4,5].
3. ORGASM
The orgasmic pleasure comprises 2 phases: the
increase in tension in the prostatic urethra wall,
and sensory stimuli arising in the area of the
verumontanum. From that point the ejaculatory
reflex can not be blocked or delayed anymore.
This is followed by the expulsive phase, when
stimuli and information are sent to the central
nervous system from the glans penis and the
whole length of the urethra. In summary, a nor-
mal sensation of orgasm needs a rigid erection,
the discharge of the tension from the orgasmic
center and good coordination between the 2
phases of ejaculation (emission and expulsion).
The exact mechanism of nocturnal ejaculation
with or without orgasm during sleep is unknown.
Several hypotheses have been suggested: autono-
mic activity of the spinal centers (ejaculation
without orgasm), lowering of the neurosensory
control of the brain, or autonomic discharge of
the «condensors» - see below.
II. NERVOUS PATHWAYS AND
AREA CONTROLLING
EJACULATION AND ORGASM
The ejaculatory reflex comprises sensory recep-
tors and areas, afferent pathways, cerebral sensory
areas, cerebral motor centers, spinal motor centers
and efferent pathways [6].
480
1. SENSORY RECEPTORS AND AREAS
The glans penis constitutes the primary erogenic
area, where Krause-Finger corpuscles are located
in the mucosa. These corpuscles act as sensory
receptors and seem to function as condensers
when repetitive and cumulative stimulation is
applied to the glans penis during sexual intercour-
se. These corpuscules discharge as soon as a cer-
tain level of excitation is achieved. The sensory
information is transmitted to the spine and the
brain.
The external genital organs (penis and testicles)
should be distinguished from the extragenital ero-
genic organs (these areas are highly variable from
one subject to another). The stimulation of these
secondary erogenic areas contributes to maintai-
ning the erection and provides sensory informa-
tion enhancing the information from the Krause-
Finger corpuscules.
2. AFFERENT PATHWAYS
Sensory information from the glans penis travels
along two different pathways: first, via the senso-
ry fibres of the pudendal nerve (dorsal nerve of
penis) up to S4. The afferent «volley» then travels
into the spine. It has been demonstrated in the
monkey that destroying the dorsal nerves of penis
will abolish or delay ejaculation. Secondly, via the
hypogastric plexus that transmits information to
the ganglia of the paravertebral lumbo-sacral sym-
pathetic chain. It seems that there is a close contact
between these autonomic and cerebrospinal ner-
vous pathways.
3. CEREBRAL RECEPTOR AREAS
Seminal emission and ejaculation are integrated
into the complex pattern of copulatory behavior by
forebrain structures that include the medial preop-
tic area (MPOA) and the paraventricular nucleus
of the hypothalamus (PVN). The MPOA, imme-
diately rostral to the anterior hypothalamus, is
essential for male copulatory behavior in all verte-
brate species that have been tested (reviewed in
Meisel & Sachs, [7]). Electrical stimulation of the
MPOA can elicit ex copula seminal emission or
ejaculation in monkeys [8] and rats [9]. Moderate
doses of a mixed D1/D2 dopamine agonist (apo-
morphine) [10] or of a D1 agonist (thienopyride-
ne) [11], microinjected into the MPOA, promote
erections and facilitate copulation of male rats,
apparently by increasing parasympathetic tone.
Higher doses of a mixed D1/D2 agonist, or of a
selective D2 agonist, shift the autonomic balance
to favour seminal emission and ejaculation [11].
Dopamine is released in the MPOAof male rats in
the presence of an estrous female, and increases
more during copulation [12]. Thus, the levels of
extracellular dopamine in the MPOA may regula-
te the phases of copulation, with high levels trig-
gering ejaculation. Electrical stimulation of the
MPOAalso elicits the urethrogenital reflex in rats,
which may mimic orgasm in humans [13]. This
reflex is usually elicited in anesthetized, spinally
transected rats by distending the urethra with sali-
ne and then suddenly releasing the pressure. This
results in rhythmic firing of the hypogastric, pel-
vic, and motor pudendal nerves and rhythmic
contractions of the perineal muscles, similar to
those seen during orgasm in humans. However,
stimulation of the MPOA elicited the reflex, even
without genital stimulation.
There are no neurons that extend from the MPOA
to the lumbosacral spinal cord; therefore, its faci-
litative effects must be mediated via other struc-
tures. One possible mediator is the periaqueductal
gray (PAG) of the midbrain, which receives input
from the MPOA and sends efferents to the lumbar
spinal cord. Another possible mediator is the PVN.
There are reciprocal connections between the
MPOAand the PVN. Stimulation of mixed D1 and
D2 receptors [10,14] or specifically of D2 recep-
tors [15] in the PVN also increases the number of
ex copula erections and seminal emissions. Neu-
rons that contain a marker (neurophysin) associa-
ted with oxytocin descend from the PVN to the
lumbosacral spinal cord [16], where they may eli-
cit seminal emission/ejaculation.
Whereas dopamine, via D2 receptors, promotes
seminal emission/ejaculation, serotonin is inhibi-
tory. Serotonin is released in the anterior lateral
hypothalamus (LHA) of male rats at the time of
ejaculation [17]. Microinjection of a selective
serotonin reuptake inhibitor (SSRI) into the LHA
delayed both the onset of copulation (as though
the male had just ejaculated) and also delayed eja-
culation after copulation had begun [17]. This
effect is similar to the reported side effects of
SSRI antidepressant drugs, which include decrea-
481
sed libido and difficulty achieving ejaculation or
orgasm. The postejaculatory decrease in libido
may result in part from decreased dopamine relea-
se in the nucleus accumbens, a major terminal of
the mesolimbic dopamine tract [18]. Dopamine in
the nucleus accumbens has been related to moti-
vation and/or reward related to numerous beha-
viors, including eating, drinking, copulation, and
drug addiction. Therefore, one site at which SSRI
drugs may inhibit both libido and ejaculation is the
LHA. While the N. accumbens probably mediates
the SSRI-induced decrease in libido, it probably
does not influence ejaculation directly. The struc-
ture mediating that effect is not known; however,
neurons from the LHA do descend to the lumbar
spinal cord, where the neurons controlling genital
reflexes reside.
Another major inhibitory influence on both erec-
tions and ejaculation is the nucleus paragiganto-
cellularis (nPGi) in the ventral medulla, which
tonically inhibits the spinal nuclei that program
the motor output to the genitals and the pelvic
musculature. Lesions of the nPGi facilitate the eli-
citation of the urethrogenital reflex and also
reflexive penile erections and anteroflexions [19].
Approximately 78% of the descending neurons
from nPGi are serotonergic [13]. Selective seroto-
nin neurotoxin lesions depleted serotonin in the
lumbosacral spinal cord and released the urethro-
genital reflex from its tonic inhibition [20]. Spinal
transection releases the spinal neurons from inhi-
bition and allows the reflex to be elicited by ure-
thral distension. Therefore, either a lesion of the
nPGi (the site of serotonergic cell bodies) or spinal
transection (cutting the descending axons) will
release the spinal neurons from inhibition. It is
interesting that stimulation of the MPOAcan elicit
the reflex, even if the nPGi and spinal cord are
intact. This suggests that the MPOA may inhibit
the nPGi, as well as stimulating an excitatory site.
The control of copulation and ejaculation is, in
many ways, similar in humans and other mam-
mals. The evolutionarily older brain areas that
subserve these functions are highly conserved
across species. Dopaminergic drugs enhance, and
serotonergic drugs impair several measures of
sexual behavior and ejaculation in humans, mon-
keys, and rats. Seminal emission is elicited by
sympathetic innervation in all species that have
been studied. One difference, however, is that rats
typically have much shorter postejaculatory inter-
vals than do men. Indeed, one to three prior ejacu-
lations actually increase the number of ex copula
erections and shorten the interval before the next
ejaculation in rats [8].
Possible treatments for ejaculatory dysfunction,
due either to a primary disorder or secondary to
SSRI antidepressants, may include administration
of either D2 agonists or selective serotonin recep-
tor antagonists. Ferrari and Giuliani [21] reported
that a selective D2 agonist, systemically adminis-
tered, produced «premature ejaculation,» which
was counteracted by a D2 antagonist. On the other
hand, administration of serotonin 5-HT1B or 5-
HT2 antagonists may reverse the effects of seroto-
nergic inhibition from either the LHA or the nPGi.
4. SPINAL MOTOR CENTERS
A «secretory center» is located at the Th12-L1-L2
spinal level. It is controlled by the sympathetic
nervous system and is responsible for emission. A
«mechanical center» is located at the S2-S4 level.
It is controlled by the somatic nervous system and
is responsible for expulsion.
5. EFFERENT PATHWAYS
The efferent sympathetic nerves emerge from the
spinal column at Th12-L2 to form the lumbar sym-
pathetic ganglia from which the descending nerves
encircle the aorta on each side before coming toge-
ther in the midline to form the hypogastric plexus
just below the bifurcation of the aorta. From there
the preganglionic sympathetic fibres conveyed by
hypogastric nerves pass through the pelvis to
synapse with postganglionic neurons in the pelvic
plexus which terminate on the bladder neck, pros-
tate, seminal vesicles and vasa deferentia [22]. The
efferent somatic fibres emerge from the anterior
horn of the S2-S4 spinal segments (Onuf’s
nucleus), they travel in the motor branch of the
pudendal nerve to innervate the pelvic floor
muscles including the bulbospongiosus and bulbo-
cavernosus muscles.
a) Anatomy
The abdominal and pelvic sympathetic nervous
system fundamentally shows a common structure
in mammalians including humans (Fig. 1). The
cell bodies of the preganglionic sympathetic neu-
rons are located in the lateral columns of the gray
482
matter in the thoracolumbar segments of the spinal
cord. Sympathetic nerve fibers exit the spinal cord
via the ventral roots and reach the sympathetic
chains bilaterally. The nerves proceed via the tho-
racic sympathetic chain to the caudal (inferior)
enteric plexus, the major/minor splanchnic nerves,
the celiac/cranial mesenteric plexuses, and the
intermesenteric nerves. The nerves proceed via the
lumbar sympathetic chain and the lumbar splanch-
nic nerves to the caudal mesenteric plexus.
In animals, the intermesenteric nerves and all lum-
bar splanchnic nerves merge into one plexus, the
caudal mesenteric plexus, from which the colonic
nerve and paired hypogastric nerves exit to the
colon and the pelvic plexus, respectively (Fig.
2A). The caudal mesenteric plexus in animals cor-
responds to two plexuses, whereas in humans, the
inferior mesenteric and superior hypogastric
plexuses are separate [22] (Fig. 2B). The former
plexus mainly innervates the colon and from the
latter spring paired hypogastric nerves. The junc-
tion of the hypogastric nerve and the pelvic nerve
constitutes the pelvic plexus in the pelvis, which is
an integration of sympathetic and parasympathetic
nervous systems. The branches from this plexus
innervate the epididymis, vas deferens, seminal
vesicle, prostate, bladder neck and urethra (Figs. 1
and 2). The pudendal nerve emanates from the
sacral spinal cord and does not enter the pelvic
plexus, but exits the pelvis through the greater
sciatic foramen, reenters it through the lesser scia-
tic foramen, and innervates the perineal striated
muscles (Fig. 1).
b) Neurophysiology
Application of retrograde axonal tracing methods
to the vas deferens [23] revealed that the majority
of postganglionic neurons distributed in the vas
deferens originate from the pelvic plexus. The pel-
vic plexus receives neural input from both the
hypogastric and pelvic nerves (Fig. 2). Electrical
stimulation of the hypogastric nerve elicited
contraction of the vas deferens in many mamma-
lians [24, 25], while stimulation of the pelvic
nerve caused no detectable motor responses [25,
26]. Histochemical studies of the vas deferens
have also shown that the adrenergic fibers mainly
innervate the smooth muscle layers, whereas cho-
linergic ones chiefly innervate the subepithelial
layer [4]. Stimulation of the hypogastric nerve has
also elicited contraction of the bladder neck and
Figure 1: Diagram showing the nervous system controlling ejaculation. Emission from both the ejaculatory orifice and pros -
tate, and bladder neck closure are controlled by the signals from the pelvic plexus. The pudendal nerve principally controls
propulsion out of the urethra. The sacral splanchnic nerve (SSN) is found in about 30-50% of humans. BCM: bulbocaverno -
sus muscle, Epi: epididymis, EUS: external urethral sphincter, HGN: hypogastric nerve, LSN: lumbar splanchnic nerve, PuN:
pudendal nerve, PN: pelvic nerve, SC: spinal cord, SHP/CMP: superior hypogastric plexus in humans/caudal mesenteric
plexus in animals, SV: seminal vesicle, SyC: Sympathetic chain

Figure 2: Diagram showing the com -

mon sympathetic pathways controlling
ejaculation (black) in mammalians (A).
The caudal mesenteric plexus in ani -
mals is divided into two plexuses in
humans, inferior mesenteric plexus
(IMP) and superior hypogastric plexus
(SHP) (B). The pathways in blue is of
minor importance in motor activity of
the seminal tract. CM: cranial mesente -
ric, CMA: caudal mesenteric artery,
CoN: colonic nerve, InMP: intermesen -
teric plexus. See Fig. 1 legend for addi -
tional abbreviations.

483
prostate as well as the vas deferens. On the proxi-
mal pathway to the hypogastric nerve, stimulation
of the lumbar splanchnic nerve caused contraction
of the vas deferens, prostate and bladder neck,
whereas that of the intermesenteric nerve elicited
no observable responses in any of those organs in
many mammalians [27].
The levels of the lumbar splanchnic nerves which
elicited motor activity of the seminal tract were
2nd-5th in rats [27] and dogs, and 1st-3rd in
humans [28,29]. Recent human anatomical study
has revealed that almost all the lumbar splanchnic
nerves originate from L2 and/or L3 lumbar sym-
pathetic ganglia (corresponding to L1-2 spinal
levels) [22]. Clinically, preservation of the L2
and/or L3 lumbar splanchnic nerve in retroperito-
neal lymph node dissection of testicular cancer
demonstrated restoration of ejaculatory function
[29]. Partial and complete interruption of the path-
way from the spinal cord to the seminal tract might
cause retrograde ejaculation and emission loss,
respectively. Partial inhibition might cause insuffi-
cient closure of bladder neck that permits the par-
tially emitted seminal fluid to flow back into the
bladder.
The cross-innervation of the peripheral sympathe-
tic nervous system, which has been suggested
from its architecture (Fig. 2), has been revealed in
the dog and rat [27]. On the way of the common
pathway from the lumbar splanchnic nerve to the
seminal tract, some signals cross to the other side
of the body at the level of the caudal mesenteric
plexus and/or the pelvic plexus (Fig. 3). The pre-
ganglionic axons passing through the hypogastric
nerve very likely provide a bilateral innervation to
postganglionic neurons in the pelvic plexuses,
which also exhibit crossing to the bilateral vasa
deferentia [27]. A similar pattern of multiple cross-
innervation has also been identified in the rodent
bladder neck.
When the sympathetic signals passing through
the above pathway reach the seminal tract, nore-
pinephrine is released from the terminal of the
postganglionic neuron. Norepinephrine induces
activation of alpha 1-adrenergic receptors on the
smooth muscle cells, which elicits a rise in cyto-
solic calcium and results in the actin-myosin
484
interaction. A combination of adrenergic and
purinergic (ATP) mechanisms are necessary for
contraction of the animal vas deferens, while
norepinephrine is most probably the only signifi-
cant neurotransmitter for contraction of human
vas deferens. Transmitter release, or the basal
tone of the smooth muscle of the vas deferens,
might be variably modulated by many sub-
stances, i.e. acetylcholine, neuropeptide-Y. Once
contraction of the smooth muscle of the seminal
tract occurs, marked elevation of intraluminal
pressure might occur at the cauda epididymis/
proximal vas, which might push the spermatozoa
out to the ampulla. Both nerve signal and disten-
tion of the wall of the ampulla might trigger
contraction of the ampulla to emit the content
into the posterior urethra.
When the common pathways described above are
interrupted, the occurrence of compensatory
mechanisms such as enhancement of the remai-
ning sympathetic pathways and reorganization of
synaptic connection in the pelvic plexus has been
reported. After transection of the canine hypogas-
tric nerve, surgical reconstruction is possible and
cross-innervation through the hypogastric nerve
described above can also be preserved [30].
The sympathetic nerves reaching the adrenal
medulla via the thoracic sympathetic chain and the
major/minor splanchnic nerves may have a possi-
bility of affecting ejaculation through hormonal
system. Catecholamines secreted from the adrenal
medulla can elicit similar systemic reactions as
those accompanying ejaculation, such as marked
elevation of blood pressure, tachycardia, tachyp-
neoa and perspiration as well as local ejaculatory
reactions.
Propulsion of the seminal fluid is caused by rhyth-
mic contractions of the perineal striated muscula-
ture including the bulbocavernosus and ishioca-
vernosus muscles. Such muscles are innervated by
the pudendal nerve and show excitement during
ejaculation. The patients with sacral cord injuries
usually show dribbling ejaculation due to the lack
of contribution of the musculature. The peripheral
nervous system controlling ejaculation has elabo-
rate mechanisms for preserving its function
against various injuries.
Figure 3: Diagram showing bilateral sympathetic efferent pathways projecting from a lumbar splanchnic nerve to the vasa
deferentia on both sides. Four routes and two points of crossing to the other side are indicated. Similar cross-innervation is
present in bladder neck and prostate. See Fig. 1 legend for abbreviations.

485

III. ELECTROPHYSIOLOGICAL
EVALUATION OF THE NERVOUS
PATHWAYS CONTROLLING
EJACULATION
Neurophysiological tests allow objective evalua-
tion of the nervous pathways controlling ejacula-
tion. Four tests are routinely used.
1. P UDENDAL SOMATOSENSORY EVOKED
POTENTIALS (PUDENDAL SEPS)
Somatosensory evoked potentials (SEPs) are defi-
ned as a transient alteration of the electroencepha-
logram (EEG) following peripheral nerve stimula-
tion. They provide objective information concer-
ning the afferent volley from the dorsal nerve of
penis to the cortex. The technique consists of elec-
trical stimulation of the dorsal nerve of penis with
recording of the evoked responses over the spine
and the scalp (2 cm behind the central vertex) (Fig.
4). First the sensibility threshold is measured. By
definition, the sensibility threshold is the lowest
perceivable sensation of the electrical current at the
point of stimulation. The latency of the response is
measured both at the onset of the response and the
peak of the first reproducible deflection. By recor-
ding the response at 2 different levels, 3 different
transit times are obtained: a total transit time (from
penis to brain), a peripheral transit time (from penis
to spine), and a central transit time (which is obtai-
ned by subtracting the peripheral from the total
transit time). The peripheral transit time is approxi-
mately 13.5 ms. The total transit time is approxima-
tely 34 msec (onset) and 43 msec (top of P1 deflec-
tion) [31,32].
2. PUDENDAL MOTOR EVOKED POTENTIALS
(PUDENDAL MEPS)
Motor Evoked Potentials (MEPs) explore the effe-
rent pathways (pyramidal tracts) from brain to tar-
get muscle (bulbocavernosus muscles). The tech-
nique consists of stimulating the motor cortex and
sacral roots by means of a magneto-electric stimu-
lator. For brain stimulation, the coil is applied 2
cm behind the vertex (Fig. 5). For sacral root sti-
mulation, the coil is applied laterally to the spine.
The response is picked up from the bulbocaverno-
sus muscles with co-axial EMG needle electrodes.
Brain stimulation is performed, first at rest, and
486
then during a voluntary contraction of the pelvic
floor (facilitation procedure). Sacral root stimula-
tion is performed only at rest. The response is
measured at the onset of the first reliable deflec-
tion. By stimulating the central nervous system at
2 levels, 3 different transit times will be obtained:
a total transit time (from brain to target muscle), a
peripheral transit time (from sacral roots to target
muscle) and a central transit time (obtained by
subtracting the peripheral from the total transit
time) (Fig 6). The total transit time measured in
the bulbocavernosus muscles is respectively 28
msec (brain stimulation patient at rest) and 23
msec (brain stimulation patient contracting the
pelvic floor). The peripheral transit time is 7 msec
(sacral root stimulation) [32].
3. SACRAL REFLEX ARC TESTING: THE SOMA-
TIC-SOMATIC REFLEX ARC
The test allows the investigation of the sensory
and motor branch of the pudendal nerve and of the
sacral segments S2, S3, S4. The technique consists
in stimulating the dorsal nerve of the penis and
recording the response from the bulbocavernosus
muscles. The response consists usually of 2
deflections. The mean latency of the first deflec-
tion is 35 msec, although a late deflection is often
observed at 80 msec [32,33].
4. SYMPATHETIC SKIN RESPONSES (SSRS)
Electrical activity from the sympathetic nerve ter-
minals controlling the sweat glands of the skin can
be recorded following electrical stimulation of any
peripheral nerve trunk. The test allows evaluation
of the sympathetic efferent outflow to the skin of
the genital organs. The dorsal nerve of the penis is
stimulated using 2 ring electrodes wrapped around
the penile shaft, the cathode being proximal. The
stimulation consists of single electrical pulses
applied at a rate of 0.05 Hz. Sympathetic skin res-
ponses are recorded from hand, foot, and per-
ineum using disc electrodes affixed to the skin.
Two tracings are superimposed to check the repro-
ducibility of the response. The right median nerve
is then stimulated, and SSRs are recorded from the
hand, foot, perineum, and penis. The mean latency
of hand, foot, and perineum SSRs following dor-
sal nerve of the penis stimulation are, respectively,
1.40 sec, 2 sec, and 1.4 sec. Following median
nerve stimulation, the latency of penile SSRs is
1.50 sec [34,35].
 Figure 4: Pudental Somatosensory Evoked
Potentials (Pudendal SEPs). The response is
recorded 2 cm behind the central vertex.The
latency of the first positive deflection (P1) is 38
msec.

Figure 5: Pudendal Motor Evoked Potentials (Pudendal MEPs):

sites of stimulation and position of the coil.
A : Transcranial magnetic stimulation : the posterior edge of the
coil is applied 2 cm behind the entral vertex
B: Sacral root magnetic stimulation : the coil is applied laterally
to the spine at the level of the iliac crest (from R.J. Opsomer et al,
1992, with permission for reproduction of Peeters Publishers [94])

Figure 6 : Pudendal Motor Evoked Potentials (Pudendal MEPs) recorded from the periurethral sphincter in a normal subject.
A: Transcranial magnetic stimulation. Subject at rest. Latency of the response is 21.5 msec. B: Transcranial magnetic stimu -
lation. Latency of the response in 30msec. Notice the increase in amplitude and shortening of the latency of the response when
the patient contracts the pelvic floor : Facilitation procedure. C : Sacral root magnetic stimulation. Latency of the response is
7.7 msec (from R.J. Opsomer et al, 1992, with permission for reproduction of Peeters Publishers [94])

487

IV. PATHOPHYSIOLOGY OF
EJACULATORY DISORDERS
1. EMBRYOLOGY AND CONGENITAL
ANOMALIES
As the male foetus develops, the Mullerian ducts
normally disappear from above downwards under
the influence of Mullerian inhibitory factor (MIF)
which is produced by the Sertoli cells in the pri-
mitive testis. Failure of complete absorption may
leave a small Mullerian duct remnant at the lower
end that lies between the ejaculatory ducts. The
Wolffian (mesonephric) ducts are composed of
three distinct areas. The upper part forms the epi-
didymis and distal vas deferens, while the proxi-
mal vas deferens, seminal vesicle and ejaculatory
duct are derived from the middle area. The most
caudal part is the common mesonephric duct, from
which the ureteric bud springs at approximately 4
weeks of development: this becomes the ureter,
and will induce the metanephric blastema to form
the kidney. The urogenital sinus reabsorbs the
lower end of this structure, and the ureteric ori-
fices are thus separated from the vasa deferentia,
Figure 7: Mullerian duct cyst shown by a. transrectal ultrasound scan, and b. percutaneous puncture (reproduced from the
British Journal of Urology with permission).
488
seminal vesicles and ejaculatory ducts. Several
complex anomalies may occur in this area leading
to ectopic opening of the vas deferens and some-
times associated with anorectal anomalies [36]. If
too much of the proximal vas precursor is absor-
bed, a variable amount of the proximal vas, semi-
nal vesicle and/or ejaculatory duct may be absent.
There may also be coexisting abnormalities in the
ipsilateral kidney or ureter.
a) Mullerian duct cyst
Persistence of a small remnant of the Mullerian
duct may lead to a cyst forming between the eja-
culatory ducts which can become obstructed and
cause diminution of the volume of the ejaculate
and infertility. Haemospermia is not uncommon in
these patients. Seminal analysis shows the changes
characteristic of ejaculatory duct obstruction with
a small volume (less than 1.5 ml), acid pH and litt-
le or no fructose. Both vasa are palpable and the
epididymes usually feel distended. The diagnosis
is established by transrectal ultrasound scan
(TRUS), and the lesion can be delineated by per-
cutaneous puncture of the cyst with instillation of
radio-opaque medium (figure 7). The cyst can be
incised or deroofed endoscopically after delinea-
ting its extent by injection of blue dye (see below).
Improvement in ejaculate volume and seminal
quality follows in most cases [37].
b) Wolffian duct abnormalities
Congenital anomalies may be either sporadic, with
a localized defect in the proximal part of the vas
deferens or there may be a generalized maldeve-
lopment due to a systemic genetic abnormality.
Local Wolffian duct abnormality involves loss of a
variable amount of the vas deferens, seminal
vesicle and/or ejaculatory duct, and sometimes
part of the ipsilateral urinary system as well. This
may be associated with maldevelopment of the
bladder neck and trigone, which fails to close
effectively producing retrograde ejaculation.
Bilateral abnormalities are often associated with
carriage of the cystic fibrosis gene [38]. Unilateral
absence of the vas deferens was observed in 5%,
and bilateral absence in 18% of 370 azoospermic
males with normal serum FSH levels investigated
by the author [39].
c) Prune belly syndrome
Patients with Prune Belly syndrome have normal
libido, erections, and orgasms. Most have abnor-
mal ejaculation and probably emission. In a study
involving nine patients, seven had retrograde eja-
culation and two produced ejaculates [40]. Five
patients provided semen or urine passed after mas-
turbation. Two produced ejaculated semen. One of
the ejaculated specimens consisted of 4.5 cc of
fluid indistinguishable from urine and one was 2.5
cc of fluid with the appearance of watery semen.
Post masturbation urine specimens were of normal
urinary appearance. None of the specimens contai-
ned sperm: no mention was made of the fructose
content. Abnormal ejaculation thus appears to be
present in the vast majority of patients with Prune
Belly syndrome. Whether the primary abnormali-
ty is retrograde ejaculation or lack of emission is
not clear
2. TRAUMATIC DAMAGE
a) Imperforate anus
Ejaculatory duct obstruction may follow correc-
tion of imperforate anus. The pull through proce-
dure passes close to the posterior aspect of the
prostate, and damage is most likely if there has
been closure of a recto-urethral fistula. Analysis of
489
20 subfertile males who had repair of imperforate
anus in infancy indicated that 7 had no ejaculate,
11 were azoospermic, 1 was severely oligozoo-
spermic and only 1 had a normal sperm concentra-
tion in a very small volume ejaculate [41]. Inves-
tigation revealed that both vasa were blocked in 5
men and one vas in a further 8 patients, apparent-
ly as a result of the original operative procedure.
b) Operations on the prostate
Antegrade ejaculation requires a closed bladder
neck (and proximal urethra). Surgical procedures
that compromise the bladder neck closure mecha-
nism may result in retrograde ejaculation. Trans-
urethral incision of the prostate (TUIP) results in
retrograde ejaculation in 5% [42] to 45% [43] of
patients and is probably related to whether one or
two incisions are made and whether or not the
incision includes primarily the bladder neck or
extends to the level of the verumontanum.
The importance of contraction of the urethral
smooth muscle at the level of the verumontanum
has been hypothesized to be important in preven-
ting retrograde ejaculation [42]. Transurethral
resection of the prostate (TURP) carries a higher
incidence of retrograde ejaculation than does
TUIP. The reported incidence of retrograde ejacu-
lation following TURP ranges from 42% [44] to
100% [45]. It occurs less frequently following
open prostatectomy (either suprapubic or retropu-
bic) then after TURP. In one series, the incidence
of retrograde ejaculation following open prosta-
tectomy was zero [44]. TURP is thought to disrupt
the closure mechanism of the vesical neck, whe-
reas open enucleation is less apt to produce this
alteration.
After radical prostatectomy, ejaculation is bound
to be lost since the seminal vesicles are removed
with the prostate gland. Erectile impotence was
the rule until detailed anatomical studies showed
where the parasympathetic nerves ran on the sur-
face of the prostate gland, and a nerve sparing ope-
rative technique was developed [46]. A sensation
of orgasm can sometimes be preserved despite loss
of ejaculation.
3. INFECTIVE DISORDERS
Genital infection such as gonorrhoea or non-speci-
fic urethritis can produce cicatrisation and obs-
truction anywhere in the male reproductive tract,
especially if treatment is delayed. Urinary infec-
tion, especially if complicated by epididymitis,
can also produce obstruction that may be situated
at ejaculatory duct level. Routine vasography in
subfertile men with azoospermia and normal
serum FSH levels revealed post-infective vasal
blocks in 8% and acquired ejaculatory duct obs-
truction in 4% [39].
Schistosomiasis is endemic in large parts of Afri-
ca, and is seen with increasing frequency in tou-
rists returning from Africa who have contracted
the disease whilst enjoying water sports: Lake
Malawi has acquired an evil reputation in this res-
pect. The disease may present with haemospermia
[47] and fibrosis and calcification may lead to
genital obstruction.
Genito-urinary tuberculosis can cause great dama-
ge to the male reproductive tracts, and since hea-
ling occurs with calcification, the lesions may be
irreparable. Plain X-ray will often show the extent
of the disease.
Haemospermia is seldom as ominous a symptom
as haematuria, but this complaint should not be
ignored. Analysis of the findings in 81 patients
revealed that an inflammatory cause could be defi-
ned in most men under 30 years of age; however,
there were a few (8%) with more serious disease
including carcinoma of prostate and bladder [48].
It should be remembered, also, that schistosomia-
sis and tuberculosis could present in this way.
Routine investigation of haemospermia by TRUS
not uncommonly reveals the presence of small
stones in the ejaculatory ducts, which may be
associated with obstruction and dilatation of the
seminal vesicles. Such stones usually pass sponta-
neously.
4. NEUROGICAL DISORDERS
a) Spinal cord injury
Damage to the spinal cord at the level of T12 to L2
may affect central reflex pathways and lead to per-
manent loss of ejaculation. Injury above T11 may
allow reflex erection and ejaculation, although this
can provoke autonomic dysreflexia with marked
rise in blood pressure. In some paraplegic patients,
application of a vibrator to the penis will lead to
ejaculation; in others, electroejaculation may be
490
necessary to produce spermatozoa that can be used
for insemination. If the spinal reflex arc is intact, a
hypogastric plexus stimulator can provide ejacula-
tion in the comfort and security of the patients'
home [49]. Alternatively, direct electroejaculation
by rectal probe may be effective, but this may
require a general anaesthetic and is done in hospi-
tal [50]. In a recent collective analysis of 40 para-
plegic patients, 22 successfully produced pregnan-
cies by natural insemination or assisted reproduc-
tive techniques [51].
Orgasm has been noted to occur in men with spi-
nal cord injuries. Via self-report 42% to 61% of
men reported the ability to achieve orgasm.
Orgasms were also noted to occur in men with
complete spinal cord injuries; however, overall
orgasms were described as different than prior to
their injuries. No laboratory-based analysis has
been performed of the physiologic events occur-
ring during orgasms in the male with spinal cord
injury [52].
b) Paraaortic lymphadenectomy
This operation is usually done to clear lymph node
metastases from testicular tumours, when the sym-
pathetic nerves and ganglia may also be removed
leading to loss of ejaculation. Early studies sho-
wed that up to three-quarters of patients lost ante-
grade ejaculation after full bilateral retroperitoneal
lymph node dissection. As a result of careful ana-
tomical studies, the technique of retroperitoneal
lymph node dissection has been modified with
nerve sparing so that antegrade ejaculation is now
maintained in 70-90% of patients.
One quarter of the patients who complete chemo-
therapy for advanced testicular tumour have resi-
dual masses in the para-aortic region [53].
Amongst 231 consecutive patients undergoing
para-aortic lymphadenectomy after chemotherapy
at the Royal Marsden Hospital, there was persis-
tent undifferentiated tumour in 21% [54]. In our
experience of 186 patients, a nerve sparing opera-
tive technique introduced in 1984 lead to a signifi-
cant reduction in ejaculatory dysfunction from
37% to 19% [55]. Loss of ejaculation occurred
significantly more often after bilateral (46%) com-
pared to unilateral (14%) dissection, and was rela-
ted to the size of the excised mass (<4 cm 4%; 4-
8 cm 19%; >8 cm 60%).
It is important to anticipate this complication in
young men with testicular tumours who may need
chemotherapy or node dissection, and arrange-
ments should be made for sperm storage before
treatment commences. Excellent results can be
obtained with artificial insemination using cryo-
preserved spermatozoa [56].
5. THE EFFECTS OF DRUGS ON ORGASM AND
EJACULATION
a) Animal studies
Ever since the late sixties, serotonin (5-HT) has
been known for its involvement in male rat sexual
behaviour. It is generally assumed that central 5-
HT has an inhibitory role in the neural control of
masculine sexual behaviour in the rat. A decrease
in 5-HT neurotransmission decreases the number
of intromissions preceding ejaculation and shor-
tens the time to ejaculation, whereas an increase in
central 5-HT neurotransmission produces the
opposite effect [57]. Administration of the selecti-
ve 5-HT1A receptor agonist 8-OH-DPAT lowers
5-HT levels in some parts of the brain, and causes
male rats to ejaculate at the first or second intro-
mission and within seconds after being put in the
vicinity of an estrous female rat. Therefore, it
could be stated that 8-OH-DPAT renders male rats
to be premature ejaculators [58]. Administration of
different selective serotonin reuptake inhibitors
(SSRIs), which results in higher levels of 5-HT,
suppresses sexual behavior in male rats [59].
b) Human studies
In humans, the side effects of antidepressants on
sexual function have been known for more than 25
years. In general, these substances increase the 5-
HT concentration in the synapses, usually by upta-
ke inhibition (e.g., SSRIs) [95]. The most common-
ly reported side effects are delay or absence of
orgasm/ejaculation. In 1973, the English psychia-
trist Eaton was the first to report on the beneficial
aspects of this side effect. He administered the tri-
cyclic antidepressant clomipramine to men with
premature ejaculation without psychiatric disorders
[60]. To date, many studies have been performed to
investigate the effects of fluoxetine, paroxetine, ser-
traline (SSRIs) and clomipramine [61]. Table 1
shows the results of the most relevant studies [62-
75]. Although no studies with long-term treatment
with SSRIs have been published, it has become an
accepted treatment for premature ejaculation.
491
Since psychiatric drugs and physical conditions
like erectile dysfunction can cause secondary pre-
mature ejaculation, it is important to exclude
and/or treat these causes before treating the symp-
tom of premature ejaculation. For example, when
a man is able to achieve a rigid erection, but not to
maintain this erection for a certain amount of time,
he could condition himself to ejaculate rapidly. It
is very likely that his secondary premature ejacu-
lation will be successfully treated by oral sildena-
fil or local vasoactive drugs, and not by SSRIs.
c) Side effects of specific drugs on ejaculation
1) Dopamine
The centrally acting neurotransmitter dopamine is
known for its involvement in control of male rat
sexual behavior. Taking the parameters of mount
and intromission frequencies and latency to ejacu-
lation as measures of copulatory activity, most
reports indicate that dopamine has a stimulatory
effect that is exerted via D2 receptors. Enhance-
ment of the ejaculatory behavior and the decrease
in intromission frequency stimulated some authors
to call this altered behaviour a rat model for "pre-
mature ejaculation".
2) Morphine
Several studies have shown that systemic and cen-
tral administration of morphine inhibits male rat
sexual behavior. However, in one study [76], a
small proportion of male rats reacted differently
on a low dose of systemic morphine: there was a
decrease of ejaculation latency, and in the number
of intromissions prior to ejaculation. These
conflicting results indicate that at least there is a
role for the enkephalines in the modulation of
sexual behavior in the male rat.
3) Ecstasy
The amphetamine analog MDMA, better known
as the recreational drug ecstasy, is known and fea-
red for its neurotoxic properties. It reduces brain
concentrations of serotonin by inhibition of the
metabolism and by long-lasting degeneration of 5-
HT nerve terminals, as well as by decreasing the
number of 5-HT uptake sites. In an experiment
with male rats, Dornan and collaborators [77]
found that a chronic administration of MDMA,
caused less rats to display mounting behavior, and
an increase in ejaculation latency in the respon-
ders. These results are conflicting with the above-
described studies with serotonin receptor agonists
Table 1: The influence of different serotonin reuptake inhibitors on ejaculation latency in men with premature ejaculation:
a summary of selected studies

AUTHOR(S) & REFERENCE N DOSE STUDYDESIGN* EFFECT/REMARKS

CLOMIPRAMINE (tricyclic serotonin reuptake inhibitor)

Segraves et al [62] 20 25-50 mg/day DB, PC, crossover placebo: 51 sec,
clomipramine: 366 sec
Althof et al [63] 15 25-50mg/day DB, PC, crossover baseline: 81 sec
25 mg: 202 sec,
50 mg: 416 sec partner ’s
satisfaction included
Haensel et al [64] 22 25 mg 12-24 h DB, PC, crossover placebo: 2 min,
prior to sexual activity clomipramine 8 min
include control group:
9->11 min
Stassberg et al [65] 34 25 mg 4-6 h placebo: 52 sec,
prior to sexual activity DB, PC, crossover clomipramine: 229 sec
include controls: 8->11 min
FLUOXETINE (SSRI)
Kara et al [66] 14 20-40 mg/day DB,PC placebo: 30->60 sec,
fluoxetine: 25->180 sec
Lee et a l [67] 11 20-60 mg/day Open label baseline: 0.9 min,
fluoxetine: 9.6 min
Haensel et al [68] 40 5-10 mg/day DB, PC, crossover increase in ejaculation
latency (p=0.007)
controls: no effect
PAROXETINE (SSRI)
Waldinger et al [69] 17 20-40 mg/day DB, PC baseline: 0.5 min, 20 mg:
7.5 min, 40 mg: 10 min.
placebo no effect
Waldinger et al [70] 27 20-40 mg/day DB, dose response 20 mg/day: 13->300 sec,
40 mg/day: 10->540 sec
McMahon and Tourma [71] 26 20 mg 3-4 h SB, crossover baseline: 0.3 min
prior to sexual activity placebo 0.45-0.6 min
paroxetine: 3.2-3.5 min
SERTRALINE (SSRI)
McMahon [72] 37 50 mg/day SB, PC, crossover baseline: 0.3 min, placebo:
0.5 min, sertraline: 3.2 min
McMahon [73] 46 25-100 mg/day Open label baseline: 1 min, 25 mg: 7.6
min, 50 mg:13.1 min, 100
mg: 16.4 min
COMBINED
Waldinger et al [74] 51 Fluoxetine DB, PC baseline: 18 sec
20 mg/day placebo: 29 sec
Fluvoxamine fluvoxamine: 55 sec
200 mg/day sertraline: 117 sec
Paroxetine fluoxetine: 211 sec
20 mg/day paroxetine: 476 sec
Sertraline
50 mg/day
Kim et al [75] 36 Fluoxetine DB, PC, crossover baseline: 46 sec,
40 mg/day placebo 2.3 min
Sertraline fluoxetine: 2.3 min
100 mg/day sertraline: 4.3 min
Clomipramine clomipramine: 5.8 min
50 mg/day

KEY: DB - double blind; SB - single blind ; PC - placebo controlled

Derived in part from: Rowland et al. [61] with permission of the author

492
and antagonists, because a decrease in central 5-
HT would cause an increase in male rats' sexual
behaviors. Probably, since MDMA has such dra-
matic effects in the brain, other factors may have
played an important role in this experiment.
GABA. The neurotransmitter gamma-aminobutric
acid (GABA) occurs in the brain tissue. Two dis-
tinct types of GABA receptors are recognized:
GABAA and GABAB. There is some evidence
that the GABAB receptor agonists (like baclofen)
inhibit sexual behavior in male rats, independent-
ly from the effects on motor systems. Efforts to
discover a role for GABAA in the modulation of
sexual behavior in the rat have failed so far.
4) Yohimbine.
The alpha2-adrenoceptor blocking agent yohimbi-
ne has been known for its aphrodisiac properties in
rats and humans. In male rat studies, it increased
mounting behavior without the need for physiolo-
gical levels of serum testosterone. When looking
at the effects on ejaculation, a decrease in ejacula-
tion latency, intercopulatory interval, and post-eja-
culatory interval is found.
d) Specific drug effects in human studies
1. MONOAMINE OXIDASE INHIBITORS.
The monoamine oxidase inhibitors (MAOIs) are
mainly used in the treatment of neurotic or atypi-
cal depression. These drugs increase the levels of
epinephrine, norepinephrine, dopamine and sero-
tonin. The MAOIs have been known for their
sexual side effects, with an incidence up to 20-
40%. Delayed or inhibited ejaculation is reported
for isocarbazid, phenelzine and tranylcypromine.
2. CYPROHEPTADINE
It is an antihistaminic, formerly used in Cushing's
disease and anorexia nervosa. It also increases
serotonin levels in the brain. Several reports indi-
cate that cyproheptadine is able to convert drug-
induced orgasmic failure in both men and women.
3. B ENZODIAZEPINES
A number of benzodiazepines effective in treating
generalized anxiety and panic attacks are also
known to inhibit ejaculation in some men, presu-
mably by enhancing gamma-aminobutyric acid
(GABA). These drugs include diazepam, loraze-
pam, lormetazepam, temazepam, flunitrazepam,
flurazepam, nitrazepam, chlordiazepoxide, and
alprazolam.
493
4. STIMULANTS
Amphetamine is a stimulating drug with affinity
for different receptors in the central nervous sys-
tem. It stimulates release of dopamine, inhibits
monoamine oxidase and blocks the reuptake of
both catecholamines and serotonin. It is reported
to delay ejaculation in subjects without ejaculato-
ry dysfunction.
Cocaine is an addictive "recreational" drug and sti-
mulates the central nervous system through bloc-
king of monoamine transporters. Different reports
confirm that delayed ejaculation appears to be the
most common sexual side effect.
The influences of different drugs on ejaculation
are delineated in table 2 [78].
6. FUNCTIONAL DISORDERS
• Seminal megavesicles
Adult polycystic kidney disease has been found in
association with pathological dilatation of the
seminal vesicles in 6 patients [79]. TRUS and per-
cutaneous puncture of the seminal vesicles before
and after resection of the ejaculatory ducts revea-
led that the gross dilatation of the seminal vesicles
was not caused by obstruction, but appeared to be
due to atonicity (megavesicles). These ultrasonic
appearances, when described previously, were
incorrectly thought to be due to seminal vesicle
cysts. Pathological dilatation of the seminal
vesicles in the absence of obstruction has been
described previously, although the aetiology
remains obscure [80].
V. INVESTIGATION
1. EVALUATION OF PATIENTS WITH
RAPID/PREMATURE EJACULATION
a) Diagnostic criteria
The diagnostic criteria for rapid or premature eja-
culation have been defined as follows:
• DSM-IV- PREMATURE EJACULATION
1) Persistent or recurrent ejaculation with minimal
sexual stimulation before, on, or shortly after
penetration and before the person wishes it. The
clinician must take into account factors that
Table 2: Side effects of different drugs on ejaculation

GROUPOFDRUGS AGENT EFFECT ON EJACULATION

ANALGESICS
NSAID’s Naproxen Decrease/absence of ejaculation/orgasm
Opoids Methadone Decrease/absence of ejaculation/orgasm
Morphine Decrease/absence of ejaculation/orgasm
ANTIHYPERTENSIVES
Alpha blockers Phenoxybenzamine Decrease/absence of ejaculation/orgasm
Retrograde ejaculation
Alpha and beta blockers Labetolol Decrease/absence of ejaculation/orgasm
Centrally acting Clonidine Decrease/absence of ejaculation/orgasm
Retrograde ejaculation
Guanethidine Decrease/absence of ejaculation/orgasm
Retrograde ejaculation
Methyldopa Decrease/absence of ejaculation/orgasm
Reserpine Decrease/absence of ejaculation/orgasm
ANTI-PARKINSONISM AGENTS
Bromocryptine Decrease/absence of ejaculation/orgasm
L-DOPA Decrease & increase reported
Pergolide Spontaneous ejaculation
APPETITE SUPPRESSANTS
Mazindol Spontaneous ejaculation
CYTOTOXICS
Methotrexate Decrease/absence of ejaculation/orgasm
Vincristine Decrease/absence of ejaculation/orgasm
HORMONE ANTAGONISTS
Cyproterone acetate Decrease/absence of ejaculation/orgasm
HYPNOTICS AND SEDATIVES
Barbiturates (all) Decrease/absence of ejaculation/orgasm
LITHIUM Decrease/absence of ejaculation/orgasm
PSYCHOPHARMACEUTICALS
Antidepressants (S)SRI’s See table X.1
Trazodone Decrease/absence of ejaculation/orgasm
Retrograde ejaculation
MAOI’s
Isocarboxazid Decrease/absence of ejaculation/orgasm
Phenelzine Decrease/absence of ejaculation/orgasm
Tranylcypromine Decrease/absence of ejaculation/orgasm
Anxiolytics Benzodiazepines Decrease/absence of ejaculation/orgasm
Neuroleptics Chlorpromazine Decrease/absence of ejaculation/orgasm
Retrograde ejaculation
Phenothiazines Fluphenazine Decrease/absence of ejaculation/orgasm
Retrograde ejaculation
Levomepromazine Retrograde ejaculation
Perphenazine Decrease/absence of ejaculation/orgasm
Pipothiazine Decrease/absence of ejaculation/orgasm
Thioridazine Decrease/absence of ejaculation/orgasm
Retrograde ejaculation
Trifluoperazine Decrease & increase reported
Thioxanthenes Chlorprotixene Decrease/absence of ejaculation/orgasm
Thioxitene Retrograde ejaculation
Spontaneous ejaculation
Zuclopenthixol Retrograde ejaculation
Butyrophenones Haloperidol Painful ejaculation
Diphenylbutylpiperidines Pimozide Decrease/absence of ejaculation/orgasm

494
Table 2: Side effects of different drugs on ejaculation (ctd)

GROUPOF DRUGS AGENT EFFECT ON EJACULATION

MUSCLE RELAXANTS
Baclofen Decrease/absence of ejaculation/orgasm
URINARY TRACT
Alpha blockers Alfuzosin Retrograde ejaculation
Phenoxybenzamine Retrograde ejaculation
Prazosin Retrograde ejaculation
Tamsulosin Retrograde ejaculation
Terazosin Retrograde ejaculation
Alpha reductase inhibitors Finasteride Less ejaculatory volume

RECREATIONALDRUGS
Alcohol Decrease/absence of ejaculation/orgasm
Amphetamines Decrease & increase reported
Amylnitrite (poppers) Increase in ejaculatory latency
Cocaine Decrease/absence of ejaculation/orgasm
Heroin Decrease & increase reported
Marihuana Decrease/absence of ejaculation/orgasm
Methadone Decrease/absence of ejaculation/orgasm
Tobacco Decrease/absence of ejaculation/orgasm
After; Moors-Mommers, [78]

affect duration of the excitement phase, such as • degree of voluntary control.

age, novelty of the sexual partner or situation,
and recent frequency of sexual activity.
2) The disturbance causes marked distress or inter-
personal difficulty.
3) The premature ejaculation is not due exclusive-
ly to the direct effects of a substance (e.g., with-
drawal from opioids).
• ICD-10- PREMATURE EJACULATION
(ICD= INTERNATIONAL CLASSIFICATION OF
DISEASES)
1) The general criteria for sexual dysfunction
(F52) must be met.
2) There is an inability to delay ejaculation suffi-
ciently to enjoy lovemaking, manifest as either
of the following:
• Occurrence of ejaculation before or very soon
after the beginning of intercourse (if a time limit
is required: before or within 15 seconds of the
beginning of intercourse);
• Ejaculation occurs in the absence of sufficient
erection to make intercourse possible.
3) The problem is not the result of prolonged abs-
tinence from sexual activity.
b) Assessment (Decision Tree A)
Rapid ejaculation is assessed along two major
dimensions:
• ejaculatory latency post-vaginal penetration and
The simplest dimension to assess is ejaculatory
latency or duration of intercourse. The clinician
inquires how long it takes for the man to reach
orgasm under each of the following circumstances:
with masturbation, partners hand and/or mouth sti-
mulation, and intercourse in varying positions. As
the patient answers these questions, the doctor lis-
tens for various factors that may enable reassurance
to be the primary treatment. These include men
with unusually high and unrealistic expectations:
for instance, that intercourse should last 45
minutes! The doctor sometimes can quickly educa-
te these men to no longer consider themselves rapid
ejaculators. Reassurance can sometimes be helpful
to men who are young, inexperienced, or trying too
hard to please a new partner.
The second major dimension to be assessed when
men complain of rapid ejaculation includes the
factors that affect the man's degree of voluntary
control. These are generally psychosocial condi-
tions. The doctor inquires whether the rapid ejacu-
lation occurs under all circumstances or only with
a specific partner or a specific circumstance.
Selective rapid ejaculation, either specific to a
partner or specific to a setting is usually acquired
rapid ejaculation. In these cases, the clinician turns
his attention to the life events that preceded the
onset of the problem. For instance, acquired rapid
ejaculation may follow a myocardial infarction or
the discovery of his wife's infidelity. Acquired

495
 DECISION TREE A :
DECISION TREE OF INVESTIGATION AND TREATMENT OF PREMATURE EJACULATION (PE)

HISTORY TAKING : PATIENT AND PARTNER

- psychosocial history
- somatic history
- (intravaginal) ejaculatory latency time
- degree of voluntary control
- duration of PE

Symptom of PE ? NO Change diagnosis/follow-up

YES

PE secundary to erectile dysfunc- Consider laboratory assessment

YES e.g., psychophysiological examination
tion or other sexual dysfunction ?
electrophysiological evaluation

NO Treat primary sexual dysfunction

Follow-up

Drug dependent PE ? YES Consider change of drug therapy

NO

Psychosocial/situational PE ? YES Psychosexual therapy

NO
Follow-up
Meet all DSM IV criteria ? NO

YES

Consider laboratory assessment

e.g., psychophysiological examination

concomitant ED or libido dysfunction ? YES consider

TREATMENT
- BEHAVIORAL TECHNIQUES
- stop/start
- sensate focus
- quiet vagina
- DRUG TREATMENT (SEE TEXT)
- INTEGRATED PSYCHODYNAMIC APPROACH
- DESENSITIZATION Follow-up
- anaesthetic ointments
- double condoms
OR A COMBINATION OFABOVE
496
rapid ejaculation may also mask an underlying
erectile disorder. In these cases the rapid ejacula-
tion is an adaptive response to prevent losing erec-
tions. The doctor should first proceed with the
work-up and treatment for the erectile dysfunction
and only treat the ejaculatory dysfunction if the
symptom remains. Even when the rapid ejacula-
tion is lifelong, the doctor needs to wonder why
the man seeks help for the condition at this time.
The answer is often that the stability of the marital
relationship is being threatened and the man looks
to the clinician for a simple face saving explana-
tion and treatment for a more complex problem:
marital deterioration.
Rapid ejaculation may also be a disguise for part-
ner sexual dysfunction. For example, a woman
may have an intense sexual aversion that has kept
her partner quickly ejaculating to minimize her
distaste for and distress during sex. Thus clinicians
need to hear about the quality of the sexual adjust-
ment over time to ascertain the social factors that
may suggest how to plan treatment.
In summary, the assessment of rapid or premature
ejaculation is done by sexual history taking. An
attempt is made to ascertain the man's social cir-
cumstances, his motivations for pharmacological or
psychological treatment and his partner's receptivi-
ty to such treatment. In some situations, it is best to
not attempt a pharmacological therapy until social
circumstances are further clarified or resolved
because the patient who may ultimately have been
helped by medications loses the opportunity becau-
se he or his partner could not surmount the psycho-
social obstacles related to the sexual dysfunction.
2. ASSESSMENT OF DELAYED RETARDED
EJACULATION
Assessment begins by reviewing the conditions
under which the man is able to ejaculate, e.g.
during sleep, with masturbation, with partner's
hand or mouth stimulation or infrequently with
varying coital positions. The course of the pro-
blem is documented, and variables that improve or
worsen performance are noted, such as the need
for unconventional fantasies or a lifelong need to
suppress spontaneous emotional expression.
Questions concerning the man's ability to relax,
sustain and heighten arousal and the degree to
which he can concentrate on sensations are posed.
If orgasmic attainment had been possible pre-
viously, the life events/circumstances temporarily
497
related to orgasmic cessation are reviewed, e.g.
following his wife's mastectomy: the man is afraid
of hurting her and therefore only partially aroused.
Societal/religious attitudes that may interfere with
excitement are noted, such as the spilling of seed
as a sin. Finally, questions concerning the quality
of the nonsexual relationship are posed and pro-
blems explored.
3. ASSESSMENT OF HAEMOSPERMIA
Haemospermia requires full investigation. Culture
of expressed prostatic secretion and urine will
define the nature of an infective process such as
prostatitis [81]and urine cytology and serum pros-
tate specific antigen should be assayed to exclude
bladder or prostatic cancer. Ultrasound scan of the
testicles and epididymes should define any local
disease. TRUS will demonstrate structural abnor-
mality in the prostate or seminal vesicles, or may
show up a stone in the ejaculatory duct or even a
Mullerian duct cyst. Cystoscopy is seldom helpful.
4. ASSESSMENT OF SMALL VOLUME EJACULATE
(DESICION TREE B)
If a man has difficulty with ejaculation, or has a
small volume or absent ejaculate, it must first be
established whether the problem is congenital or
acquired. Acareful clinical history should be taken,
and physical examination will establish whether the
testicles and epididymes are normal, and whether
the vasa are present or absent, on each side. Next, it
is essential to establish whether there is retrograde
or completely absent ejaculation, by examination of
a deposit of urine after centrifugation. The presence
of spermatozoa indicates retrograde ejaculation.
These facts will allow the patient to be placed into
one of several broad categories, after which more
detailed evaluation can take place.
Patients with ejaculatory duct obstruction usually
(Decision Tree C) present with infertility. Seminal
analysis may simply be reported a showing azoo-
spermia or oligozoospermia, but the characteristic
biochemical changes should be sought. There
should be absence of part or the entire component of
the ejaculate that comes from the vasa and seminal
vesicles via the ejaculatory ducts. The volume is low
(usually less than 1.5 ml), the pH is low (less than 7)
and the fructose content is either low (less than 120
mg/100ml) or absent. If both vasa are palpable, a
diagnosis of ejaculatory duct obstruction is very
likely.
 DECISION TREE B :
DIFFERENTIAL DIAGNOSIS OF DIMINISHED EJACULATION

Presenting complaint : - little or no ejaculate

Is there orgasm ? NO Anorgasmia

? nocturnal emission
YES
psychologist

Is there any ejaculate ? YES Seminal analysis

? low volume
NO
Decision tree C

? Are there sperm present Retrograde ejaculation

YES
in urine after orgasm
urologist
NO

Aspermia Decision Tree C

DECISION TREE C :
INVESTIGATION OF DIMINISHED EJACULATE

HISTORY
- little or no ejaculate ?
- infertility ?
- epdidymitis ?
- haemospermia ?
⇓
SEMINAL ANALYSIS
- low volume ?
- acid pH ?
- reduced fructose ? No ? functional
⇓
TRUS
- distended vesicles ?
- abnormal cyst ? No ? Diabetes mellitus
⇓
SEMINAL VESICULOGRAPHY
Percutaneous puncture
or vasography
- confirms obstruction ? No ? Polycystic kidney disease ? megavesicles
⇓
TRANSURETHRAL RESECTION
- volume increased ? No Redo TUR
⇓
SEMINAL ANALYSIS
- sperm count improved ? No Epididymo-vasostomies
⇓
Treatment success
498
When there is absence of the vasa, it is important
to establish whether the condition is unilateral or
bilateral. With unilateral absence of the vas defe-
rens, the urinary system must also be checked by
ultrasound scanning, as coexisting renal anomalies
may be present [82]. With bilateral absence or
malformation of the vasa, it is essential to consider
whether the anomaly may be part of a genetic
defect associated with carriage of the potentially
harmful cystic fibrosis chromosome anomaly [38].
5. ASSESSMENT OF EJACULATORY DUCT
OBSTRUCTION ON IMAGING
The lesion may be suspected by finding distended
seminal vesicles on transrectal ultrasound scan-
ning. However, the exact site of obstruction should
be defined radiologically by vasography or percu-
taneous puncture of the seminal vesicles (figure
8). Subsequently, methylene blue dye may be ins-
tilled to outline the ejaculatory system so that it
can be recognized after it has been entered at
transurethral resection [83].
VI. TREATMENT
1. PSYCHOLOGICAL TREATMENT FOR RAPID
EJACULATION
Since the early 1970's, an array of individual,
conjoint, and group therapy approaches
employing behavioral strategies, such as the stop-
start, squeeze technique, progressive sensate focus
exercises, masturbatory exercises and "quiet vagi-
na" with the female astride, have evolved as the
treatments of choice for rapid ejaculation. Beha-
vioral treatment often begins with the man alone,
having him repeatedly stimulate himself to
midrange levels of excitement before pausing.
After several repetitions he is permitted to ejacula-
te. The aim of this exercise is to help him learn
intermediate levels of excitement and begin to
slow down his arousal.
After mastering the self-stimulation exercise the
partner is asked to repeatedly bring the man to

Figure 8: Vasograms showing a) Normal seminal vesicles and ejaculatory ducts, b) Mullerian duct cyst, c) Wolffian duct
abnormality with absence of seminal vesicle, the duct terminating in a cystic malformation close to the prostatic urethra, d)
seminal megavesicles (reproduced from the British Journal of Urology with permission).

499
high levels of excitement, initially through stimu-
lation by her hand or mouth and later by vaginal
thrusting, but stopping prior to ejaculation. This
stop-start procedure allows the man's arousal to
decrease and thereby delays orgasm. This beha-
vioral sequence is repeated several times after
which the man is permitted to ejaculate. Masters
and Johnson [84] subsequently developed a modi-
fication of this procedure known as the squeeze
technique. At the point at which stimulation is
stopped, the man's glans penis is squeezed firmly
but quickly by the partner which lowers arousal.
Often however, this technique results in a partial
loss of erection.
Sensate focus exercises are designed to allow the
man to develop an awareness of his arousal level
by lessening the demand characteristics of the
sexual experience. In a slow, graduated fashion the
man and his partner take turns giving and recei-
ving pleasure. Initially the touching is restricted to
nongenital/non breast stimulation; upon achieving
ejaculatory control these areas are also pleasured.
"Quiet vagina" is an extension of the stop-start
maneuver to include intercourse. After successful
hand stimulation the woman sits astride or lies on
top of the man and, without any thrusting or rhyth-
mic movement envelops his penis in her vagina.
The aim of this exercise is to desensitize the man
to the wet, warm sensations of the vagina. After
the man masters the "quiet vagina" for a prolonged
period of time, movement by the woman is slowly
introduced. The man directs her to stop when his
excitement has increased. The couple sit/lie quiet-
ly until his arousal decreases whereupon they
resume the exercise. This is repeated several times
before the man eventually is allowed to ejaculate.
It is crucial for the therapist to monitor the part-
ners' needs and responses during therapy. The
female partner may feel used and unimportant.
This must be acknowledged while helping her to
focus on the ultimate goal of pleasurable sex for
both partners. Also, the therapist must monitor
both patient and partner for the emergence of any
resistance that will sabotage treatment.
Cognitive-behavioral treatment for this dysfunction
focuses on challenging self-defeating ideas about
sexuality or women while replacing them with faci-
litating thoughts about ejaculatory control, sexuali-
ty and intimacy. In addition, the behavioral skill of
identifying the point of ejaculatory inevitability is
500
learnt through the use of the stop-start technique
and alternating intercourse positions or thrusting
movements. Finally, a cooperative, intimate and
satisfying relationship is established.
An integrated psychodynamic approach seeks to
have the man or couple understand the hidden
meaning of the rapid ejaculation, appreciate the
interference of performance anxiety and, when
ready, embark on a series of behavioral tasks. Cli-
nicians need to be aware of the man or couple's
need for a symptom and how rare it is to find
"simple cases" of rapid ejaculation.
It has been found that the impressive treatment
success rates of 60% to 95% reported by Masters
and Johnson [84] can not be replicated and are not
sustainable. Three years after behavioral treat-
ment, success rates dwindle to 25%. This data sug-
gest that behavioral clinicians may have failed to
recognize psychodynamic causes of the disorder
or to develop long-term strategies that allow
patients to maintain their initial therapeutic gains.
2. PSYCHOLOGICAL TREATMENT FOR
DELAYED EJACULATION
Treatment efforts are guided by the assumptions
underlying the contrary theoretical models of cau-
sation. Proponents of the inhibition model unders-
tand the symptom as the man's muting of his exci-
tement and prescribe techniques to increase exci-
tement through prolonged, intense, rough stimula-
tion or by interpreting the man's unconscious
aggressive impulses. Diametrically opposed to the
inhibition model is the paradigm that considers
delayed ejaculation as a failure of the man to be
excited enough to achieve orgasm. Treatment
efforts are aimed at having the men acknowledge
their lack of both desire to have intercourse and
arousal during intercourse. This model mirrors the
conventional therapy for female anorgasmia focu-
sing on decreasing demand and helping the patient
focus on heightening erotic sensations.
Masters and Johnson [84] reported a low failure
rate of 17.6% using a treatment combination of
sensate focus, vigorous non-coital penile stimula-
tion and modifications of intercourse technique. In
another study 81% of men who were anorgasmic
prior to treatment were successful in reaching
orgasm through vibrator stimulation. No outcome
statistics are known for treatment model that
considers men insufficiently aroused.
3. DRUG TREATMENTFOR RAPID EJACULATION
Reducing penile skin sensitivity with the applica-
tion of local anaesthetic gel can treat premature eja-
culation. By keeping the cream in contact with the
skin with a condom for thirty minutes, significant
improvement was obtained [85]. It was, however,
important to wash off the local anaesthetic prior to
intercourse if diminution of vaginal sensitivity in
the female partner was to be avoided [86]. Clomi-
pramine, a tricyclic antidepressant, has been shown
to produce significant delay in time to orgasm with
increased satisfaction with sex life in prospective
controlled trial, given in a dose of 25 mg 12 to 24
hours before inter course [64]. Fluoxetine (Prozac)
given in a dose of 20 mg daily for 1 week and 40
mg daily thereafter has also been used, and produ-
ced significant benefit after 4 weeks treatment [87].
The female partners involved in the latter study sub-
jected the effects to careful scrutiny including veri-
fication of intravaginal latency time.
Retrograde ejaculation can be treated with adre-
nergic drugs such as ephedrine, 30 - 60 mg, or a
tricyclic antidepressant with anticholinergic
effects such as desipramine, 50 mg, taken 1 - 2
hours before sexual activity. One patient with
azoospermia and small volume ejaculate associa-
ted with an open bladder neck and unilateral
absence of the vas deferens responded well to
ephedrine with normalization of the seminal ana-
lysis, and subsequently a pregnancy was produ-
ced. Alternatively, spermatozoa can be retrieved
from post-orgasmic urine by centrifugation after
retrograde ejaculation, resuspended and used for
artificial insemination with success: a cumulative
pregnancy rate as high as 72% at 6 months has
been achieved [88].
4. SPINAL INJURIES
In some paraplegic patients, application of a vibra-
tor to the penis will lead to ejaculation; in others,
electroejaculation may be necessary to produce
spermatozoa that can be used for insemination. If
the spinal reflex arc is intact, a hypogastric plexus
stimulator will provoke ejaculation [49]. This
method has the advantage that it can be used in the
security of the patients' home, and repeated ejacu-
lation can improve the quality of the semen. Alter-
natively, direct electroejaculation by rectal probe
may be effective, but this generally requires a
general anaesthetic and is done in hospital [50]. In
a recent analysis of 40 paraplegic patients, 22 suc-
501
cessfully produced pregnancies by natural insemi-
nation or assisted reproductive techniques [51].
5. LOSS OF EJACULATION AFTER RETROPERI-
TONEAL LYMPH NODE DISSECTION
Drug treatment for loss of ejaculation after para-
aortic lymphadenectomy is not very successful
[89] but electroejaculation can produce spermato-
zoa for insemination [90]. It is important to antici-
pate this complication in young men with testicu-
lar tumours who may need chemotherapy or node
dissection, and arrangements should be made for
sperm storage at the earliest opportunity before
treatment commences. Excellent results can be
obtained with artificial insemination using cryo-
preserved spermatozoa [56].
6. SURGICAL TREATMENT OF EJACULATORY
DUCT OBSTRUCTION
It is very helpful if the lesion is accurately defined
preoperatively by TRUS, so that all necessary
arrangements can be made in advance. The obs-
truction should then be defined radiologically by
vasography or percutaneous puncture of the semi-
nal vesicles, and 5 - 10 mls of 1% methylene blue
dye are instilled to indicate when the ejaculatory
system has been entered. The patient should be
placed in the lithotomy position and suitable
drapes applied to allow access to rectal examina-
tion during the procedure. After preliminary cysto-
scopy, the resectoscope or optical urethrotome is
inserted. A Mullerian duct cyst may simply be
incised, releasing a gush of fluid, but there is a ten-
dency for the incision to heal over and it may be
preferable to resect the edges or make a cruciate
incision. If the ejaculatory ducts are blocked at
their lower ends, it may be simpler to resect the
verumontanum, commencing just above it in the
prostatic urethra and drawing the loop carefully
downward. The appearance of the ejaculatory
ducts is characteristic and easily recognized,
resembling a horse's nostrils. Pressure on the semi-
nal vesicles will produce abundant efflux once the
obstruction has been relieved.
Analysis of results obtained with 87 patients with
ejaculatory duct obstruction is summarized in
Table 3 [91]. It may be seen that incision of Mul-
lerian duct cyst was much the most successful pro-
cedure, but satisfactory results have been obtained
in other patients, and have continued to be seen
Table 3 : Number of patients with ejaculatory duct obstruction by
group, number successfully treated/number with adequate follow VIII. RECOMMENDATIONS
up in each group (from Pryor and Hendry (91)).

Group Total Number Post- Pregnan- 1. Care should be taken to distinguish erectile
Number with operative cies dysfunction from difficulties with orgasm
follow up patency produced and ejaculation.
CONGENITAL 2. The difference between emission (deposition
Mullerian 17 12 10 5 of semen into the posterior urethra) and eja-
Wolffian 19 6 1 1 culation (from the urethral meatus) should
be recognized.
Traumatic 15 6 2 1
Infective 19 6 4 2
3. The presence of retrograde ejaculation should
be established early in the diagnostic work-up
Tuberculous 8 1
of patients with loss of ejaculation by appro-
Megavesicles 8 1 1 priate examination of centrifuged urine after
Neoplastic 1 orgasm.
4. The afferent nervous pathways, cerebral
TOTAL 87 31 18 10
receptor and motor areas, and efferent spinal
and sympathetic nerves controlling orgasm
since this study was completed. If reconstruction and ejaculation should be clearly understood
is not possible, sperm can be withdrawn by micro- by physicians dealing with sexual dysfunction.
scopic epididymal sperm aspiration (MESA) or 5. The facilitative role of dopamine and the inhi-
percutaneously (PESA) and used for in-vitro ferti- bitory role of serotonin (5-HT) in the produc-
lization [92]. Attempts to insert a permanent sperm tion of orgasm and ejaculation must be
reservoir gave only limited success and this treat- understood.
ment has now been abandoned [93]. 6. The effects of antidepressant and other drugs
on the normal cerebral biochemical transmit-
ters (See above : 5) should be appreciated.
VII. CONCLUSIONS
7. Neurological tests to study the connections
between the genitalia and the central nervous
It is clear that there is much to study and unders- system should be more widely understood.
tand in disorders of orgasm and ejaculation. Expe- 8. The embryology of the male genital tract, and
rimental evidence has shone light onto the bioche- congenital anomalies leading to ejaculatory
mical function of the brain, especially in the lim- malfunction should be familiar to all urolo-
bic system and hypothalamus. The side effects of gists.
drug therapy have provided insight into functional 9. Damage caused to the ejaculatory system by
disorders, and indicated effective methods of treat- rectal pull-through procedures for imperfora-
ment. Congenital malformations and their rela- te anus should be more widely recognized by
tionship to genetic disorders are now more clearly
paediatric surgeons dealing with this condio-
understood: these are matters of importance in the
tion.
present era of assisted reproduction, if perpetua-
tion of serious anomalies such as fibrocystic disea- 10. The effects of bladderneck incision and pros-
se is to be avoided. Surgically induced injuries that tatectomy on ejaculation must be explained
impact upon male reproductive function are now to patients prior to surgery.
recognized and largely preventable by careful 11. The possibility of ejaculatory duct obstruc-
attention to preservation of normal structures tion should be considered in men with infer-
during extirpative surgery. tility who have had genital infection inclu-
ding sexually transmitted diseases, Schisto-
It seems likely that in the future, these will be somiasis, tuberculosis and unexplained uri-
areas of much fruitful research. nary infection.

502
12. The effects of neurological disease and spinal
cord injury on sexual function should be
widely understood (see section 14).
13. Nerve sparing techniques of retroperitoneal
lymph node dissection should be used whe-
never possible.
14. Arrangements for sperm storage should be
made prior to administration of chemothe-
rapy likely to interfere with spermatogene-
sis or surgery that may interfere with eja-
culation.
15. Rapid or premature ejaculation may be
defined as inability to delay ejaculation suf-
ficiently to enjoy lovemaking, or, alternati-
vely, persistent or recurrent occurrence of
ejaculation with minimal sexual stimulation
before, on, or shortly after penetration and
before the person wishes it.
16. Patients with rapid ejaculation should be
fully evaluated with objective data. It is use-
ful to measure ejaculatory latency time by
stopwatch.
17. Psychosocial background to rapid ejacula-
tion should be investigated, with involve-
ment of the partner.
18. Societal and religious attitudes to sex should
be recognized.
19. Treatment of rapid ejaculation should inclu-
de behavioural therapy including the female
partner.
20. Results of treatment of rapid ejaculation
should be evaluated in both short and long
term.
21. Drug therapy for rapid ejaculation may be
given immediately prior to sexual activity
(e.g. Clomipramine) or more chronically
(e.g. Paroxetine). The dose schedule, effects
and unwanted side effects of such therapy
must be carefully monitored.
22. The volume, pH and fructose content of
semen in subfertile men with oligozoosper-
mia or azoospermia should be measured and
the result noted by doctors caring for inferti-
le couples.
23. Abnormalities in seminal volume or bioche-
mical characteristics should be evaluated by
a urologist. Transrectal ultrasound scanning
is recommended as the first investigation,
which may be supplemented by vasography
503
or percutaneous puncture of the seminal
vesicles to establish the presence of ejacula-
tory duct obstruction.
24. Urologists should be familiar with the anato-
my of the ejaculatory ducts in relation to
surrounding structures and be able to relie-
ve ejaculatory duct obstruction safely by
appropriate resection.
25. Electroejaculation should be available at
selected fertility centres for patients with spi-
nal injuries or loss of ejaculation after abdo-
minal surgery.
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_____________________
 Committee 14

Female Sexual Dysfunction

Chairman
I. GOLDSTEIN,

Members
A. G RAZIOTTIN,
J. R. H EIMAN,
C. JOHANNES,
E. LAAN,
R. L. L EVIN,
K. E. M CKENNA

507
 CONTENTS

IV. NOSOLOGY AND DIAGNOSTIC

I. EPIDEMIOLOGY OF FEMALE
SEXUAL DYSFUNCTION
1. INTRODUCTION
2. METHODOLOGICAL DIFFICULTIES IN THE
STUDY OF FEMALE SEXUAL DYSFUNCTION
3. REVIEW OF PUBLISHED EPIDEMIOLOGIC
INVESTIGATIONS OF FEMALE SEXUAL
DYSFUNCTION
4. RISK FACTORS FOR FEMALE SEXUAL
DYSFUNCTION
II. ANATOMYAND PHYSIOLOGY
OF SEXUALAROUSAL OF THE
HUMAN FEMALE GENITAL TRACT
CLASSIFICATION: USE IN
ASSESSING PSYCHOSEXUAL
TREATMENT OF FEMALE SEXUAL
DYSFUNCTION
1. INTRODUCTION
2. PSYCHOSEXUAL TREATMENT OPTIONS
3. PSYCHOSEXUAL TREATMENT EFFICACY
BY DIAGNOSIS
V. FEMALE SEXUAL FUNCTION
AND BREAST OR GYNECOLOGIC
CANCER: ASSESSING THE
BIOLOGICAL ISSUES
1. INTRODUCTION « SINE DESIDERIO MENS
NIHIL INTELLIGIT»

2. FEMALE SEXUAL FUNCTION

1. INTRODUCTION
VI. PHYSIOLOGIC MEASURES OF
2. ANATOMY
FEMALE GENITAL BLOOD FLOW
3. P HYSIOLOGY
1. INTRODUCTION
III. CENTRAL NERVOUS SYSTEM
PATHWAYS INVOLVED IN THE 2. PHYSIOLOGICAL MEASURES
CONTROL OF FEMALE SEXUAL 3. ORGANIC ETIOLOGY
FUNCTION
4. DIFFERENTIAL DIAGNOSIS
1. INTRODUCTION 5. FEELINGS AND STIMULI
2. O VERVIEW 6. SEX AND THE BRAIN
3. SENSORY MECHANISMS 7. PHARMACOLOGICAL INTERVENTIONS
4. SPINAL REFLEXES
5. ASCENDING SENSORY PATHWAYS VII. CONCLUSIONS
6. BRAINSTEM REGIONS
7. HYPOTHALAMUS
REFERENCES
8. FOREBRAIN

508
 Female Sexual Dysfunction
I. GOLDSTEIN,
A. GRAZIOTTIN, J. R. H EIMAN, C. J OHANNES, E. L AAN, R. L. L EVIN, K. E. MCKENNA
The goal of the committee on Female Sexual
Dysfunction was to prepare a detailed, litera-
ture-based, state-of-the-art review of current
knowledge of female sexual dysfunction concer -
ning: epidemiology, anatomy and physiology,
sexual response cycle, classification, diagnosis
and treatment.
I. EPIDEMIOLOGY OF FEMALE
SEXUAL DYSFUNCTION
1. INTRODUCTION
The epidemiology of female sexual dysfunction
(FSD) is not well understood for many reasons.
Unbiased prevalence estimates from population-
based samples have been rare, and incidence esti-
mates have been nonexistent. Most published pre-
valence estimates have been based on selected cli-
nical or volunteer samples. Until the recently
convened «International Consensus Development
Conference on Female Sexual Dysfunction» [1],
where an interdisciplinary consensus conference
panel, consisting of 19 experts in female sexual
dysfunction selected from 5 countries expanded
female sexual dysfunctions to include both psy-
chogenic and organic causes of desire, arousal,
orgasm and sexual pain disorders, there has been a
contemporary lack of standard uniformly applied
definitions of FSD. Thus, there has been difficul -
ty in measuring FSD in non-clinical samples.
Accurate estimates of prevalence and incidence
are important in understanding the burden of
509
female sexual dysfunction in the community and
in identifying risk factors for prevention efforts.
Recognizing the distinction between prevalence
and incidence is important, as each measure
contains different information. Incidence is defi-
ned as the number of new cases of a condition or
disease that occur during a specific time period in
a population that is at risk for developing the
condition [2]. Because incidence measures the
transition from a non-affected (or non-diseased) to
an affected state, it is a measure of risk. Preva -
lence measures the number of persons affected
with the condition in the population at a given
point in time, but does not determine when the
condition developed [2]. Because the prevalence
estimate contains persons who have had the condi-
tion for different lengths of time, it is not a mea-
sure of risk. Incidence estimates are useful for the
identification of etiologic, or causal factors and for
monitoring the efficacy of prevention programs
[3]. Prevalence measures are useful for estimating
the burden of a particular condition on a commu-
nity. Such information is valuable for planning
appropriate health services for treatment and pre-
vention efforts. Although suspected risk factors
are often evaluated in relation to the prevalence
of a condition, cause can only be determined
using incidence.
2. METHODOLOGICAL DIFFICULTIES IN THE
STUDY OF FEMALE SEXUAL DYSFUNCTION
There are a number of difficulties, discussed
below, specific to the study of sexual function that
contribute to the current paucity of epidemiologic
knowledge in this area.
a) Definitions
The first standardized method of classification of
the various categories of female sexual function
for use in research was published in 1980 as the
Diagnostic and Statistical Manual of the American
Psychiatric Association (DSM-III) [4]. In the
World Health Organization’s ICD-10 system
(1992), sexual dysfunction was defined as inclu-
ding: «the various ways in which an individual is
unable to participate in a sexual relationship as he
or she would wish» [5]. Specific categories in the
ICD-10 nomenclature, limited to consideration of
psychiatric disorders only, included a lack or loss
of sexual desire (F52.0), sexual aversion disorder
(F52.1), failure of genital response (F52.2), orgas-
mic dysfunction (F52.3), nonorganic vaginismus
(F52.5), nonorganic dyspareunia (F52.6), and
excessive sexual drive (F52.7). Subsequently, in
1994, the DSM-IV defined four categories of dys-
function based on the sexual response cycle
model: sexual desire disorders, sexual arousal
disorders, orgasmic problems, and sexual pain
disorders [6]. This DSM-IV system was also limi-
ted in that it described psychogenically-based dys -
functions, and was not used widely outside of
psychiatry.
The most contemporary definition and classifica-
tion system of female sexual dysfunction resulted
from an international consensus panel (1998)
which employed a modified Delphi method in the
development of consensus definitions and classifi-
cations and built upon the existing framework of
the ICD-10 and DSM-IV [1]. Female sexual dys -
functions were expanded to include both psycho-
genic and organic causes of desire, arousal, orgasm
and sexual pain disorders. An essential element of
the new diagnostic system was the inclusion of a
«personal distress» criterion. In particular, new
definitions of sexual arousal disorder and hypoac-
tive sexual desire disorder were developed and a
new category of non-coital sexual pain disorder
was added. In addition, a new sub-typing system
for clinical diagnosis was devised (see table 4).
There remain no «gold-standard» objective diag-
nostic criteria making it difficult to formulate
standard operational definitions that can be
applied to large, non-clinical population groups.
Comparison of published studies remain proble-
matic due to the many different ways in which
510
sexual function has been defined in the past in
individual studies, the different aspects of sexual
function measured, and the frequent use of non-
validated instruments.
b) Assessment
Epidemiological assessment of sexual dysfunction
requires the use of self-reported data. Lengthy cli-
nical assessment questionnaires and physiological
measures of the female sexual response, while
useful for diagnosis in a clinical or laboratory set-
ting are not feasible for large population-based
studies due to the expense, logistics, and concerns
with participant burden and acceptability. Most
studies have used either self-administered ques-
tionnaires or interviewer administered instru-
ments. Self-administered instruments completed
in private may be able to elicit more honest res-
ponses to sensitive questions than with a face-to-
face interview. These questionnaires, however,
must be kept fairly short and simple because long,
complicated questionnaires may lead to missing or
inaccurate data. Interviewer-administered instru-
ments can be more complex and the interviewer
can probe for more detail. Respondents, however,
may be reluctant to answer sensitive questions,
leading to underreporting. Reporting biases due to
lack of candor and comprehension, however, were
negligible with interviewer-collected data in the
National Health and Social Life Survey, the largest
and most representative population survey to date
of sexual function [7].
c) Type of population
Most published research on FSD is based on
samples of patients from general practice, special-
ty clinics, or other non-representative convenience
samples such as volunteer samples or college stu-
dents. Selection bias is a real consideration in
these studies, as not all women experiencing
sexual difficulties seek medical care, and those
who do may have more severe or bothersome
symptoms. Volunteer samples may be comprised
of women experiencing sexual problems with
unaffected women less likely to participate. Thus,
prevalence estimates based on selected samples
cannot be considered accurate, although such esti-
mates may be useful for allocating resources
within a particular medical care facility or for
identifying trends in help-seeking behavior [3].
Glatt and coworkers [8] noted that less than half
(41%) of 104 women with persistent dyspareunia
in their study had consulted a physician or health
care provider for this problem. Even among
women who seek medical care, sexual problems
are often underreported. Practitioners may not
routinely ask about sexual difficulties or patients
may be reluctant to provide such information. In
a survey of consecutive patients attending a gene-
ral practice in the UK, although 42% of the
women and 35% of the men reported some form of
sexual dysfunction to the study interviewer, sexual
problems were recorded in only 2% of the general
practitioner notes [9]. Similarly, of 887 consecu-
tive gynecologic outpatients in a US clinic, only
3% presented with specific sexual complaints
[10]. An additional 16% admitted sexual pro-
blems following direct inquiry. In addition, avai-
lability of treatments may affect who presents to
clinics. Public perception of lack of effective
treatments will result in fewer affected persons
seeking medical care. If a new, widely publicized
treatment becomes available for a particular type
of disorder, persons who may not have otherwise
sought treatment may do so, leading to inflated
prevalence estimates for that disorder. Another
study examined the prevalence of female sexual
arousal disorder in the partners’ of impotent men
undergoing urologic evaluation [11]. In this report,
subjects anonymously and voluntarily completed
questions concerning arousal response quality
during sexual activity. Female sexual arousal
disorder was considered to exist if the respondent
answered postively to 1 or more of 6 symptoms,
present and persistent for at least 6 months during
the course of the sexual relationship and adversely
affecting her satisfaction. The presence of 1, 2, or
3 or more of the symptoms was considered to
represent mild, moderate or severe forms of fema-
le sexual arousal disorder, respectively. Of the 268
females, 260 respondents returned complete medi-
cal and sexual data. A total of 152 (58.5%) ful-
filled the criteria for female sexual arousal disor-
der; 22.7%, 13.8% and 22% had mild, moderate
and severe forms, respectively [11].
Reliable prevalence estimates can only be ob-
tained from well-designed population-based stu-
dies, but even the best of these can suffer from
nonresponse bias, a particular problem with a sen-
sitive topic area like FSD. If women without
sexual difficulties are less likely to participate,
511
prevalence rates can be inflated, if women with a
problem tend to skip key questions or do not ans-
wer truthfully, prevalence will be underestimated.
There are many factors such as age, socioecono-
mic status, marital status, the availability of a
sexual partner, partner limitations, concurrent ill-
nesses, and others that can affect the prevalence
and incidence of FSD. Lack of adjustment for such
factors may lead to distorted estimates.
d) Lack of incidence data measuring risk
To estimate incidence, longitudinal data are need-
ed. To date there are no published incidence esti -
mates of FSD from well-designed, longitudinal,
population-based samples. Two studies of women
in mid-life have gathered longitudinal data on
sexual functioning, The Melbourne Women’s Mid-
life Health study [12] and the Massachusetts
Women’s Health Study II [13] which to date have
published only cross-sectional results. These stu-
dies are limited to women in mid-life because the
purpose of both is to examine the effects of the
menopausal transition on many factors, including
sexual functioning. Longitudinal data in younger
populations of women initially free of sexual dys-
functions are needed to estimate the incidence and
to study the natural history of FSD.
3. REVIEW OF PUBLISHED EPIDEMIOLOGIC
INVESTIGATIONS OF FEMALE SEXUAL DYS-
FUNCTION
a) Non-population-based studies
Most published studies of the prevalence of sexual
dysfunctions in women were performed in clinic
or other selected samples. An excellent review of
earlier studies published prior to 1988 was written
by Spector and Carey [3]. From this review it is
apparent that the prevalence of most sexual dys -
functions is higher in clinical than in communi -
ty samples. For instance, inhibited female orgasm
ranged from 18% to 76% in clinics, but only 5% to
20% in community samples [3]. Similarly up to
62% of females seeking sex therapy experience
arousal disorder, while community estimates are
closer to 11%.
Table 1 summarizes more recent studies of general
or specialty clinics or selected community
samples. Use of different measures and time
frames for symptoms makes comparison of out-
512
comes difficult among studies. Sample sizes
varied widely from 43 women in a premenstrual
syndrome clinic [14] to 887 consecutive gyneco-
logy outpatients [10]. Those studies less likely to
suffer from selection bias are the studies by Schien
[15] with a wide age range, racial minority repre-
sentation, and a detailed questonniare; Rosen [16]
with a wide age range of healthy women recruited
from a wellness center; and Read [9] with patients
recruited from a general practice in the UK where
98% of the population is registered with a GP.
The overall prevalence of dysfunction was repor -
ted by three studies, and ranged from 19% to
42% [9, 10, 14]. The lower estimate is based on a
study that asked only two brief questions about
sexual functioning without probing further as to
the specific type of problem [10]. Dyspareunia
was experienced by about 12% of women in two
studies [14, 16], and 33% in a third. The higher
estimate was from a study with a high non-
response rate and subjects were prior participants
in a study of sexually transmitted diseases, so may
be an unrepresentative sample. Problems with
orgasm ranged from 5% to 23% [9, 14-16].
b) Population-based studies
Table 2 summarizes results regarding the preva-
lence of FSD from published population-based
studies throughout the world. Although most stu-
dies included samples of men and women, only
the results for women are presented here. Some
strengths and limitations of each study are discus-
sed below. The best information is from the large,
well-designed National Health and Social Life
Survey (NHSLS) [7, 17]. This was a true popula-
tion-based study of a representative sample of US
adults ages 18-59. Particular strengths of the study
are its large sample size, minority representation
(African Americans and Hispanics), excellent res-
ponse rates, inclusion of a number of detailed
measures of sexuality, and many other variables
pertaining to demographic, health, social, and psy-
chological characteristics. A few limitations of the
study should also be noted. These include the
cross-sectional design preventing measurement of
incidence, inability to measure cause and effect of
related factors, or risk, the inability to examine
sexual dysfunction in women aged 60 and older,
and the lack of adjustment for menopause status.
The NHSLS found a high overall prevalence of
FSD (43%) in US women ages 18-59 (Table 2).
513
Low desire was reported by 22%, arousal pro-
blems by 14% and sexual pain by 7% using cate-
gories similar to the DSM-IV defined by latent
class analysis [17]. A prior publication from the
same study [4] reported unadjusted frequencies of
individual sexual dysfunction variables. About a
third of women ages 18-59 reported a lack of inter-
est in sex during the past 12 months, and a quarter
of women with a partner were unable to achieve
orgasm (Table 3). The prevalence of dyspareunia
among women with partners was 15.5%, and
trouble lubricating was experienced by about 21%.
In general sexual dysfunction was more common
among younger women; the one exception was
trouble with lubrication [7].
Estimates of dysfunction from an older population
(> 60 years) is provided by a probability sample of
adults in Michigan [18]. Two thirds of 448 women
were sexually inactive, 12% of married women
had difficulty with intercourse and about 13%
experienced pain with intercourse [18]. Activity
was strongly related to marital status, with only
5.3% of non-married women being sexually
active. Additional limited information from
women 60 years and older is reported by Marsiglio
and Donnelly [19]. In cross-sectional study of a
representative sample of the US population, 49
percent of women reported no sexual activity in
the past month. Women were less likely to have
sex if they were older, if their partner was of poor
health, and if they had low feelings of self-worth.
It should be pointed out that lack of activity does
not imply sexual dysfunction for older women.
As shown by these two studies and others [20],
lack of a partner or limitations of a partner are
important reasons for lack of activity. Neither of
these studies of older women included specific
measures of sexual dysfunction.
The other studies in Table 2 were performed in
middle-aged women. The overall prevalence of
sexual dysfunction was estimated at 33% in the
UK [18] and 22% in Iceland [19]. Interestingly,
although a third of the women in the UK had at
least one operationally defined sexual dysfunc-
tion, only 10% of them thought that they had a
sexual problem [21]. If few women perceive
sexual dysfunction to be a problem, it may
explain in part why only a portion of women seek
medical attention for these conditions.
514
Table 3: Frequency of Female Sexual Dysfunction in NHSLF study [17], although due to the cross-sec-
women ages 18-59 from the National Health and Social tional nature of the data, the factors identified can-
Life Survey. Unadjusted prevalence of individual dysfunc -
tion measures not be expressed truly as risk, but as correlates of
dysfunction. In contrast to men, age is inversely
SEXUAL ALL WOMEN, WOMEN WITH associated with dysfunction in women. Younger
DYSFUNCTION N= 1,622* PARTNER age was a significant predictor for pain during sex,
12 MONTHS,
N= 1,486$
lack of pleasure, and anxiety about performance
[17]. Women with a lower level of education were
Lack of interest also more likely to experience pain during sex
in sex 33.4 31.6 [17]. Low desire was more likely among women
Unable to achieve who had ever experienced a sexually transmitted
orgasm 24.1 25.7 disease, those reporting emotional problems or
Dyspareunia 14.4 15.5 stress, women with more than a 20% drop in
Sex not pleasurable 21.2 22.6 household income from 1988-1991, and those
with infrequent thoughts about sex. Arousal disor-
Anxiety about
performance 11.5 12.3 der was higher among women with a urinary tract
symptom, emotional problems or stress, infre-
Trouble lubricating 18.8 20.6
quent thoughts about sex, and a history of being
Climax too early 10.3 Not reported sexually touched before puberty and sexually
forced by a man ever. Sexual pain was increased in
* From : Laumann EO, Gagnon JH, Michaels S. The Social women with a urinary tract symptom, and emotio-
Organization of Sexuality : Sexual Practices in the United States. nal problems or stress, and among those reporting
Chicago, III: University of Chicago Press; 1994, p.371 [7] poor to fair health, and a 20% decrease in house-
$ From Laumann EO, Paik A, Rosen RC. Sexual dysfunction in hold income. Low physical and emotional
the United States. Prevalence and predictors. JAMA 1999, satisfaction and low general happiness were
281:537-544 (sample sizes vary from 1,475 to 1,486 depending
on outcome measure) [17]
significant correlates of all three sexual dysfun-
ction categories: low desire, arousal disorder and
Population estimates of inhibited desire are 22% sexual pain [17]. The Melbourne Women’s Midli-
in the US [17] and 16% in Iceland [21]. fe Health Study reported that a decline in sexual
interest among mid-aged women was significantly
Almost a third of mid-life women in Australia related to the natural menopause transition,
reported decreased sexual interest, related in part decreased well-being, decreasing employment,
to the menopausal transition [12], and 17% of and increased vasomotor, cardio-pulmonary and
women ages 35-59 in the UK reported impaired skeletal symptoms and hormone therapy use [8].
interest. The prevalence of dyspareunia was fairly Unpublished cross-sectional results from the
consistent across studies, ranging from 7% to Massachusetts Women’s Health Study II indicate
13%, except for the Icelandic study that reported a decreased sexual desire among married women,
3.1% prevalence of functional dyspareunia [22].
those with psychological symptoms, current ciga-
Orgasmic difficulties were reported by 3.5% of
rette smokers, and perimenopause status [23]. Fre-
Icelandic women [22], 10% of Massachusetts quency of sexual intercourse was inversely related
women [13] and 16% of women in the UK [21]. A to depression, physical limitations of a partner,
rigorous comparison of outcomes is difficult
and smoking, but unrelated to menopause status.
because of the different outcomes studied and the
Pain during intercourse was related to recent vagi-
different ways in which they were measured.
nal dryness and recent urinary tract infection. No
statistically significant correlates were found for
4. R ISK FACTORS FOR FEMALE SEXUAL DYS-
difficulty reaching orgasm. Preliminary longitudi -
FUNCTION
nal results from the MWHS II examining a chan-
Limited published information is available concer- ge in sexual functioning over about a six-year time
ning risk factors for sexual dysfunction in women. per-iod, in which women transitioned from pre- or
The most thorough information is from the perimenopause to postmenopause, indicate that

515
decreased desire is related to increased age,
increased body mass and poorer self-perceived
health and higher desire to starting hormone thera-
py use.
The study of groups of women with chronic medi -
cal conditions can also provide some clues as to
etiology for various sexual dysfunctions. Studies
of sexual dysfunction in women with diabetes,
although far from being conclusive, suggest an
increased prevalence of problems such as decreased
lubrication and libido that may be related to dura-
tion of diabetes and presence of neuropathy [24].
Although treatment with antihypertensive agents
has been associated with sexual dysfunction in
men, there is little comparable research in women
[24]. One study has shown a disproportionate fre-
quency of sexual dysfunction among black and
Mexican-American women who had both diabetes
and hypertension [25]. There is some evidence
that decreased libido and difficulties with orgasm
may be related to antidepressant use in women
[26]. More research is needed concerning the
relation of medications and comorbidities on the
occurrence of sexual dysfunction in women.
II. ANATOMY AND PHYSIOLOGY
OF SEXUALAROUSAL OF THE
HUMAN FEMALE GENITAL TRACT
1. INTRODUCTION
The internal and external anatomical structures
that comprise the female genitals are shown and
listed in Figures 1 and 3-7 and further detailed in
Figure 2A and B. During penile coitus certain
aspects of these structures, classified as erogenous
friction and pressure sites, are stimulated by the
movements of the penile thrusting which are trans-
duced by specific nerve endings [27] and relayed
via the spinothalamic, spinoreticular and dorsal
column systems of the spinal cord and possibly the
vagus [28] to the brain where they are interpreted
as sexual stimuli and converted into sexual arou-
sal. If the stimuli are psychologically acceptable
and physiologically effective they can create
enough sexual excitement to activate an orgas -
mic response. The structure(s) of these erogenous
sites and the sexual changes induced by coitus of
each will be described individually.
516
2. ANATOMY
a) The clitoris (Figures 1 & 2)
Although the erogenous function of this organ has
been known since antiquity [29], remarkably, the
detail of its highly vascular anatomical structure is
still in dispute. It is formed from the tubercle of
the undifferentiated common tissue anlagen in the
embryo. In the presence of androgens this deve-
lops into the penis while in their absence the clito-
ris is formed. Current dissections of adult female
human cadavers [30] have been interpreted to
indicate that the organ is a triplanar complex of
erectile tissue with a midline shaft lying in the
medial sagittal plane about 2-4 cm long and 1-2
cm wide which bifurcates internally into paired
curved crura 5-9 cm long (attached to the under
surface of the pubic symphisis) and externally is
capped with a glans about 20 -30 mm long with a
similar diameter. The range of external dimensions
have been given by Verkauf, Von Thron &
O’Brien [31].
The erectile tissue of the shaft consists of two
parallel corpora cavernosa surrounded by a fibrous
sheath (tunica albuginea) and the whole structure
is covered by a clitoral hood formed in part by the
fusion of the upper part of the two labia minora
while the lower parts meet beneath the clitoris (see
Figure 2 A). The clitoral cavernosal erectile tissue
consists of smooth muscle and connective tissue.
Tufan et al [32] utilized computer assisted histo-
morphometric image analysis to determine the
age-associated changes in clitoral cavernosal
content of smooth muscle and connective tissue.
Human clitorises were obtained from fresh cada-
vers (age: 11 to 90 years) and from patients under-
going clitoral surgery (age: 6 months to 15 years).
The percentage of clitoral cavernosal smooth
muscle in age group of 6 months to 15 years was
65 ± 1.5, in 44 to 54 years was 50 ± 1.2 and in 55
to 90 years was 37 ± 1.3 (ANOVA, p=0.0001).
These studies, which revealed a strong link be-
tween increase in age and decreased clitoral
nerve cavernosal smooth muscle fibers, illustrate
that aging women undergo histologic changes in
clitoral cavernosal erectile tissue which may play
an as yet undetermined pathophysiology in age-
associated female sexual dysfunction.
According to O’Connell et al [30] the paired, so-
called vestibular (vaginal) bulbs of erectile tissue,
 P.S. = Pubic symphysis
l= Clitoral glans and shaft
2 = Clitoral crura
3 = Urethral meatus
4= Periurethral glans
5 = Vaginal introitus (labia
not shown)
6 = Halban's fascia
7 = Urethra
8 = G-spot
9 = Anterior fornix erotic zone
10 = Cervix
11 = Peritoneal membrane
12 = Anus

Figure 1: Highly schematic diagram of the human female genitalis. See text for explanatory details.

A B

Figure 2 a, b: Highly schematic diagrams of the clitoral tissue complex. In Figure 2a the clitoral glans, shaft and paired crura
are indicated in grey. The urethral meatus (small black dot) is shown with the urethra (dotted tube that would actually be at
right angles to the page). On either side of the urethra, closely applied, are the paired vestibular or vaginal bulbs of erectile
tissue. The inner and outer labia are shown together with the vaginal introitus elongated black shape) with the anus lower
down. In Figure 2b the extent of the periurethral glans is displayed as the hatched area extending from the glans to the cli -
toris to the upper edge of the vaginal introitus. See text for details.

517
Figure 3: External antomical structures which comprise the female genitals.

Figure 4: Internal antomical structures which comprise the female genitals.

518
Figure 5: Autonomic and somatic innervation of the female genitals.

519
Figure 6: Motor and sensory nerves innervating the external female genitalia.

520
Figure 7: Arterial inflow to the external female genitalia.

521
which have normally been illustrated on either
side of the vagina practically as if in the labia
minora, are actually closely applied anteriorly on
either side of the urethra (Figure 1). In the male
the corpus spongiosum is a single tubular struc-
ture of erectile tissue that ensheaths the urethra
ending internally as the penile bulb and externally
as the penile glans pierced by the urinary meatus.
The location and extent of the female corpus spon-
giosum is contentious. It has been described as
being the vascular tissue surrounding the female
urethra, as the bilateral vestibular bulbs and as the
tissue between the bladder and anterior vaginal
wall (Halban’s fascia). Most authors claim that the
clitoris has no spongiosus tissue. However, the
extension of the corpus spongiosus tissue into the
clitoris has been described by van Turnhout, Hage
& van Diest [33] from their dissections and histo-
logy of the adult female cadaver. They observed
that the bilateral vestibular bulbs unite ventral to
the urethral orifice to form a thin strand of spon-
giosus erectile tissue connection (pars intermedia)
that ends into the clitoris as the glans. The corpo-
ra cavernosa of the shaft do not extend into the
glans.
Because the shaft and the glans of the clitoris have
no subalbugineal layer between the erectile tissue
and the tunica albuginea the organ becomes
tumescent or swollen with effective sexual stimu -
lation but does not become erect or rigid [34].
Nevertheless, human clitoral erectile tissue has the
capacity to develop drug-induced priapism which
responds by detumescing following administration
of alpha-adrenergic agonists [35]. The earliest
attempt to characterise the possible mechanism(s)
by which the crura and vestibular bulbs changed
from the flaccid to the tumescent state was publi-
shed first in diagrammatic form by Danesino &
Martella [36] in Italian. The paper was later trans-
lated into English and republished in 1976. Their
working hypothesis, based on the early mecha-
nisms suggested for penile erection, was that
during sexual excitement smooth muscle polsters
(«cushions») in the arteries supplying the two ves-
tibular bodies became relaxed. Those polsters in
the draining veins became contracted as did those
in the a-v anastomoses (see Levin [71] for simpli-
fied diagram). This diverted blood into the lacu-
nae, filling them and creating tumescence. For
detumescence, the arterial polsters contracted
522
while those in the veins and a-v anastomoses
relaxed, reducing the flow to the lacunae and
allowing the blood restricted in them to flow away.
Despite this mechanism being published in En-
glish for over 23 years, no independent confirma-
tion of either the mechanism or the polsters in the
female arteries and veins have yet appeared. It
must be regarded as a speculative working hypo-
thesis.
The finding that human clitoral tissue has nitric
oxide synthase (NOS) present in nerves and blood
vessels [37] suggests that nitric oxide (NO) may
be involved in controlling clitoral blood flow as it
does in the penis. Park et al [38] have further exa-
mined the possible role for nitric oxide in the regu-
lation of human clitoral corpus cavernosum smoo-
th muscle contractility. In this study, cGMP and
cAMP hydrolysis by phosphodiesterases were
characterized in the high speed supernatant frac-
tion (cytosol) and in partially purified preparations
of human clitoral corpus cavernosum smooth
muscle cells. Sildenafil was found to inhibit PDE
type 5 cGMP-hydrolytic activity, in the crude
extract (Ki=7 nM) and in partially purified prepa-
rations (Ki=5-7 nM) in a competitive fashion.
Synthesis of cyclic nucleotides was also carried
out in intact cells in culture in response to sodium
nitroprusside (NO donor) and forskolin (direct
adenylate cyclase activator). Intracellular cGMP
was increased by 35% in presence of sildenafil
(10nM) in intact cells in culture. The results of this
study support a role for nitric oxide in regulation
of human clitoral corpus cavernosum smooth
muscle tone.
b) The periurethral glans (Figure 2B)
As has been described previously, the clitoris
develops in the embryo from the genital tubercle
of the common anlagen in the absence of andro-
gens. However, the male glans is pierced by the
urethra unlike that of the clitoral glans. Sevelly
[39] suggested that there were really two glans in
the female, that of the clitoris (clitoral glans) and
that surrounding the urethra (female glans). The
latter was renamed the periurethral glans [40] to
avoid confusion and is defined as the triangular
area of mucous membrane surrounding the ure-
thral meatus from the clitoral glans to the vaginal
upper rim or caruncle (Figure 2B). It is mobile and
was shown to be pushed into and pulled out of the
vagina by penile thrusting during coitus [39, 40].
No studies have been undertaken on the erotic sen-
sitivity of the periurethral glans in those women
who can have orgasms from penile thrusting alone
compared with those who cannot. An obvious sug-
gestion is that the former will have a much higher
erotic sensitivity than the latter. Hoch’s clinical or
sexological examination of the sensitivity of the
female genitalia for erotic arousal completely
ignored the periurethral glans [41]. Given the
complexity of the anatomy of the external female
genitalia it is possible that the periurethral glans is
in fact yet a further part of the corpus spongiosum
of the female [33].
c) Urethra (Figure 1)
The female urethra is a short conduit (approxi-
mately 3-5 cm long) running from the base of the
bladder and exiting in the periurethral glans area to
the outside. For nearly its entire length it is sur -
rounded by numerous venous/sinus channels
which, according to Berkow & Amboy [42],
constitute the corpus spongiosum of the urethra.
This submucosal vascular tissue is physiologically
important in that it contributes approximately one
third of the normal urethral closing pressure [43].
It becomes further vasocongested during sexual
arousal [44] converting the urinary urethra into the
sexual urethra. Scattered in the lining lumenal epi-
thelium are cells containing 5-HT (serotonin).
Their function is unknown but they are thought to
be chemosensing or mechanoreceptor paracrine
cells [45, 46] that release the 5-HT on being sti-
mulated by stretch or luminal chemicals. In the
animal urethra, 5-HT sensitizes neural mechan-
isms [47]. It may be that the stretching or massage
of the human female urethra by the thrusting penis
during coitus causes the release of 5-HT from the
urethral paracrine cells enhancing neural afferent
input from the organ.
d) G-spot (Figure 1)
Grafenberg [44] reported that the digital stroking
of the anterior vagina along the urethra, espe -
cially in the region of the base of the bladder,
sexually aroused female subjects greatly. In a
number of women this area swelled up to the size
of a kidney bean and projected into the vaginal
lumen. Few took any notice of this finding. The
area was rediscovered and renamed the G-spot in
honour of Grafenberg [48]. Other investigators
could not locate a «spot» but found, rather than a
523
punctate locus, a general excitable area along the
whole length of the urethra running along the ante-
rior vaginal wall [41]. When this was stimulated
manually, the sexual arousal induced was almost
immediate. Alzate & Londono [49] located the
erotic sensitive area in closer relation to the blad-
der base than the urethra while Lenck, Vanneu-
ville, Monnet & Harmand [50] localised by ultra-
sound in the living subjects the underlying struc-
ture in the anterior vaginal wall that gave the ero-
tic sensations on stimulation as the urethral
sphincter confirming it by dissection in the cada-
ver. Other investigators have implied that the G
spot/area represents that part of the urethra that
contains the periglandular or paraurethral tissue,
corresponding to the female equivalent of the
prostate (see Zaviacic and Whipple [51] for refe-
rences). These glands are present to a greater or
lesser degree in about 90% of women. In some
women, when stimulated sexually, a fluid secre-
tion claimed to be dissimilar to urine or vaginal
fluid can be produced which is controversially
«ejaculated» from the urethra [51, 52]. Exclusion
of urethrocoeles in such subjects, where urine
could pool and subseqently be modified, has never
been undertaken.
e) Halban’s fascia (Figure 1)
The space between the trigone of the bladder and
the anterior part of the vaginal wall according to
Minh, Smadja & Herve de Sigalony [53] and Tord-
jman [52] is filled with mesenchymal lamina, a
fibro-elastic sheet made up of collagen, elastic and
muscular fibres with a rich blood supply and a
nerve supply with Krause bodies or pseudo-cor-
puscular nerve endings. Tordjman [52] regards
this area as the homologue of the corpus spongio-
sum. On stimulation it becomes vasocongested
and creates an erotic pleasurable response. It is
obvious from Tordjman’s descriptions that he
includes the G-spot in his analysis of the pleasu-
rable response from Halban’s fascia.
f) Anterior fornix erogenous zone (Figure 1)
More recently Chua Chee Ann [54] has reported
that in 271 women, the gentle digital stimulation
of the inner half of the anterior wall of the vagina,
lasting some 10-15 minutes, gave rise to a «reflex»
vasocongestion of the outer half of the anterior
vaginal wall with a concomittant lubricative and
erotic response in 63% of the subjects. Stimulating
the outer half of the anterior wall before the inner
half did not give consistant responses. The
claimed vasocongestion and lubrication responses
were judged subjectively and were not confirmed
by objective measurements. The technique was
described as inducing a «local reflex» vasodilata-
tion that did not involve the central nervous sys-
tem and that this was the reason for the rapidity
and effectivenes of the stimulation. Moreover,
women can be taught to undertake the stimulation
for themselves, thus improving their arousal and
orgasmic responses to subsequent coitus. From the
descriptions of the author it appears that the digi -
tal technique would stimulate the urethra-G spot
- Halban’s fascia complex and need not imply a
new and specialised area of the anterior vagina.
The concept that the stimulation created only a
local reflex with no afferent input to the higher
centres is impossible to verify from the described
study.
g) Pubococcygeus muscle
Kegel [55] and a number of other authors have
claimed that the pubococcygeal muscle, located at
the 4 and 8 o’clock points of the vagina, contain
sensory and motor elements of the orgasmic res-
ponse and that its stimulation gave rise to sexual
pleasure and even could induce orgasm. Exerci-
sing the muscle was said to enhance both. Hoch
[41], however, could not confirm these findings
and reported that in the great majority of cases he
examined the pubococcygeal lacked erotic sensiti-
vity altogether.
h) Cervix
The cervix is a relatively insensitive structure
with no erotogenic capabilities per se but it has
been implicated by some authors as being impor-
tant when jostled or buffeted by deep penile thrus-
ting so that the uterus is pushed or rubbed against
the peritoneal lining (Figure 1). This is claimed to
create sexually pleasurable feelings [53, 56] but in
others it creates discomfort [41]. In some women
who have had their cervix/uterus removed, a signi-
ficant loss in sexual arousal and orgasm by coitus
occurs [57] but others have reported no differences
[41]. This extreme individual variation in dysfunc-
tion may be accounted for by the extent of surgi-
cal nerve damage and loss. According to the
EPOR (E = excitation, P = plateau, O = orgasm,R
= resolution) human sexual response model of
Masters & Johnson [58], sexual arousal in the E-
524
phase leads to vaginal tenting and elevation of the
cervix up with the anterior vagina wall. Thus
penile-cervix contact should rarely occur (see
Levin [59] for discussion). Ultrasound imaging of
penile disposition during human coitus was illus-
trated in Hessel [60] and described by Riley, Lees
& Riley [61]. Penile-cervix contact was not obser-
ved in the missionary or face-to-face position (the
preferred position in the Western world) but Riley
et al found it could occur in the rear-entry
sideways and rear-(«doggie») positions.
An intriguing aspect of the cervix is that it has the
second highest concentration of VIP of the fema -
le genitals yet no function has been ascribed to the
Vipergic innervation. Its possible role in the secre-
tion of mucus by the infolded crypts of the cervi-
cal epithelium has not been investigated.
3. PHYSIOLOGY
a) Vaginal lubrication- basal and during sexual
arousal
The vagina is a squamous epithelium devoid of
glands which is surrounded by a sheath of smooth
muscles set in a bed of striated pelvic muscles with
an extensive blood, lymphatic and nerve supply.
The latter, richer in the more distal and anterior
wall areas compared to the more proximal and
posterior wall parts, contain a great variety of clas-
sical and peptidergic transmitters (5HT, nor-epine-
phrine, acetylcholine, dopamine, VIP, NPY, GRP,
TRH, CGRP, somatostatin, substance P, oxytocin,
cholecystokinin (CCK) and relaxin) but the exact
function of most of these whether motor or senso-
ry or modulatory is unknown [40, 62]. The organ
is a potential space with its anterior and posterior
walls usually in apposition. They can be easily
separated because their surfaces are normally «just
moist», lubricated by a basal vaginal fluid (swab-
bed volume approximately 1ml). In the intermens-
truum, this can consist of multiple secretions that
collect finally in the vagina (peritoneal, follicular,
tubal, uterine, cervical, vaginal, Bartholin’s and
Skene’s glands). However, the more remote the
anatomical site where the fluid is formed from the
vagina, the less influence it has on the volume and
ionic content of the vaginal fluid.
In the sexually unstimulated state, vaginal fluid
has a higher K+ and lower Na+ concentration
compared to plasma throughout the phases of the
menstrual cycle [63]. The actual basal vaginal
transudate that percolates through the vaginal epi-
thelium from the plasma circulating in the capilla-
ry tufts supplying the epithelium is modified by
the limited Na+ lumen-to-blood reabsorptive
transport capacity of the vaginal epithelial cells
[64]. This activity can be inhibited by luminal ami-
loride. The reabsorption of Na+ by the vaginal epi-
thelium is presumably the ionic driving force for the
reabsorption of the vaginal fluid [65] and maintains
its level under basal conditions to the «just
moist» condition. Autologous plasma placed in a
subject’s vagina for up to 5 hours shows increased
K+ and decreased Na+ concentrations indicating
that the epithelium is capable of undertaking such
ion transfer in vivo ( see Levin [40] for references).
The basal lubrication is usually not sufficient to
allow painless penile penetration and thrusting so
an enhancement of the lubrication is essential for
coitus. Despite many inaccurate accounts in physio-
logy textbooks, vaginal lubrication during sexual
arousal does not occur from any increased secre -
tion of vaginal glands (nonexistant), cervical fluid
or from Bartholin’s glands.
On sexual arousal the blood supply to the vaginal
epithelium is rapidly increased by neural innerva-
tion via the sacral anterior nerves S2-S4 [66] and at
the same time the venous drainage is probably
reduced creating vasocongestion and engorgement
with blood. Park et al [67] used an animal model
with direct electrical stimulation of the pelvic motor
nerve to quantitate the local changes in vaginal
hemodynamics. They showed significant vaginal
hemodynamic changes, including increased vaginal
wall arterial blood inflow, vaginal wall pressure,
vaginal canal length and decreased vaginal luminal
pressure compared to the unstimulated state.
In the vaginal epithelium, sexual arousal induces
a neurogenic transudate to be created that filters
through the labyrinthine pathways of the epithe-
lium and saturates its limited Na+ reabsorptive
capacity [59, 64]. It appears within seconds of suc-
cesful sexual arousal initially on the surface of the
vagina as bead-like droplets which then coalesce
to create a lubricative film [58] that can partially
decrease the acidity of the vaginal basal fluid [68].
The smooth, slippery quality of the formed fluid is
probably due to its pick up of sialoproteins coating
the vaginal epithelium from the cervical secretion.
The enhanced blood flow is activated by the
525
VIPergic innervation of the large vessels sup -
plying the epithelium and the transudation possi -
bly aided by the CGRP (calcitonin gene regula -
ting peptide) enhanced permeability of the capil -
lary tufts [62]. NPY, neuropeptide Y, a known
vasoconstrictor, may be involved in constricting
the venous drainage [59]. There appears to be very
little NOS in the blood vessels of the premeno-
pausal vagina and none in the postmenopausal
[62]. This suggests that NO would not be a major
factor influencing vaginal blood flow, unlike the
situation in the penis. After orgasm or the cessa-
tion of sexual stimuli, the continuous lumen-blood
transfer of Na+ by the epithelium slowly reabsorbs
the excess fluid of the neurogenic transudate by
osmotic drag and resets the vagina back to its just
moist basal state.
b) Pelvic and genital muscular activity in the
basal and sexually aroused states
The vagina is a tube of autonomically innervated
smooth muscle (a longitudinal inner and a circular
outer layer) set amidst three sets of powerful pelvic
striated muscles (1, superficial- ischiocavernosus
and bulbocavernosus; 2, the transverse perineii and
3, deep- the levator ani forming the pelvic dia-
phragm across the anterior of the pelvis of which
the largest medial portion is classified as the pubo-
cocyggeus). The uterus, composed of three layers of
smooth muscle, is situated in the lower pelvic part
of the abdomen. The motility patterns of these
organs, especially during sexual arousal to orgasm,
have been studied infrequently, rarely measured and
are poorly characterised [40, 58, 59, 69, 70, 71].
Their activity is usually monitored either by small
luminal balloons or pressure catheters or by elec-
trodes (needle or surface) that pick up the electro-
myographic activity (EMG) that increases when the
muscles contract [69]. Because of the setting of the
vagina, smooth muscles amongst striated, contrac-
tion of either or both will influence the pressure
motility pattern obtained and the interpretation of
the records often relies on the fact that at orgasm the
striated motility dominates. No studies have been
published that record simultaneously, but inde -
pendently, both the striated and the smooth muscle
activity thus allowing their interaction to be better
interpreted and characterised.
In the basal or sexually quiescent state the striated
muscle plays little or no role but the smooth
muscle of the uterus and vagina is active especial-
ly perimenstrually when it contracts periodically
to expel the uterine/vaginal contents. These uter-
ine and vaginal contractions are normally not
consciously recognised [40, 71, 72]. They only
become obvious if they reach painful, spasmotic
levels (dysmenorrhoeic pain). During arousal to
orgasm, the few records obtained show an increas-
ing vaginal lumenal pressure [40]. At orgasm a
series of pelvic, clonic, striated muscle contrac-
tions occur at approximately 0.8 second intervals
which gradually get longer and the contractions
weaker [58, 69]. They can last for 5-60 seconds.
These contractions are concommittant with the
subjective feeling of orgasm. Voluntary contrac-
tions of the pelvic striated muscles do not give a
feeling of intense pleasure but are often used to
enhance arousal. Few records of the intrauterine
pressure exist and those that do could well be
influenced by the size of the devices used to mea-
sure the intrauterine pressure (see Levin [40] for
discussion). During sexual arousal up to orgasm,
individual uterine contractions may occur while
at orgasm a series occurs mediated by the sym -
pathetic system via the hypogastric nerve. These
have been implicated by some to be important in
rapid sperm uptake into the uterus/fallopian tubes
but this ignores the effect of vaginal tenting on
cervical elevation from the ejaculated pooled
semen (see previous section on cervix and Levin
[59] for discussion). It has been proposed that
sexual satiation in the female occurs only when
the orgasmic uterine contractions are intense but
there has been no quantitative studies to back up
this speculation.
Two studies have reported that vaginal distention
induced by rapid increases in volume by inflation of
luminal balloons cause i) contractions of the bulbo-
cavernous and ischiocavernous muscles [73] and ii)
an increase in the velocity of clitoral arterial blood
interpreted as an increase in flow [74]. The volume
increase used was between 100 to 300ml although
the normal volume of the human penis is about 70
ml. Thus penile volume per se would have little
effect, but penile thrusting would stretch the vaginal
walls and cause the reflex actions. The enhanced
clitoral flow and its engorgement and introital
tightness around the penile shaft are all features
suggested to enhance the pleasure of coitus for
both male and female partners.
526
III. CENTRAL NERVOUS SYSTEM
PATHWAYS INVOLVED IN THE
CONTROL OF FEMALE SEXUAL
FUNCTION
1. INTRODUCTION
Almost nothing is known of the central nervous
system (CNS) pathways controlling sexual func -
tion in human females. No imaging studies of
neural activity during sexual arousal or orgasm in
women have been reported. A few studies have
correlated brain lesions with sexual dysfunction
[75], but precise localization of sexual function
has not been possible. Thus, almost all conclusions
must be drawn from studies in animals, and to a
much lesser extent, in men.
Many animal studies have been performed exami-
ning the CNS control of penile erection (see
review in McKenna, [76]). In contrast, the CNS
control of the female genital organs has been the
focus of far fewer studies. There is a large amount
of literature dealing with the pathways and hor-
monal control of receptive behavior in female ani-
mals (reviewed in Rose, [77] and Pfaff and
Schwartz-Giblin, [78]). The most studied recep-
tive behavior is the lordosis reflex in rodents, for
which the neural pathways have been significant-
ly elucidated. Several factors make it problematic
to draw conclusions about human female function
from these studies. Human females do not display
lordotic behavior or anything which is arguably
homologous to lordosis. The pathways controlling
lordosis behavior appear to be primarily involved
in the expression of this behavior and not nece-
ssarily involved in the generation of sexual desire
[79]. The pathways mediating sexual desire
remain to be elucidated.
2. O VERVIEW
Some general principles of the CNS organization
of sexual function in the female can be identified.
Sexual responses (eg. genital arousal and cli -
max) are largely the product of spinal cord reflex
mechanisms. These reflexes are mediated by
genital afferents, primarily from the pudendal
nerve. The efferent arm of the reflexes consist of
complex, coordinated somatic, sympathetic and
parasympathetic activity. Thus, the reflexes in-
volve several spinal segments. The organization of
the interneurons generating the reflexes is poorly
understood. Anatomical studies indicate that the
interneurons are located in a column within the
central portion of the spinal gray matter and
extend for several segments, linking the various
sensory inputs with the efferent neurons. The spi-
nal reflex mechanisms are largely unaffected by
gonadal hormones.
The spinal reflex circuits are under descending
control from a variety of supraspinal sites. This
control is both inhibitory and excitatory. A
powerful inhibitory control of spinal sexual
reflexes derives from the nucleus paragigantocel-
lularis in the rostral medulla. This site provides a
tonic suppression of sexual reflexes. The inhibi -
tory neurotransmitter is probably serotonin. A
variety of other brainstem sites have been shown
to project to the relevant neurons in the spinal
cord, but their functional role is unknown. Within
the hypothalamus, important facilitatory roles in
sexual function have been demonstrated for the
medial preoptic area and the paraventricular
nucleus. In the forebrain, the medial amygdala, the
bed nucleus of the stria terminalis, septal nuclei,
and regions of the cerebral cortex have been impli-
cated.
In addition to its spinal reflexive role, genital sen-
sory information is also relayed to many of the
supraspinal structures. Thus, genital stimulation
is able to modify the descending control of spinal
reflex mechanisms. A very strong degree of inter-
connection has been noted in most of the sur-
paspinal sites identified with sexual function.
They receive inputs from a variety of higher sen-
sory systems. Supraspinal sites are also influenced
by gonadal hormones. These findings indicate that
multiple factors interact at supraspinal levels to
influence the excitability of spinal sexual reflexes.
3. SENSORY MECHANISMS
Sensory stimuli relevant to sexual function are
conveyed by afferents in the pudendal, pelvic and
hypogastric nerves. The pudendal nerve conveys
most of the sensory stimuli from the external geni-
talia and perigenital area. The pelvic and hypogas-
tric nerves convey information from the internal
pelvic organs. The afferents terminate primarily in
527
the medial portions of the dorsal horn and in the
medial central gray matter (dorsal gray commis-
sure) of the lumbosacral spinal cord (80; 81; 82;
83). The pudendal afferents have an almost exclu-
sively medial distribution. Visceral pelvic affe-
rents, on the other hand, also terminate in the late-
ral edge of the gray matter in the vicinity of the
intermediolateral cell column, the site of the pre-
ganglionic neurons, but probably do not make
synaptic contact with them.
Stimulation of the pudendal nerve gives rise to
spinal field potentials. These were mapped in the
cat. The largest field potentials and greatest num-
ber of synaptically activated neurons were found
in the medial portions of the lumbosacral spinal
gray [84]. Anatomical and physiological investi-
gation in the cat also identified interneurons in the
medial gray of the sacral spinal cord which
responded to pelvic visceral and perineal stimula-
tion [85]. Putative spinal interneurons related to
pelvic function have been identified using the c-
fos technique. Strong activation of neurons often
causes expression of the immediate early gene, c-
fos and its gene product Fos [86]. Stimulation of
genital afferents resulted in labeled neurons in the
medial dorsal horn, the central gray commissure
and the region of the intermediolateral cell
column, consistent with the distribution of pelvic
sensory terminals. The distribution of interneurons
was similar in males and females [87, 88, 89].
Putative interneurons have also been identified by
injection of neurotrophic viruses into pelvic
organs. The virus is picked up by nerve terminals,
retrogradely transported to the neuronal cell body,
replicated and picked up by nerve terminals
presynaptic to the infected neurons. In this way, a
chain of functionally linked neurons can be identi-
fied [90, 91]. Following injection into the penis,
clitoris or uterus, a similar finding was observed
[92, 93, 94, 95]. The majority of labeled neurons
in the spinal cord were located in the central gray
region of the spinal cord and in the vicinity of the
intermediolateral cell column. The majority of
neurons were located in lumbosacral segments.
Thus, several independent techniques have indica-
ted that pelvic and sexual reflexes are dependent
on spinal neurons in the central gray region of
the lumbosacral segments.
4. SPINAL REFLEXES
Sexual function is composed of numerous spinal
level reflexes, most activated by pudendal affer-
ents. Perhaps the best studied is the bulbocaverno-
sus reflex. This reflex is a polysynaptic response
seen in males and females elicited by low thresh-
old pudendal sensory fibers. These activate puden-
dal motorneurons to contract the striated perineal
muscles [80, 96, 97, 98]. This reflex is often used
as a neurological test of the integrity of the puden-
dal nerve. Its sexual significance is unclear. Howe-
ver, tonic stimulation of the clitoris could lead to
the development of the orgasmic platform, ie.
contraction of the levator ani and circumvaginal
muscles, through the mechanism of the bulboca-
vernosus reflex. This reflex would also lead to
contraction of the external urethral sphincter, pro-
moting urinary continence during sexual activity.
In addition to the contraction of the urethral
sphincter, stimulation of the clitoris and vagina
leads to an inhibition of bladder activity. This
reflex is mediated by pudendal nerve afferents. It
leads to inhibition of pelvic nerve activity to the
bladder and an increase in hypogastric nerve acti-
vity to the bladder neck, leading to detrusor inhi-
bition and bladder neck contraction [99, 100].
The reflex mechanisms involved in sexual arousal
(clitoral erection, vaginal engorgement and lubri-
cation) have not been investigated in females.
Given that these responses are mediated by the
cavernous nerve, it is likely that female reflexes
are similar to the cavernous nerve mediated erec -
tile response in males. Stimulation of the dorsal
nerve of the penis (a division of the pudendal
nerve) results in long latency discharges in the
cavernous nerve [101] and results in increases in
intracavernous pressure [102, 103]. Stimulation of
the cavernous nerve in New Zealand White fe-
male rabbits resulted in increases of mean clitoral
intracavernosal pressure, clitoral arterial blood
inflow as well as vaginal wall arterial blood
inflow, vaginal wall pressure and vaginal wall
length [67]. The long latency response clearly indi-
cates that this is a polysynaptic reflex response.
The mechanisms underlying female sexual res-
ponses remain to be elucidated.
Evidence indicates that sexual climax is also a
spinal level reflex. Following spinal cord injury, a
significant number of women are still able to expe-
rience orgasm [104]. In anesthetized, acutely spi-
nalized female rats, genital stimulation gives rise
528
to a response which resembles climax in humans:
rhythmic contractions of the striated perineal
muscles and vaginal and uterine contractions [47].
It also includes strong activation of the cavernous
nerve, driven by both hypogastric and pelvic nerve
preganglionic activity. This response is neurologi-
cally very similar to the ejaculatory response seen
in male rats.
5. ASCENDING SENSORY PATHWAYS
Sexual afferents enter the spinal cord in the sacral
segments. Sensory information is relayed to
supraspinal sites via the spinothalamic and spi -
noreticular pathways. The spinothalamic path-
ways primarily convey the fastest fibers related to
the encapsulated nerve endings of the phallus.
They travel in the dorsal columns and consist pri-
marily of fast myelinated fibers [105]. These
fibers terminate in the posterolateral nucleus of the
thalamus and subsequently relayed to the medial
thalamus. Spinoreticular fibers tend to be slower
than the spinothalamic fibers. They travel in the
contralateral (and to a lesser extent ipsilateral)
lateral spinal columns and terminate in brainstem
reticular formation.
Studies in humans have examined cortical evoked
potentials following electrical stimulation of the
dorsal nerve of the penis/clitoris. Evoked poten-
tials are recorded bilaterally from cortical areas,
with the highest amplitude in the midline (Cz-2)
over the sensory cortex [106, 107]. This distribu-
tion is confirmation of the identification of
pudendal representation deep in the midline
interhemispheric fissure in humans [108)] and
cats [109]. The amplitudes of cortical evoked res-
ponses are larger in men than in women [110]
although slightly shorter in latency in women
[111]. The smaller size in women may be related
to fewer fibers innervating the clitoris relative to
the penis or to the greater accessibility of stimula-
tion of the male dorsal nerve.
Studies in children (3-13 years old) revealed that
the cortical evoked potentials from the phallus
shorten in latency with maturation and show a nar-
rower volley [112]. These results indicate that the
nerve conduction velocity of CNS perineal senso -
ry pathways increases and shows a greater uni -
formity with maturation. However, these changes
were gradual and did not show abrupt changes
around puberty. No major differences were repor-
ted between boys and girls.
6. BRAINSTEM REGIONS
Spinal sexual reflexes have long been known to be
under descending control from brainstem sites
[113] but the details of this control have not been
explored until recently. One site has been identi-
fied in males as important in inhibitory control of
climax-like responses. Given the high degree of
similarity of this climax-like response described
above between males and females, it is highly like-
ly that this region plays a similar role in females.
The nucleus paragigantocellularis projects directly
to pelvic efferent neurons and interneurons in the
lumbosacral spinal cord [92]. Neurons in this area
are transneuronally labeled following virus injec-
tion into the penis [114] and the clitoris [93].
Lesions of this nucleus are as effective as spinal
transection in suppressing a tonic inhibition of the
climax-like response [92]. Most of the neurons in
this region stain positively for the neurotransmitter
serotonin and serotonin applied to the spinal cord
inhibits spinal sexual reflexes [92]. This is a like -
ly candidate for mediating the high incidence of
orgasmic dysfunction seen with the use of SSRI
antidepressants, which elevate brain serotonin
levels [116, 117]. Neurons in the nucleus paragi -
gantocellularis receive genital sensory informa -
tion in males and females [77, 118].
Several other sites have been anatomically iden -
tified for their projections to lumbosacral spinal
cord, but their functional role in sexual response
is unknown. The lumbosacral spinal cord receives
strong projections from other serotonergic nuclei
in the brainstem, the raphe nuclei pallidus, magnus
and parapyramidal region [119, 120,121, 122].
There are also significant noradrenergic projec-
tions from the A5 catecholaminergic cell group
and from locus ceruleus [123, 124]. These provide
a dense innervation of pudendal motoneurons and
other lumbosacral targets [125, 126]. Future
research is needed to identify the functional signi-
ficance of these projections.
In conventional and viral tracing studies, a projec-
tion from Barrington’s nucleus in the parabrachial
region of the pons to lumbosacral cord has been
identified [93, 95, 119]. This region has long been
known to play a role in micturition [127, 128]. It
has also been implicated in pelvic contractions
related to defecation and parturition [129, 130,
131, 132]. Its role in sexual responses has yet to be
investigated.
529
In the midbrain, the periaqueductal gray is known
to be an important relay center for sexually rele -
vant stimuli. It has extensive connections with all
of the brainstem sites just discussed and has
connections with many hypothalamic sites in-
volved in sexual function [133]. Neurons in this
area are labeled following viral injection into the
clitoris and uterus [93, 95]. The great majority of
these neurons in this region are activated during
copulatory behavior [77].
7. HYPOTHALAMUS
The hypothalamus is an essential site for repro-
duction and sexual behavior, as well as for a very
large number of homeostatic and motivated beha-
viors [134]. The large number and complexity of
these activities make it difficult to precisely de-
fine the hypothalamic role in sexual arousal and
performance. The medial preoptic area has long
been known to play a role in the control of male
sexual behavior. Lesions of this region severely
attenuate or abolish male copulatory behavior in
every species tested [135]. However, medial
preoptic lesions do not abolish erections caused by
sleep (Schmidt, personal communication), expo-
sure to volatile odors from estrus females [136] or
masturbation [137]. Nor do medial preoptic
lesions decrease sexual motivation [138]. The
conclusion is that in the male, the medial preop -
tic relates to the animal’s ability to recognize a
sexual partner. A similar conclusion may be true
in the female. Lesions of the medial preoptic
region in female rats resulted in greater display of
lordosis, but when given the option, females avoi-
ded male partners. A tentative conclusion is that in
both sexes, the medial preoptic is not directly
involved in sexual motivation or performance but
with mate selection.
The ventromedial nucleus of the hypothalamus is
critical for the expression of lordosis behavior
[78]. Neurons in this region are labeled following
virus injection into the uterus [95]. The role of the
ventromedial nucleus in the control of genital res-
ponses has not yet been investigated.
The paraventricular nucleus of the hypothala -
mus is a likely candidate for control of genital
responses. It is known that during sexual arousal
and orgasm, oxytocin from the paraventricular
nucleus is secreted from the posterior pituitary
into the blood stream [139, 140]. There is a direct
projection from the paraventricular nucleus to the
autonomic outflow from multiple segments as
well as direct projections to pelvic autonomic and
somatic efferents [141, 142, 143]. The paraventri-
cular nucleus is extensively connected with the
medial preoptic area [144]. The paraventricular
nucleus was consistently labeled after pseudora-
bies virus injection into the clitoris and uterus [93,
95]. Neurons in the paraventricular nucleus are
activated during copulation in female rats [145].
Further studies, such as stimulation studies and
oxytocin pharmacological studies are needed to
further characterize the sexual role in females of
the paraventricular nucleus.
8. F OREBRAIN
Forebrain regions involved in female sexual
function have largely been identified on the basis
of Fos staining in copulatory tests and viral stai-
ning. Medial amygdala, bed nucleus of the stria
terminalis and some other regions are most consis-
tently identified [95, 146, 147, 148, 149]. The Fos
labeling in these regions is strongly affected by
vaginocervical stimulation during copulation. The
medial amygdal is believed to be involved in the
control of sexual motivation in the male [135].
Similar conclusions in the female cannot currently
be drawn.
In one series of studies, intracranial stimulation
of human males and females elicited subjective
pleasurable response, which were described as
sexual in nature [151]. An area consistently asso-
ciated with this response was the septal region.
Electrical stimulation or stimulation with choliner-
gic and adrenergic agents were effective. Howev-
er, it should be noted that the subjects of these
experiments were patients with severe neurologi-
cal and psychiatric conditions, so interpretation of
these studies is problematic. A functional imaging
study in men identified cortical sites associated
with visually-evoked sexual stimulation [152].
Sexual arousal was associated with an increased
activity in the right insula and right inferior frontal
cortex, which are two paralimbic areas relating
highly processed sensory information with moti-
vational states; and the activation of the left ante-
riorcingulate cortex, another paralimbic area
known to control autonomic and neuroendocrine
functions. No similar studies have yet been repor-
ted in women.
530
IV. NOSOLOGY AND DIAGNOSTIC
CLASSIFICATION: USE IN
ASSESSING PSYCHOSEXUAL
TREATMENT OF FEMALE SEXUAL
DYSFUNCTION
1. INTRODUCTION
It is essential to specifically and thoroughly de-
scribe the sexual problem a woman is experien-
cing. There are two formal systems of diagnostic
classification in general use. While a recent
consensus conference panel recommended adop-
tion of a new female sexual dysfunction diagnos-
tic and classification system shown in table 4,
based on physiological as well as psychological
pathophysiologies and a «personal distress» crite-
rion for most of the diagnostic categories, this new
diagnostic and classification system in not yet in
general clinical use.
One diagnostic classification system in general use
is the World Health Organization’s International
Classification of Diseases (ICD-10) [5]. The other
is the American Psychiatric Association’s Dia-
gnostic and Statistical Manual (DSM-IV) [6] sys-
tem. As can be seen from Table 5, the categories
across the two systems are similar in certain ways.
Both systems view sexual dysfunction as invol -
ving a combination of psychological and somatic
components. Both rely heavily on the sexual res -
ponse cycle as proposed by Masters and Johnson
[58, 153] and modified by Kaplan [154] to organi-
ze categories of desire, arousal and orgasm. The
categories of pain disorders, vaginismus and dys -
pareunia are not part of the sexual response
cycle. It should be kept in mind that the sexual
response cycle is based on a conceptual frame-
work that sees the response categories as separate
and temporally ordered «phases,» though there is
minimal basic research on the processes of sexual
response. In men there are phase exceptions, such
as orgasm with a flaccid penis or electro-ejacula-
tion, where orgasm may not be preceded by parti-
cularly noticeable sense of genital or sexual arou-
sal. Parallel exception in women has not been
well-described in research but have some basis cli-
nically where women not infrequently report a
blending of the sense of desire and interest.
 Table 4: Female sexual dysfunctions as defined by the International Consensus Development Conference on Female Sexual
Dysfuncffon.
I. Sexual Desire Disorders
IA. Hypoactive Sexual Desire Disorder
Hypoactive Sexual Desire Disorder is the persistent or recurrent deficiency (or absence) of sexual
fantasies/thoughts, andJor desire for, or receptivity to, sexual activity, which causes personal distress.
IB. Sexual Aversion Disorder
Sexual Aversion Disorder is the persistent or recurrent phobic aversion to and avoidance of sexual
contact with a sexual partner, which causes personal distress.
II. Sexual Arousal Disorder
Sexual Arousal Disorder is the persistent or recurrent inability to attain or maintain sufficient sexual
excitement, causing personal distress. It may be expressed as a lack of subjective excitement or a
lack of genital (lubrication/swelling) or other somatic responses.
III. OrgasmicDisorder
Orgasrnic Disorder is the persistent or recurrent difficulty, delay in, or absence of attaining orgasm
following sufficient sexual stimulation and arousal, which causes personal distress.
IV. Sexual Pain Disorders
IVA. Dyspareunia
Dyspareunia is recurrent or persistent genital pain associated with sexual intercourse.
IVB. Vaginismus
Vaginismus is recurrent or persistent involuntary spasm of the musculature of the outer third of the
vagina that interferes with vaginal penetration,which causes personal distress.
IVC. Non-Coital Sexual Pain Disorder
Recurrent or persistent genital pain induced by non-coital sexual stimulation.

Table 5: Female dysfunctions classifications

531
The two diagnostic systems differ from one ano-
ther in several respects. For example, the ICD-10
has one unique category, Excessive Sexual Desire,
and its sexual arousal category has a different
label, Failure of Genital Response. The genital re-
sponse label is actually more precise than the term
Sexual Arousal Disorders since sexual arousal
disorder in both systems is restricted to genital
functioning and excludes loss of subjective sexual
arousal. The DSM-IV’s lack of a specific category
of hyperactive sexual desire is conceptually pro-
blematic and leaves a diagnostic void for indivi-
duals who are both attracted and distressed by
their own high frequency of sexual desire and/or
behavior. The DSM-IV specifies that the sexual
problem must, «cause marked distress or interper-
sonal difficulty», while the ICD-10 more oblique-
ly states that the sexual problem interferes with the
person’s ability to «participate in a relationship in
a way he or she would wish». Although there is
some overlap in these two statements, «marked
distress and interpersonal difficulty» conveys
more disturbance than the more vague inability to
get what one would wish for in a sexual relation-
ship.
Criticism about these two systems has come from
two main sources. One is from the clinical theore-
tical position, which reminds us that these systems
focus primarily on genital responses and inter -
course-interfering symptoms rather than a broa-
der set of sexual activities. In addition, these dia-
gnostic systems, in keeping with the usual medical
focus, are individually as opposed to interactio -
nally conceptualized [155]. These «biases» may
be very important for women who less often report
sexual dissatisfaction focused on genital response
and more often report sexual complaints based on
other experience, particularly desire [7, 17]. A fur-
ther criticism is that the categories either artificial-
ly isolate physical from psychological etiology or
pay little attention to etiological factors in general
[1]. Nevertheless, given that most clinicians do
use one of these two systems, there are several
guidelines that seem to increase the likelihood of
getting a diagnosis that is representative of the key
complaints that a woman might have.
Using the DSM-IV as a basis of illustration:
1. If a woman comes in stating that she has diffi-
culty in one of the categories, it is important to
532
briefly identify comorbidity by asking whether
there are also problems in each of the other
major categories (sexual desire, sexual arousal,
orgasm and pain). The interviewer must also
ask about the degree of distress that she expe-
riences with each category.
2. The DSM-IV offers important subcategories
that are useful for diagnosis and treatment
planning. They include whether the particular
category is lifelong or acquired and whether it
is global or situational.
3. If there is more than one dysfunction, the order
in which each dysfunction occurred needs to be
documented.
4. The above clarification should be made in the
context of a broader sexual history interview so
that etiological factors might begin to be iden-
tified. The international Consensus Conference
[1] raised this point as one that had been igno-
red by the current diagnostic systems. Particu-
lar etiological factors that are important are
whether the etiology appears to be primarily
physical, primarily psychological or of mixed
origin.
5. Another issue to review is whether the sexual
partner also has difficulties in these categories
of sexual functioning. For example, if a woman
reporting low arousal and anorgasmia has a
male partner who ejaculates within 30 seconds
of stimulation, this information significantly
impacts the etiological conceptualization and
the treatment plan.
6. Relationship factors, current and historic, may
be important factors causing or maintaining the
sexual dysfunction. Common examples are
sexual or physical abuse, relationship conflict
and loss of attachment. The last two items,
partner sexual dysfunction and relationship
factors, are not mentioned directly in either of
the diagnostic systems but are considered
essential in clarifying etiology and treatment
needs. Precise identification of etiological fac-
tors is often difficult particularly with women.
The reason is that there are few data which
identify specific biologic, physiologic, anato-
mic and neural factors which play a role in a
woman’s sexual functioning and how these fac-
tors might interact with each other and with
psychological functioning.
Two diagnostic categories deserve special
remarks. One is the category of Hypoactive
Sexual Desire (HSD). It is clear, if useful treat-
ments are to be recommended for hypoactive
sexual desire, then a subclassification system for
this diagnosis is necessary. At the present time, the
only data-based subtype is HSD secondary to hor-
mone imbalance. Other subtyping categories
remain to be identified. Physiologically, one can
hypothesize that some combination of adrenergic,
dopaminergic and seritonergic factors may play a
role [156, 157]. Psychosocially, depression (bear-
ing in mind that depression has both biochemical
and psychosocial consequences), even if adequate-
ly treated and compensated, and relationship fac -
tors probably play major roles [158].
The other category of dysfunction that deserves
mention is Female Sexual Arousal Disorder. This
has recently been acknowledged as a potentially
physiologically based dysfunction with symptoms
that include difficulty with gential vasoconges -
tion and lubrication [159]. The human data for
this position are currently minimal and actively
being pursued. In addition, the degree to which
women’s self-report of low arousal is at all related
to a lack of physiological level of arousal remains
to be clarified. As can be seen from earlier work
in psychophysiology, the correlation between
subjective and genital response in women varies
by a number of factors, but data do suggest that
sexual arousal is less likely to be identified at
lower levels of arousal, in the presence of less
erotic stimuli, under psychological conditions of
inhibition such as sexual guilt, or in a context
that the woman does not identify as being parti -
cularly sexual [160, 161, 162].
2. PSYCHOSEXUAL TREATMENT OPTIONS
There is a body of research that describes and
documents the effectiveness of psychosexual indi-
vidual and couples’treatments for sexual dysfunc-
tions in women. The following comments are
intended to highlight empirically supported treat-
ments and report efficacy by diagnosis. More spe-
cific details of these studies are elsewhere descri-
bed [163].
a) Treatment definitions
Psychosexual treatments are those which focus on
sexual symptomatology while being aware of phy-
533
siological, psychosocial and cultural influences on
sexual experience and expression. The treatment is
typically delivered to either individuals or couples
although some treatment has been documented to
be effective in groups. Psychosexual treatment
involves actively focused therapeutic interven -
tions in which the therapist reacts to the patient’s
problems by both discussing them in session and
recommending various activities to do outside of
the session. Therapy of this type is usually rela-
tively short-term (i.e., 6-14 sessions) although it is
not clear what the optimum number of sessions
might be for each diagnosis.
b) Overview of treatment issues
There have been fewer psychosexual treatment
efficacy outcome studies for sexual disorders
especially when compared to other mental health
conditions such as anxiety and depression in
which psychological and physiological factors
obviously interact. The reasons for this difference
have to do with the availability of funding for sex
research and the fact that sexual adequacy is consi-
dered a quality of life issue that rarely threatens
health in general. An important exception is the
extent to which sexual problems impact enduring
relationships and the stability of marriages, which
themselves have complex correlations to health
variables [164].
The American Psychological Association created a
task force in the early 1990’s to begin to identify
criteria that would define empirically supported
psychotherapeutic procedures [165]. The task
force identified a set of criteria and were calling a
treatment either well-established or probably effi-
cacious. Alterations to these categories have since
been suggested [166]. Nevertheless for the pur-
poses of the current description we will use the
original categories because they are useful and
correspond well with some parallels in clinical
trial work.
The more restricted category, well-established,
includes the following criteria:
a) group studies showing superiority to another
treatment must be done by different investiga-
tors, or
b) demonstrate equivalence to another established
treatment with adequate statistical power, or
c) a large series of well designed single case stu-
dies that
d) use treatment manuals and
e) have clearly specified client samples.
Probably efficacious categories must meet the fol -
lowing criteria:
a) at least two studies showing treatment more
effective than waiting-list control, or
b) studies meeting well-established criteria except
for the fact that treatment manuals were not
available, or
c) a small series of single case studies otherwise
meeting the well-established criteria except for
the group study criteria.
The well-established criteria are familiar as they
have a lot in common with randomized placebo-
controlled clinical trial methodology in pharmaco-
logical research. However there are some distinc-
tions between good psychotherapy research desi-
gns and randomized placebo-controlled clinical
trials.
In psychotherapy outcome research:
1) Placebo controls are infrequent as it is difficult
to provide an ethical placebo;
2) Double-blind control conditions are not fea-
sible, since the provider of therapy cannot be
blinded to the therapy she or he is providing;
3) Until recently comparable treatments often
have not been available for the treatment of
sexual dysfunction;
4) There is greater variance in psychotherapy
treatment delivery than in medication delivery.
Psychotherapeutic treatment delivery may
vary based on an array of heterogeneous quali-
ties of patient and provider. This is one reason
manuals have been recommended as a criteria
of psychotherapeutic treatments. Manuals may
reduce some of the variance but many provi-
ders object to them because they do not ade-
quately account for patient differences. Thus
even with manuals, individual subject and pro-
vider variance will still be an issue;
5) Many patients react to characteristics in their
treatment provider which are sometimes more
obvious or at issue in psychotherapeutic inter-
actions. In the sexual dysfunction research,
there also has been a problem with having very
heterogeneous patient samples, combining
534
several dysfunctions in one category or not
identifying the comorbidity that exists. Another
problem with sex therapy in particular is that
outcome measures have been improving but
have suffered from being either too inclusive or
exclusive of symptoms and having few stan-
dardized measures of sexuality and sexual
satisfaction [167].
In addition to efficacy, which addresses the inter-
nal validity of a treatment, effectiveness evaluates
external validity. Efficacy studies examine what
goes on in actual clinical practice, without deman-
ding such methodological constraints as randomi-
zation, controlled number of sessions and con-
trolled content of therapy. The current opinion of
clinical researchers is that efficacy is necessary to
demonstrate whether the treatment has a benefit
under controlled conditions, while effectiveness
informs about its broader scale applications. The
present review primarily summarizes the studies
on efficacy. Occasionally effectiveness research is
identified and discussed.
It is clear that well controlled, treatment compari-
son or event wait-list control research on sexual
dysfunction treatment is uncommon and where
these designs exist statistical power is often low
[163]. Though outcome measures vary considera-
bly, the patient’s self-reports are the most common
forms and are focused typically on symptom
change, sexual satisfaction and occasionally rela-
tionship satisfaction.
3. PSYCHOSEXUAL TREATMENT EFFICACY BY
DIAGNOSIS
a) Sexual desire disorders
There are no efficacy studies demonstrating empi-
rically supported treatments for the Sexual Desire
Disorders. There are a few effectiveness studies,
however. Masters and Johnson based sex therapy
methods [153] have, overall, shown positive but
rather modest results for hypoactive sexual desire
disorders [168, 169]. In the Hawton et al. field
study of 60 British couples in which the female
partner reported low desire, 56% had a positive
outcome to treatment that included Masters and
Johnson’s treatment methods. Similar success
levels (65%) were found by Sarwer and Durlak’s
[170] field study of behavioral treatments for 124
women with Hypoactive Sexual Desire Disorder.
Success levels above 50% are noteworthy, but we
do not know from these effectiveness data what
the waiting-list control response might have been
which would help to put these figures into per-
spective.
b) Sexual arousal disorders
Similarly, there are no empirically-supported psy -
chosexual treatments designed to treat Female
Sexual Arousal Disorder which the DSM-IV spe-
cifically defines as the inability to attain or main-
tain «an adequate lubrication/swelling response of
sexual excitement [5]». Few women, in fact, com-
plain of a sexual arousal disorder in these words
and researchers until recently have rarely specifi-
cally asked beyond a complaint about lubrication
related to pain disorders. We thus have no idea of
the prevalence of this condition, whether it is more
than one condition, the precision with which
women can identify degrees of genital lubrication
or vasocongestion, and the extent to which women
label these symptoms as problems. Anestrogenic
women will note a lack of lubrication, even when
subjectively sexually aroused. For this condition
the administration of estrogen replacement com -
pounds or topical lubricants may be effective
treatments. Whether these approaches would also
solve a «swelling response» difficulty is not
known. Current attempts to describe and docu-
ment Goldstein and Berman’s [159] proposed
categories of vaginal engorgement insufficiency
and clitoral erectile insufficiency syndromes will
be important to clarify diagnosis and treatment for
female sexual arousal disorder. At the moment
research from the psychophysiological lab sug -
gests considerable separation is possible between
female genital lubrication (subjectively mea-
sured), vasocongestion (objectively measured)
and a subjective sense of sexual arousal [160,
161]. Addressing treatment interventions with
these findings in mind is necessary. One could
make a case that sexual arousal problems in
women have been treated by way of anorgasmic
conditions. Indeed, orgasm dysfunction treat-
ments focus on the woman paying attention to
her physical and subjective responses during
arousal and seeking more stimulation if needed
[163, 171, 172].
c) Orgasmic disorders
There are effective treatments for the condition of
535
orgasmic disorders. We located 17 comparison
controlled studies (n = 577) and an additional 4
own control or wait-list control studies (n = 65).
When diagnostics of categorization was clarified
in the methods, there were more women identified
as secondary (n = 244) than as primary anorgas -
mic (n = 198). Specific active ingredients in this
treatment are unknown and there are often too few
details about the treatment, but it is clear that a
step-wise masturbation program in some version
is successful for primary anorgasmic women
though less so for secondary orgasmic women.
Systematic desensitization was shown to be relati-
vely less effective. Hurlbert and Apt [172] have
successfully used the «coital alignment tech-
nique,» positioning the male partner’s body to pro-
vide more direct clitoral stimulation, so that 56%
of the women increased their coital orgasmic abi-
lity. Non-controlled research has suggested that
these treatments are less effective for older women
[153]. There is also some suggestion that there are
more complex relationship issues for secondary
anorgasmia and a combination of sex therapy
and relationship therapy may be indicated [173].
d) Pain disorders
Vaginismus partially fulfills the probably effica-
cious treatment category. There are 55 women
across two uncontrolled studies along with several
case studies that make up the bulk of this clinical
research. The difficulty in validating treatments
for vaginismus is that it is a relatively rare condi -
tion and it can often coexist with other genital
pain conditions. Also, until recently there has only
been one clearly helpful treatment for this condi-
tion, preventing a good comparison treatment
study. The most studied intervention is the use of
a series of progressively larger dilators that the
woman inserts into her vagina over a number of
weeks, while also doing exercises for general
relaxation as well as specific exercises to increase
her control and relaxation of her pubococycegeal
muscles. Often the partner is involved in learning
to use the dilators, under the woman’s careful gui-
dance, as a prelude to gradually transferring to
digital and penile penetration. There are a number
of clinical reports of using biofeedback to the
genital area, using either anal or vaginal probe or
perineal electrodes. There is a general sense that
this is effective treatment for a subgroup of vagi-
nismic women. The particular advantage to a
biofeedback procedure to the genital area is that
it helps identify women who are chronically tense
in the genital area. These women do not benefit
from Kegel muscle exercises [55] because they are
never able to relax their muscles and are unaware
of this chronic tension until penetration is attemp-
ted. It would be interesting to see a comparison of
sex therapy using dilators and physical therapy
including genital biofeedback as well as the com-
bined use of these two therapies.
Dyspareunia is an extremely difficult diagnosis to
treat, in part because it probably needs further
diagnostic subcategorization in order for effective
treatments to be developed and tested. It typically
has been treated with medical management and
surgical interventions due to the high prevalence
of organic causes though there is also a fair
amount of case documentation showing psycholo-
gical factors as having treatment potential. An
obvious example of the latter is for the condition
of vulvar vestibulitis [174, 175, 176, 177] where
one study found that combining surgery and beha-
vioral therapy was equally effective to behavior
therapy alone, although none of the treatments
were standardized [177]. Because pain disorders
also greatly impact the partner, brief sex therapy
involving both partners can be helpful in moving
from a sexual interaction centered on the expecta-
tion of pain to a more normal and pleasure focused
experience.
V. FEMALE SEXUAL FUNCTION
AND BREAST OR GYNECOLOGIC
CANCER: ASSESSING THE
BIOLOGICAL ISSUES
1. I NTRODUCTION «SINE DESIDERIO MENS
NIHIL INTELLIGIT»
Cancer has become much more a chronic than
fatal disease. This shift in outcome has concomi-
tantly resulted in an increased emphasis on quali -
ty of life (QOL), of which sexuality is a leading
aspect [177, 178]. A diagnosis of breast (BC) or
gynecologic (GC) cancer catapults the woman
into several crises simultaneously, all different
but interrelated: female sexual identity, female
sexual function and sexual relationship. All three
crucial and personal factors may be dramatically
536
damaged, physically and emotionally, by the many
changes and challenges the woman has to face
when cancer diagnosis adversely affects her life
and that of her relatives [179,180].
Retrospective [181] and prospective [182, 183,
184, 185, 186] research has been carried out on the
many psychosocial issues faced by the woman
diagnosed with BC during this difficult transition
of her life, including direction and quality of sup-
port and optimal type of psychologic intervention
during BC diagnosis and treatment. The research
does not address the biological issues involved in
the sexual changes. This bias is probably second-
ary to a number of factors: the persistent gender
bias in sexological research, the lack of a medical-
sexologic background among the majority of
researchers and research on the biological aspects
of female sexuality being many years behind that
of male sexuality [40].
Often QOL outcomes are confused with their
determinants [187]. Objective measures of QOL
often include the assessment of functional status
which may not correlate with a patient’s subjecti-
ve impression of her life experience, e.g. sexual
pain, limitations and impairment, consciously or
unconsciously minimized for the relief of being
alive [188]. The role of objective limitations is
inadequately addressed and treated relative to the
many sexual problems from which these patients
suffer, especially in younger GC survivors; dia-
gnostics and therapeutics need to be balanced bet-
ween psychodynamic and physical factors.
2. FEMALE SEXUAL FUNCTION
Linear models (arousal, plateau, orgasm, resolu-
tion) have been widely used since the pioneering
work of Masters and Johnson [153] and Kaplan
[189]. More recently, Graziottin [180,190] sugges-
ted that human sexual function can be conside -
red as a circuit, with four main stations: libido,
arousal, orgasm, and satisfaction, including both
the physical phase of resolution, with its homeo-
static function of returning to baseline, and the
emotional evaluation of the experience (Figure 8).
Physical and emotional post-coital memories are a
critical part of satisfaction, summarizing the over-
all subjective evaluation of each sexual experi-
ence by itself and collected over time. This model
may help in understanding how positive or nega-

Figure 8 : Human sexual function as a circuit.
tive feed-back may affect sexual function [190]
and help to clarify the frequent overlapping of dif-
ferent sexual dysfunctions in women [191], parti-
cularly during BC and GC diagnosis and treat-
ment.
a) Libido
«Libido» is a Latin word that means «desire». It
has three major dimensions: biological, motiva -
tional-affective and cognitive [192] which have a
complex interplay with both inhibition and enhan-
cement. A useful working definition is that «sexual
desire is normally an activated, unsatisfied mental
state of variable intensity, created by external- via
the sensory modalities- or internal stimuli- fantasy,
memory, cognition...- that induces a feeling of a
need or want to partake of sexual activity (usually
with the object of desire) to satisfy the need» [193].
1. B IOLOGICAL
Biological roots of libido have been extensively
discussed elsewhere [190,194,195]. In short, hor -
mones are the necessary but not sufficient factors
to maintain a satisfying human libido. In women,
estrogens prime the central nervous system, acting
as neurotrophic and psychotrophic [196, 197, 198]
factors throughout life. They prime the sensory
organs, key receptors for external sexual stimuli,
and secondary sex characters. Sensory organs
transmit the basic information that, mixed with
emotional and affective messages, contribute to
the structuring of core sexual identity and self
image, relevant for the personal perception of
being an «object of desire» and for the direction
(homo or heterosexual) of the libido itself [199].
537
The interplay between estrogens and the dopami -
nergic system is the key process in determining
the appetitive and receptive side of sexual beha-
viour [198, 200] which can be further excited by
the peak of androgens at ovulation. Together with
frequency of desire, intercourse and orgasm, these
are the strongest indicators of quality of sexuality
[201]. Prolactin has an inhibiting effect on libido
and on the resulting neurovegetative and vascular
responses, via the same dopaminergic system
[198]. Small increases over normal levels may be
sufficient to reduce libido, sexual arousal and
vaginal lubrication [202].
Progestins act as mild sedatives, through a com-
plex mechanism that is central and, probably, per-
ipheral: they are of inte-rest when prescribed at
high dosages in hormonal treatment of advanced
adenocarcinoma. Their loss after bilateral ovariec-
tomy may lead to Female Sexual Arousal Disorder
(FSAD) [203], but supplementation improves libi-
do, arousal, assertiveness and well-being in
patients with benign conditions [204, 205, 206].
Androgens have a definite excitement role in
women [203] as well as in men. Hormones, in
their complex interplay, seem to control the inten-
sity of libido and sexual behaviour rather than its
direction [192]. GC survivors report decrease of
libido [207] and frequency of coital intercourse
[208], the worst outcome reported by irradiated
patients [209].
Although little attention is paid to the effect of
hormones on the function and morphology of sen-
sory organs as sexual targets and sexual determi-
nants of libido, sensory organs are open to envi-
ronmental sexual stimuli. A growing body of evi-
dence shows that sexual hormones have a speci -
fic effect on smell [194, 210, 211] and taste [210].
Libido, which may be lessened by loss of estro -
gens secondary to menopause, may be further
decreased with chemotherapy [188, 190] by an
increase in smell aversion [212] and reduction of
salivary secretion, particularly in young BC
patients [181, 184, 211]. Skin is the organ with the
largest brain representation: this may explain why
touch is so important in human love and commu-
nication. Non-sexual tenderness, caresses, holding
and loving behaviour seem to remained unchan-
ged or even increased in the majority of couples
after BC diagnosis and treatment, so that an avera-
ge 70-80% of women with BC report an overall
good adjustment [181, 184, 185, 186]. Much less
is known about the role of estrogens on hearing,
despite its having a strong excitatory role for libi-
do and arousal in women and sight, which is the
most potent sexual sense in men. Subtle changes
in sensory organ function and morphology could
contribute to the biologic deterioration of libido
with age, accelerated in many women in early
postmenopausal years [213, 214], usually in cases
of premature menopause [181, 215].
Loss of libido in BC patients may be secondary to
a number of biologic factors such as: arousal disor-
ders [181, 194, 216, 217, 218, 219]; pelvic floor
dysfunction [220]; psychodynamic [221], motiva-
tional or relational causes [154, 215, 218, 222],
sexual pain related disorders [223], orgasmic disor-
ders [154], and physical and/or emotional sexual
dissatisfaction. Loss of libido in GC patients may
be secondary to: arousal disorders [190, 194 217];
pelvic floor dysfunctions [220]; sexual pain related
disorders [223] including severe dyspareunia post-
radiotherapy and/or pain after vulvar laser CO2
[188], or vulvectomy [224] and persistent pelvic
pain after GC diagnosis and treatment [188]; orgas-
mic disorders [154]; sexual dissatisfaction [221]
and motivational or relational causes [154]. Diffe-
rential diagnosis requires a careful evaluation and
definition of objective criteria. BC or GC diagno -
sis and treatment may contribute to the complexi -
ty of sexual dysfunction.
2. MOTIVATIONAL-AFFECTIVE ASPECTS OF LIBIDO
Human beings undertake sexual activity for pro-
creation,“reproductive sex”, with strong biologi-
cal roots, and pleasure «recreational sex», with
deep relational roots [193]. The unpredictability of
life is reported to be perceived as an aphrodisiac.
Libido may be felt as more intense than ever,
sometimes with acute transgressive needs, and
increased sense of physical and emotional satis-
faction. There are a host of motives [225] with a
common denominator: «instrumental sex», a
means to obtain conscious and/or unconscious
advantages and/or to express motivations different
from pleasure and/or procreation. Coitus may be
used to confirm one’s identity, particularly in
young patients that perceive hysteroannessiecto-
my and the disappearance of periods as a major
wound to their female sex identity; «save the mar-
riage»; satisfy attachment needs; rebel against des-
tiny; overcome loneliness or boredom; show that
538
sexual access was still possible; obtain more atten-
tion in the relationship; satisfy masochistic needs;
control the relationship and/or the partner; repair
psychosexual wounds; or even for livelihood.
Unfortunately, instrumental sex with its strong
«defensive» nature is usually accompanied by a
low physical drive and is therefore more vulner-
able to dysfunctional outcomes [220] which seem
more frequent in BC and GC patients. The quality
of the non-sexual relationship [226, 227] and qua-
lity and intensity of transfer from past significant
relationships contribute to the motivational-affec-
tive aspect of sexual desire and may help maintain
the sexual relationship that is a vital part of the
«personality of marriage» over the time.
3. COGNITIVE
Sexual behaviour cognitively involves both wish
and risk. There may be a paralysing effect when
the perception of risks by a BC patient, i.e., rejec-
tion by a new partner «because of breast disfigure-
ment» and his «fears of cancer recurrence» and/or
wounded body image, or by a GC patient rejection
by a new partner «because of fear of infection»
after an HPV dependent intraepitelial or invasive
cervical or vulvar neoplasia and/or a wounded
body image [188, 201], may prevent women from
engaging in sex or starting a new relationship. An
enhancing effect could be perceived in those
women that consciously wish to «urgently» chal-
lenge their seductiveness and enjoy sex «before
the worst comes».
Psychosocial variables have been well document-
ed [177, 181-186, 188, 209, 215, 216, 228- 231].
Iatrogenic menopause, lymphedema, dyspareunia
and chemotherapy seem to affect the biologic
bases of libido in BC patients [179, 181, 219, 232-
234]. Iatrogenic menopause, with the special
contribution of the loss of ovarian androgen lea-
ding to FSAD, vaginal biological damages secon-
dary to radiotherapy and surgery leading to dyspa-
reunia, potential mental damages of chemotherapy
and vulvar damages secondary to conservative and
radical treatments seem to be the major factors that
may damage the biological bases of libido in GC
survivors.
b) Sexual arousal
Libido is different from sexual arousal, a state with
specific feelings usually associated with the genitals
[193]. In women, arousal has three main expres-
sions: central arousal, characterized by mental acti-
vation leading to erotic dreams, sexual daydreams
and/or voluntary sex fantasies which may activate
physical genital and non genital peripheral arousal;
non genital peripheral arousal, expressed by increa-
sed salivary secretion, sweating, cutaneous vasodi-
latation and nipple erection; and genital arousal,
associated with clitoral and vestibular bulb conges-
tion, and vaginal lubrication [40].
Arousal difficulties may be
a) central,
b) non genital peripheral and
c) genital [40].
Estrogen and androgen loss, secondary to iatrogenic
menopause, may affect these aspects of the arousal.
1. CENTRAL
Biological central difficulties may be secondary to
loss of sexual hormones [194, 204, 205, 235, 236],
but may be worsened by depression [194, 237],
anxiety [238], chronic stress and insomnia [220],
which may be biologically rooted, and by estrogen
and androgen deprivation [239-243]. Reduced fre-
quency of erotic dreams, fantasies, sexual day-
dreams and spontaneous mental arousal are the
clinical consequences of central arousal difficul-
ties reported in BC patients and GC patients irra-
diated for cervical carcinoma [208, 209, 244].
2. NON GENITAL PERIPHERAL
Problems in non genital peripheral arousal may be
better exemplified by «touch-impaired» disorders.
Sarrel and Whitehead [245] reported 35.71% of
patients described a change in touch perception
suggestive of peripheral neuropathy that may lead
to avoidance of skin contact during foreplay inclu-
ding nipple (personal unpublished data) and clito-
ris, interfering with sexual arousal. A chronic
hypoandrogenic condition may be a cofactor in
this loss of clitoral sensitivity, particularly in BC
patients with reduced ovarian androgen produc-
tion secondary to chemotherapy or bilateral ovar-
iectomy. Decreased salivary secretion, secondary
to chronic estrogen loss, affects 45% of normal
postmenopausal women [246], affecting mostly
oral intimacy and oral pleasure [194, 237]. This is
all the more important in women whose coital
receptivity is impaired by vaginal stenosis and
fibrosis leading to severe dyspareunia. Schover
[247], reports a significant decrease in the mean
number of sexual acts, including oral intimacy, in
the first year after treatment for cervical cancer.
539
3. GENITAL
Without estrogen, 35 to 50% of normal postmen-
opausal women complained of vaginal dryness
and dyspareunia [196, 214, 245]. Loss of estrogen
is the primary biological cause of genital arousal
difficulties in women after pre-existing arousal
disorders, and may be the critical precipitating fac-
tor leading to dyspareunia in women with iatroge-
n ic premature menopause [248]. Preexisting arou-
s al disorders may be worsened by the menopausal
loss of estrogens leading to avoidance of inter-
course. In addition to estrogen, regular and contin-
ued painless sexual activity has been found to
protect against vaginal dryness [249].
Tamoxifen is the contemporary endocrine treat-
ment most widely used in BC. It interacts with
ovarian estrogen synthesis and elevates plasma
estrogen levels in premenopausal women. In post-
menopausal BC patients tamoxifen increases plas-
ma levels of estrone sulfate (E1S) while plasma
estradiol and free plasmatic testosterone are re-
duced, and increases the liver production of Sex
Hormone Binding Protein (SHBG), thus further
reducing the free levels of both estradiol and tes-
tosterone [250, 251]. One third of patients on
tamoxifen had vaginal problems such as dryness,
itching and discharge [184]. Other studies seem to
confirm the negative effect of tamoxifen on
sexual response [219, 252, 253].
In cases of GC, because of the direct anatomical
involvement of vaginal and perivaginal vascular,
nervous, connective and supportive structures,
arousal is the dimension of sexual function that
is more directly affected [247]. Its involvement is
maximized in women treated for cervical cancer
with combined surgery and radiotherapy [254-
257]. Radiotherapy creates a major insult to the
vascular and neurological bases of the lubrication
process, the elasticity of the mucosal and submu-
cosal tissues leading to a dry, retracting, narrow
and rigid «tube», instead of a wet, elastic and
receptive organ. This «radiation vaginitis» may
cause vaginal discharge, spontaneous and contact
bleeding, besides dyspareunia, all of which may
cause anxiety for the similarity to the presenting
symptoms of the cervical cancer, raising threaten-
ing fears of recurrence [258, 259]. Topical and
systemic estrogen replacement therapy (ERT)
may improve the recovery process and is one of
the critical therapeutic steps to be performed even
during radiotherapy, to minimize retraction and
irreversible loss of vaginal elasticity [254]. Clito-
ral responsiveness in the arousal phase may be
impaired after menopause. A chronic hypoandro-
genic condition, particularly in patients who
underwent bilateral ovariectomy or actinic castra-
tion, may be a co-factor in this loss of clitoral sen-
sitivity. Clitoral arousability may be compromised
in vulvar cancer, when vulvectomy is performed
[224], with disruption of the excitement and reso-
lution phase, leading to a two to threefold increase
in the frequency of sexual dysfunction.
A second biologic cause of arousal difficulties is
vaginismus, either primary or, more frequently,
secondary to vaginal dryness and dyspareunia
with secondary defensive spasm of pubococcygeal
muscle [220, 260]. It is present in all patients
after vaginal radiotherapy. Secondary vaginismus
may account for half the cases of postmenopausal
dyspareunia.
The third most reported cause of genital arousal
difficulties is urinary incontinence. Urinary dys-
function symptoms due to estrogen loss and
expected with age may be increased with iatrogen-
ic premature menopause unless appropriate hor-
monal replacement therapy (HRT) is prescribed.
Voiding disorders are more frequent after radical
hysterectomy for cervical cancer [261- 263]. Uri-
nary incontinence may also be a complication
after radical vulvectomy. Women suffering from
stress incontinence secondary to disruption of pel-
vic floor anatomy and function, or urge inconti-
nence secondary to detrusorial instability, may
suffer from occasional loss of urine during sex and
may become inhibited for fear that it would recur
[264]. Appropriate diagnosis and treatment of
incontinence may contribute to a renewed self-
confidence [220].
Vascular problems have recently been claimed as
critical factors in female arousal problems [162].
Women who smoke, who have high levels of cho-
lesterol which increase after the menopause, with
diabetic vasculopathy and/or with severe athero-
sclerosis may have a significant reduction in their
genital arousal and lubrication with increased
vaginal dryness and dyspareunia. Vascular fac -
tors, specifically diabetes and hypertension,
increase vulnerability to radiation damage, e.g.
bladder and rectal injury, and extent of vaginal
retraction [255]. A cancer related decrease in the
540
vasculature to the genitalia from direct tumor
compression of the vessels [258], surgical disrup-
tion and/or vascular fibrosis from radiation thera-
py [177] can also interfere with sexual functio-
ning. With persistent good libido, vascular causes
might have significant clinical improvement with
vasoactive drugs such as sildenafil [38]. Among
GC patients, sildenafil in combination with appro-
priate HRT could significantly reduce dyspareu -
nia except in cases of hormone dependent adeno -
carcinoma where HRT is contraindicated.
The prospective longitudinal study of Ganz et al.
[184] reported 61 and 57% of BC patients respec-
tively had difficulty in becoming sexually aroused
and lubricated. Survivors attain maximum recov-
ery from the physical and psychological trauma of
cancer treatment by one year after surgery, but a
number of aspects of QOL, including rehabilita-
tion and sexuality significantly worsen after that
time, suggesting that biological factors may be
responsible. According to the retrospective study
of Schover et al. [181], BC women who received
chemotherapy reported more vaginal dryness and
dyspareunia. Overall, postmenopausal BC women
were more likely to report vaginal dryness, tight-
ness and genital pain with sexual activity.
Rehabilitation of the pelvic floor as an interven-
tion is usually dismissed, as average recommen -
dations focus most on estrogen cream and pas-
sive dilatation of the vagina [247, 259, 265].
Through contracting, relaxing and gentle pushing
the woman may gain active control of the muscle’s
tonus and opening of the vagina [220]. This repre-
sents a trophic stimulus at the level of the neuro-
muscular plaque, helping maintain a more elastic
and trophic muscle and vaginal sensitivity. Preser-
ving a healthy vaginal space is a critical part of the
recovery of the sexual function after GC diagnosis
and therapy [216, 220]. Local vaginal massage
may also improve vascularization and tissue elas-
ticity, counteracting the retraction secondary to
radiotherapy. Moulds or dilators are frequently
recommended in clinical settings in the treatment
of dyspareunia [247, 259, 265]. They should be
used in conjunction with the previous procedures
to allow for active control over muscle contraction
and health and reduce the perception of the mould
as painful and aggressive. After application of an
estrogenic cream, the dilator may also contribute
to reduction of vaginal retraction and stenosis
secondary to radiotherapy. Lubricants are fre-
quently recommended to ease penetration for both
partners, but the woman should be taught to relax
the levator ani, increase the vaginal opening and
ease penetration. Active perineal muscle contrac -
tions [55] after penetration may contribute to
improvement of pleasure.
Encouraging GC patients to be active in their reco-
very process increases their sense of control over
the situation, reduces passivity that accompanies
depression and improves the patient’s relationship
with the professionals allowing for the best pos-
sible QOL.
c) Orgasm
Orgasm is an «altered state of consciousness»,
with centripetal (inward neural activity from the
genitalia) and centrifugal (outward neural activity
from the brain to the muscular apparatus of the
genitalia) components underlying the experiential
event [40]. Sensory trigger points include the cli-
toris and vagina, clitoral and periurethral glans,
uterus, anal mucosa, and proprioceptive stimuli
from the levator ani and perivaginal muscles. Non
genital trigger points include nipple and sensory
organs, skin first, particularly in certain regions of
the body [40]. Anatomic and functional modifica-
tions of trigger points and areas may deeply affect
the orgasmic potential, particularly in BC patients
and GC patients after radical surgery and/or radio-
therapy.
Motor orgasmic response involves an average of
3 to 8 0.8 second contractions of the «orgasmic
platform», consisting of congested tissues and
muscles of the pelvic floor [189, 266]. The uterus
contracts some 2-4 seconds after the subjects awa-
reness of orgasm [267]. Uterine contractions at
orgasm are possibly the terminator of sexual arou-
sal in women inducing a terminal orgasm, much
like that of men [267].
Orgasmic difficulties may be the endpoint of a
number of biological, motivational-affective and
cognitive factors [189, 266, 220], particularly in
BC survivors. They may arise from decreased
sexual hormones, with secondary libido and arous-
al problems, vaginal and vulvar trophism includ-
ing the clitoris, and pelvic floor status. Many of
these aspects may be altered by surgery, chemo or
radiotherapy. Hypertonic conditions, muscle
541
retraction, increased connectivity and vascular and
neurological damage after radiotherapy may cause
dyspareunia, vaginismus and post-coital cystitis,
impairing the formation of the orgasmic platform
[266], due to the negative association of fear,
anxiety and pain. Hypotonic conditions, leading to
vaginal hypo-anesthesia, especially in patients
treated with simple hysteroannessiectomy, should
be rehabilitated with Kegel exercises [189, 201,
266].
Difficulty in reaching orgasm is reported in 55%
of BC patients in the study by Ganz et al. [184],
with a significant worsening in sexual functioning
over the three year follow-up. In the Schover et al.
[181] study, the ability to reach orgasm through
intercourse was significantly reduced in women
who received chemotherapy, although their ability
to reach orgasm through non coital caressing did
not differ from control women. In GC patients,
difficulty in reaching coital orgasm was reported
in 16.5% of patients at initial diagnosis of cervical
cancer and in 60% of patients one year later [247].
Sexual function worsened significantly and the
repertoire of sexual acts and number of inter-
courses performed decreased.
d) Sexual satisfaction
Sexual satisfaction is both physical and emotion-
al. In the physical dimension, the physiological
resolution phase controls the level of physical
satisfaction and is probably mediated by the oxy -
tocin levels [200]. In the emotional domain, satis-
faction is more dependent on the quality of emo -
tional and physical intimacy and the overall qua -
lity of the relationship. The final satisfaction
depends on the quality of post-coital and/or post-
orgasmic memories that may affect human sexual
function [190] which may explain the positive or
negative feed-back mechanisms that modulate the
circuit of sexual function, both at the physical and
emotional level [190].
Memory of pain, particularly from dyspareunia, in
strongly emotional contexts such as sexuality, is
submitted to «long-term potentiation» processes
[268] mediated mainly by Nerve Growth Factor
(NGF), and will remain long after the resolution of
the etiological cause [220, 269]. This memory or
fear may cause loss of libido and arousal difficul-
ties with reduced lubrication despite restored ana-
tomic and/or endocrinologic conditions. This
negative effect may be responsible for the the long
term significant worsening of sexual function and
satisfaction among BC survivors in studies by
Ganz et al. [184], Schover et al. [181] and Dorval
et al. [185, 186], who reports eight years after pri-
mary treatment, and in GC survivors noted by
Schover [247] and Andersen [224] in a retrospec-
tive study of vulvar cancer patients. Pain and an
overall disappointing sexual experience might also
be responsible for the significantly reduced fre-
quency and type of sex and willingness of women
to initiate sex, although in both Schover’s and
Andersen’s series satisfaction remains intact
across time, possibly due to denial mechanisms
[270] and improved emotional intimacy with the
partner which acts to soften the impact of the spe-
cific sexual limits. Andersen [258] reported that
while frequency of intercourse dropped one year
after treatment, other sexual or affectionate beha-
viours remained constant.
Among vulvar cancer patients a specific disrup-
tion of the physical «resolution» phase was found
[224]: many patients reported «residual tension»
and general sexual dissatisfaction. However, the
patients’ global evaluation of their sexual life was
not significantly different from that of healthy
controls [224].
Women should be encouraged to continue rehabi-
litation training of the pelvic floor for six months
after the clinical resolution of the condition, use a
lubricant to ease penetration and avoid pain, help
a still inadequate physical arousal, and achieve full
recovery.
VI. PHYSIOLOGIC MEASURES OF
FEMALE GENITAL BLOOD FLOW
1. INTRODUCTION
Physiological measures for the assessment of
sexual arousal in women have a relatively short
history in sexology [274]. To date, knowledge of
the underlying physiological mechanisms in-
volved in female sexual arousal is scarce. Most of
the real advances of the past two decades have
come about mainly from the application of
methods used to monitor changes in vaginal vaso-
congestion. These methods vary in terms of vali -
dity, specificity, and practical applicability.
542
2. PHYSIOLOGICAL MEASURES
At present, the two most widely used techniques
to measure vaginal vasocongestion are vaginal
photoplethysmography, first introduced in 1975 by
Sinchak and Geer [275], and the oxygenation-tem-
perature method developed by Levin and Wagner
in 1977 [276] (see [277] for a more extensive
review of available methods).
Levin and Wagner’s device consists of a heated
oxygen electrode fitted into a suction cup that is
attached to the vaginal wall. The electrode is heated
by an electric current to a set temperature. The
amount of electrical power needed to keep the disc
at this temperature can be monitored. Heat is lost
from the disc mainly by conduction through the tis-
sue and tissue fluid to the blood. Increased blood
perfusion under the electrode will increase its heat
loss and a greater power output will therefore be
needed to maintain the electrode at the set tempera-
ture. The changes in power in milliwatts thus be-
come an indirect measure of the changes in blood
flow under the electrode, reflecting the pooling of
blood in the vascular bed. The electrode also
records the amount of oxygen that diffuses across
the skin, reflecting transient changes in blood flow.
The vaginal photoplethysmograph is a menstrual
tampon-sized device, easy to insert and sterilize,
containing incandescent light, or an infrared or
visible red light-emitting diode as a light source,
and a photo transistor as a light detector. The light
source illuminates the blood vessel plexus under
the epithelium of the vaginal wall, and the photo
transistor picks up the light that is backscattered
from the illuminated area [278]. Two signals are
usually obtained from the photo transistor. When
the signal is coupled to a Direct Current amplifier,
slowly developing changes in vaginal blood vol-
ume (VBV) are observed, which are thought to
reflect pooling of blood in the vaginal tissue. With
AC coupling, a measure of vaginal pulse ampli -
tude (VPA) is obtained, reflecting phasic changes
in vaginal engorgement with each heart beat. The
greater the blood content of the vaginal tissue, the
greater the signal’s amplitude. VPA has been
shown to have excellent divergent and convergent
validity and is a much more sensitive and reliable
measure than VBV [279]. For a representative
example of VPA recording during neutral baseline
and erotic film, see Figure 9.
Figure 9: A representative trace of vaginal pulse amplitude during a one-minute baseline recording and one minute of ero -
tic film exposure.
Each technique has its advantages and limita -
tions. [160]. For instance, the oxygenation-tempe-
rature measure can be calibrated in terms of abso-
lute blood flow and is relatively free of movement
artifacts. The reliability of the signal does not
seem to be compromised by masturbation, clitoral
vibration, and orgasm. Disadvantages are its
expense, the fact that the electrode should not be
applied for very long periods of recording to pro-
tect the vagina from heat damage, and that the
device needs to be attached by the experimenter.
The vaginal photoplethysmograph does not deter-
mine absolute levels of blood flow and is not
reliable during and after orgasm [275], but sur-
passes the other measure with respect to practical
applicability. It can be inserted by the subject her-
self and is well tolerated, thus diminishing the
intrusiveness of the measure and allowing for long
recording periods. With the right statistical design,
that is a one-session within-subjects design or a
placebo-controlled cross-over design in the case of
pharmacological studies, the data obtained from
vaginal photoplethysmography can be readily
interpreted.
A relatively new and promising technique is
duplex ultrasonography adapted for measuring
vaginal and clitoral blood flow. Several studies
have used this techniques in the past including;
Lavoisier et al. who reported on the use of Doppler
ultrasonography to measure blood velocity in the
clitoral cavernosal artery and to record changes in
flow associated with intravaginal pressure
changes; and Sarrel who described the use of laser
Doppler velocimetry for measurement of vaginal
blood flow in the evaluation of the effects of estro-
gen compared with estrogen-androgen treatment
543
in post menopausal women [280]. Such studies
report that vaginal blood flow is an objective mea -
sure of sexual function and that laser Doppler
velocimetry proved readily adaptable for measure-
ment of vaginal blood flow.
The use of Duplex Doppler ultrasonography to
assess the changes in female genital hemodyna-
mics occurs during sexual arousal. This technique
provides continuous, real time imaging of anato-
mic, as well as vasocongestive components of the
female sexual response. In addition, it records
blood velocity in absolute units; centimeters per
second (cm/s). Clitoral, labial (vestibular bulb),
urethral, iliac, uterine and vaginal peak systolic
velocity and end diastolic velocity are able to be
measured using Duplex Doppler ultrasonography.
The probe (12 mHz) may be used externally to
measure right and left labial, urethral and clitoral
cavernosal arterial blood flow velocity. A transva-
ginal probe may be used to measure right and left
vaginal, iliac and uterine arterial blood flow. All
measurements are first recorded at baseline and
following sexual stimulation, with a 15-minute
standardized erotic video on a 3-D surround sound
headset (I.O. Display Systems and a vibrato.
Visual and vibratory stimulation are maintained
during the majority of the ultrasound exam, except
where the vibratory stimulation interfered with
certain measurements (clitoral and right and left
labial blood flow velocity values).
Sexual arousal results in an increased blood flow
to the hypogastric-pudendal arterial bed, an
important indicator of sexual arousal in women in
the early stages of sexual arousal. This increased
pelvic blood flow leads to increased perfusion of
the sexual organs, specifically the vagina, clitoris
and labia. Duplex Doppler ultrasonography is able
to document significant increases in genital blood
flow velocity to these structures with sexual sti-
mulation. Following sexual stimulation, the phe-
nomenon of genital tumescence is able to be ade-
quately demonstrated on ultrasound, anatomically
by increased venous pooling, and physiologically
by increased end diastolic velocities in the genital
arteries.
Practical applicability of measuring blood flow in
the genital arteries before and after sexual stimula-
tion is not a trivial issue. Studies measuring sexual
responses in the vagina are limited as it is, with its
restriction to solo sexual activities and its con-
trived context [161, 277]. So it seems crucial to
use a measure and a procedure that most women
would be willing to undergo, respecting a
woman’s privacy, allowing her to become sexual-
ly aroused in the laboratory. Balancing validity
and applicability concerns, we feel that at present,
vaginal photoplethysmography is the method of
choice.
3. ORGANIC ETIOLOGY
Recently, investigators interested in the pathophy-
siology of female sexual dysfunction have pro-
posed that in some women, female sexual arousal
problems are associated with vascular and clitoral
erectile insufficiency [67]. These authors suggest
that future management strategies for women with
sexual arousal problems should be aimed at asses-
sing vasculogenic sexual dysfunction, especially if
these women are postmenopausal. Of course, it is
highly unlikely that organic factors in female
sexual dysfunction are absent. We therefore
believe that (psycho)physiological assessment
should be more routinely implemented as a dia-
gnostic tool in post- as well as premenopausal
women. We nevertheless have to be careful not to
oversimplify and take any vascular irregularity as
the organic factor causing the sexual difficulties.
As will be outlined below, even in postmenopau-
sal women reduced vaginal vasocongestion is not
always indicative of sexual dysfunction.
4. DIFFERENTIAL DIAGNOSIS
How well do the available vaginal vasocongestion
measures differentiate between women with and
544
without sexual problems? The answer to this ques-
tion is that we don’t know yet. Only seven studies
exist to date that assessed differences in vaginal
response between women with and without
sexual problems, all using vaginal photoplethys-
mography. Three studied sexual responses to ero-
tic stimulus materials in low arousal or nonorgas-
mic women [281- 283], two studies combined
women with different sexual dysfunctions into one
group [284, 285], one studied low desire and anor-
gasmic women [286], and the last study examined
sexual responses of women with dyspareunia to
oral sex and intercourse scenes [287]. It is difficult
to compare these studies and make sense of the
differential findings, because the nature of the
sexual problems varied between and even within
studies, different erotic stimuli were used, and
studies differed with respect to the way vaginal
responses were measured (using either VPA or
VBV or both) and analyzed.
The Meston and Gorzalka [286] study was the first
to compare different diagnostic categories, thus
making the important step toward differentiating
patterns according to the presenting sexual prob-
lem. Wouda et al [287] were the first to study vagi-
nal responses of women with sexual problems to
sexual stimuli differing in content. Eighteen
women with dyspareunia participated. In this
study, a neutral baseline period was followed by
an erotic scene depicting fellatio and cunnilingus.
Then the women were subjected to a return-to-
baseline period followed by a cunnilingus scene
and an intercourse scene. There were no differ-
ences in VPA between the women with dyspareu-
nia and a control group of women without sexual
problems in the first four phases of the experi-
ment. But during the intercourse scene responses
of the control group further increased while in the
dyspareunia group responses declined. There were
no differences in subjectively reported sexual
arousal to the last scene. These results suggest a
number of things. First, differences in vaginal
vasocongestion response may be highly situa -
tion- or stimulus specific. Only during the inter-
course scene VPA was significantly lower in the
clinical group. Second, genital measures and sub -
jective feelings did not correspond.
5. FEELINGS AND STIMULI
A large number of studies have addressed the cri-
tical issue of subjective feelings and physiologic
responses. In some studies positive correlations
between VPA or VBV and subjective feelings of
sexual arousal were reported, but the majority fai -
led to find a relationship between genital and
subjective sexual arousal [274, 288]. This issue
seems to be unique for women. In men without
sexual problems correlations between penile cir-
cumference change and subjective report are
usually fairly high [274].
In recent years we studied this phenomenon more
closely. We consistently found VPA to occur fairly
automatically in response to an explicit erotic sti-
mulus such as erotic film [288]. That is, vaginal
vasocongestion increases within seconds after the
onset of the stimulus (cf. Figure 4), without most
women being aware of this happening, even when
the stimulus is negatively evaluated or induces lit-
tle or no feelings of sexual arousal. Women do not
simply attend to genital changes when assessing
their subjective feeling state. Their subjective
experience of sexual arousal is determined both by
feedback from their genitals (which becomes more
important as genital arousal increases) and by the
intensity and appraisal of the sexual stimulus.
Therefore, genital measures should always be
used concurrent with subjective measures of
sexual arousal.
These findings suggest an important role for the
sexual stimulus in psychophysiological studies.
Not only is blood flow directly dependent upon
the intensity of the sexual stimulus, subjective fee-
lings depend on the intensity and appraisal of the
sexual stimulus as well. And what is intense in
terms of blood flow may differ from what is
intense in terms of subjective sexual arousal. In
order to meaningfully compare clinical groups
within and between labs, some level of standardi -
zation with respect to the type of erotic stimulus
seems essential.
Finally, measuring vaginal vasocongestion in the
absence of a sexual stimulus may lead to false
conclusions. For instance, a recent study demon-
strated an estrogen related difference in VPA be-
tween premenopausal and untreated postmeno-
pausal women during initial baseline, before any
erotic stimulation had taken place [202]. During
subsequent erotic stimulation however, this diffe-
rence in VPA between groups disappeared, sug-
545
gesting that inadequate erotic stimulation may be
more important in sexual arousal disorders than a
vasculogenic dysfunction related to menopause
[67]. This study demonstrates that depending on
whether one measures VPA without or with sexual
stimulation, one could either decide for or against
organic factors contributing to arousal problems.
Furthermore, these findings again point to the
importance of measuring genital function in a
sexually stimulated state, and to devise physiolo-
gical measures that generate valid data in a situa-
tion that allows women to become sexually stimu-
lated.
6. SEX AND THE BRAIN
The recent focus of the medical literature on the
peripheral components of sexual response, i.e.
erection and vaginal vasocongestion, ignores the
fact that genital response is dependent on com-
mands from the central nervous system [76]. For
instance, the importance of stimulus features and
the apparent dissociation between genital and sub-
jective response suggest a significant contribution
of central processes to sexual arousal. The amyg-
dala play a crucial role in mediating between
multi-sensory inputs and their emotional and moti-
vational significance [289]. These influences are
modulated by prefrontal processes where stimulus
features are matched with memories of previous
experience [290].
There is evidence that the amygdala are directly
linked with autonomic motor output, implying an
automatic pathway between sensory input and re-
sponse. In addition, there is a second pathway
through projections from the amygdala to the
medio-dorsal thalamic nucleus, and from there to
the prefrontal cortex. This pathway eventually
enables subjective awareness of sexual excitement
and (conscious) sexual action. The dissociation be-
tween genital and subjective measures of sexual
excitement may thus be explained by the overriding
influence of central, possibly prefrontal, processing.
Whether there is a gender difference in neural pro-
cessing that may explain the difference in associa-
tion between genital and subjective sexual response
for women and men could become clear in future
functional brain imaging studies.
7. PHARMACOLOGICAL INTERVENTIONS
Given the above observations, what would be the
minimal requirements for a psychophysiological
laboratory study designed to test the efficacy of a
pharmacological agent? First and foremost, genital
responses should be measured under sexual stimu-
lus conditions, because they determine the intensity
of both VPAand subjective sexual arousal. By now
we know quite well which stimuli yield, on avera-
ge, the highest levels of VPA in functional women,
without causing movement artifacts [288]. This
means we can reliably predict and control VPA
levels by means of the sexual stimuli that are pre-
sented. Another quite obvious reason for measuring
VPA to a sexual stimulus is that the new generation
of vasoactive drugs (e.g.. sildenafil) work under
sexual conditions only. Second, a physiological
measure is needed and we have argued that VPA is
the best measure that is now available, even though
it is far from perfect. Such a measure is essential
simply to prove that the pharmacological agent
indeed enhances blood content in the vaginal wall
during sexual stimulation relative to placebo. And
third, it is necessary to assess subjective sexual
arousal concurrently, preferrably in a variety of
ways, because subjective sexual arousal is not only
dependent upon VPAintensity but also on the eval-
uation of the sexual stimulus.
Evidently, it is relatively easy to control for the
sexual stimulus in the laboratory. It is far more dif-
ficult to control sexual stimulation in the real
world. We will finish by speculating a bit on ways
in which to assess the quality and intensity of
sexual stimulation outside the laboratory, again in
the case of a study designed to test the efficacy of
a pharmacological agent.
What seems of importance is knowing to what
extent the sexual stimulation is adequate for the
subject who takes the drug. You need to get some
grip on the quality and intensity of the sexual sti-
mulation. This is quite difficult, because in theory
anything that has positive sexual meaning for an
individual can be sexually stimulating. By way of
example, let us limit ourselves to relationship fac-
tors. A partner’s sexual attractivity seems related
to relationship duration. We know that in long
term relationships, habituation occurs [291]. Pos-
sibly, in a new relationship a partner’s looks are
more important than his or her sexual skills, such
as timing, intensity of stimulation, and so on. In
ongoing relationships sexual skills probably be-
come increasingly important. So we need to try
and measure both partner-attractivity and partner-
546
skills. We would predict that a pharmacological
agent would add little to sexual arousal when
someone rates his or her partner low in sexual
attractivity and sexual skills.
VII. CONCLUSIONS
Female sexual dysfunction is a common condition,
with population estimates ranging from 22% to
43% [17, 21, 22]. Population estimates of the pre-
valence of dyspareunia, a sexual dysfunction that
causes many women to seek medical attention,
ranges from 3% to 15%; estimates from clinic or
other selected samples are generally higher (12%
to 33%). Epidemiologists, clinicians, therapists,
and physiologists should work together to formu-
late standard definitions that can be applied to
large population groups to obtain reliable and
valid estimates of the prevalence and incidence of
various types of female sexual dysfunction in the
community. In this way, the true burden of these
disorders can be established.
Little is known about risk factors for female sexual
dysfunction or changes over the life span (natural
history). Longitudinal data from representative
samples are needed for this. A thorough epidemio-
logic examination of suspected risk factors for
well-defined categories of sexual dysfunction can
provide help in identifying etiologic factors, an
important first step in planning treatment and pre-
vention efforts.
There remain large gaps in our understanding of
the central nervous control of female sexual func-
tion. This problem is especially acute with regard
to higher centers. Most of the animal work relates
to receptive behavior in female animals and very
little on the control of genital responses. There is
considerably more research on these issues in
males. It is likely that there will be significant
homology between males and females in the
control of sexual function. However, significant
differences may also be present, especially in fore-
brain regions. Therefore, it is unwise to assume a
complete correspondence between the male and
female and to try to construct a neural wiring dia-
gram of the female based largely on research in the
male. Obviously, there is a tremendous need for
more research in this area.
Breast and gynecologic cancer may affect female
sexual function, female sexual response and
couple relationship in a complex way, involving
both psychosocial and biological factors. The
overall quality of life of BC survivors is positive in
an average of 70 - 80% of cases, except in the
areas of sexual function and satisfaction [181,
184-186, 219]. GC survivors, on average, show a
50% reduction of sexual activity, both in quantity
and physical satisfaction. There may be a sub-
group of cancer survivors whose quality of life is
more seriously affected by the cancer treatment
[224, 247, 269, 272]. Moreover, sex hormones
contribute to the biological femininity, the basic
biology of sexual function and the biological
signals, leading to sexual attraction and affective
bonding that reverberates in the couple relation-
ship. Their action in human female sexuality is
strongly context-dependent [273].
Traditional academic medical training usually
overlooks the complex interplay of biological,
psychoemotional and social factors in human
sexuality, especially in female sexual identity and
function. Based on a review of existing research,
there is a need for prospective longitudinal beha-
vioral diary-based studies on the impact of cancer
treatment on sexual function with regards to fre-
quency of activity; desire, arousal, pain, orgasm
and satisfaction; changes in practices; quality of
oral sex and salivary lubrication, types of genital
caressing, positions for intercourse, feelings about
body appearance and desirability, quality of mari-
tal relationship, focusing on both physiopathology
and behaviour [209, 229, 232]. Age, lymphedema,
side effects of surgery, chemo and radiotherapy,
pregnancy related problems during and after
breast cancer, infertility and iatrogenic premature
menopause with its cohort of damage secondary to
the chronic loss of estrogen should all be reeval-
uated. A strong, biologically focused line of
research must be pursued to guarantee breast and
gynecologic cancer patients a medically-oriented
diagnosis of their sexual problems followed by
competent, satisfying treatment.
Presumably any measure would suffice that tries
to assess the extent to which a sexual interaction or
solo sexual activity such as masturbation, sexual
fantasy or daydreams, yield adequate sexual sti-
mulation in the opinion of the individual. This
may not only help us better understand the under-
lying mechanisms of sexual arousal or the mode of
547
action of new pharmacological agents, but also
enable us to better differentiate responders from
non-responders.
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______________________
Committee 15

Priapism

Chairman
W. S TACKL,

Members
P. BONDIL,
R. CARTMILL,
D. K NOLL,
E.S. PESCATORI

557
 CONTENTS

I. INTRODUCTION IV. MEDICAL TREATMENT

1. VENOUS OR LOW-FLOW OR ISCHEMIC

II. CLASSIFICATION PRIAPISM
2. ARTERIAL OR HIGH-FLOW OR NON-
1. VENOUS OR LOW-FLOW OR ISCHEMIC
ISCHEMIC PRIAPISM
PRIAPISM
2. ARTERIAL OR HIGH-FLOW OR NON- 3. RECURRENT PRIAPISM/PROLONGED
ISCHEMIC PRIAPISM ERECTION
3. RECURRENT PRIAPISM
V SURGICAL TREATMENT
III DIAGNOSIS

1. HISTORY REFERENCES
2. EXAMINATION
3. INVESTIGATIONS

558
 Priapism
W. STACKL,
P. BONDIL, R. C ARTMILL, D. K NOLL, E.S. P ESCATORI
I. INTRODUCTION
Priapism is an involuntary, non physiologic, usual-
ly painful prolonged erection that does not result
from sexual desire. The corpus spongiosum and
glans are not affected. It is not relieved by ejacu-
lation and may ironically result in impotence.
Priapism is a rare condition that can occur in any
age. In younger patients sickle cell disease is the
most common cause, whereas in older men most
priapism is due to intracavernous injection of
vasoactive drugs [1].
II. CLASSIFICATION
Priapism may be defined as a pathological erec-
tion provoked by hemodynamic anomalies (Fig. 1)
[2]. These anomalies may arise from several ori-
gins involving either the arterial or above all veno-
occlusive component. Thus, priapism is common-
ly classified as venous (low-flow or ischemic) and
arterial (non-ischemic, high-flow). This hemody-
namic definition eliminates the false priapisms, in
particular, many of the malignant priapisms (the
”erection” is a priapistic appearance only due to an
infiltration of penile tissue by the cancer without
any hemodynamic anomalies).
1. VENOUS OR LOW-FLOW OR ISCHEMIC
PRIAPISM
a) Pathophysiology
Venous priapism reflects a failure of the cavernous
559
detumescence mechanism leading to an obstruc-
tion of venous outflow (Fig. 2). Rarely, initial
impairment of venous outflow results from an obs-
truction of cavernous drainage outside of the
cavernous bodies. Any penile and / or perineal
compression whatever its origin (inflammation,
infection, tumor, trauma...) of the pericavernous
veins may slow down the cavernous venous out-
flow and potentially induces a veno-occlusive
priapism during the occurrence of a physiological
erection (nocturnal...).
However the most frequent initial impairment
occurs within the corpora cavernosa by two main
mechanisms:
• Hematological changes of cavernous blood
Physiologically, during the rigidity phase, the
cavernous venous outflow is reduced because ana-
tomically the cavernous body acts like a kind of
funnel for the venous outflow. If the viscosity of
the intracavernous blood increases, the cavernous
drainage will decrease at the same time. Thus, any
disease increasing the blood hyperviscosity may
provoke a veno-occlusive priapism by slowing
down the cavernous venous outflow. The contrac-
tion of the smooth erectile tissue draining off the
blood of the corpora cavernosa is present but inef-
ficient.
The most typical cause is sickle cell anemia. The
increase of the viscosity of the intracavernous
blood results from the clotting of the intracaver-
nous blood sickle red cells [3]. Hematological
malignancies with hypercellularity (especially leu-
kemia and thrombocytemia) and hyperlipidic
parenteral nutrition are the main causes inducing
priapism by the same mechanism [4].
• Pathologic prolonged relaxation of cavernous
smooth muscle
The vascular lacunar spaces cannot be emptied
because the re-contraction of the cavernous smoo-
th muscle tissue is absent preventing the de-acti-
vation of the veno-occlusive mechanism necessa-
ry for the drainage of blood from the cavernous
bodies. Physiologically, it has been demonstrated
that the erectile smooth muscle tissue recontrac-
tion is under both local (neuronal and endothelial)
and spinal or central control. So, any impairment
of the contractile ability of the smooth muscle
cavernous tissue leads to a temporary or definitive
”paralysis” [2].
These muscular ”paralyses” resulting from several
causes still are not completely understood. The
most typical cause is the prolonged erection indu-
ced by intracavernous erectogenic drugs. Overdo-
sage of the drug saturates the smooth myorelaxant
receptors provoking a persistent smooth myore-
laxation. The duration of the blockage depends on
both the saturation of drug receptor and the drug’s
pharmacological half-life. This smooth muscle
paralysis likely results from several causes acting
at the level of the erectile peripheral and central
nervous centers either by stimulation of inductor
centers or by inhibition of inhibitor centers whate-
ver be the pathological stimulation (drug, hormo-
nal, tumor, inflammation...) [5].
Venous priapism is the most common form of
priapism and also the most dangerous because it is
a real acute ischemia of the cavernous bodies. Its
Figure 1: Priapism hemodynamic definition
560
seriousness is directly correlated to both the seve-
rity of the obstruction and the duration of corpora
cavernosa drainage blockage, themselves related
to the priapistic etiology.
In fact, the cavernous venous outflow blockage
may be temporary or definitive, partial or comple-
te. These changes depend on two parameters:
Etiology of the priapism:
In the case of ”hematological” priapism there is
still a little venous outflow explaining a better pro-
gnosis. For this reason, the hematological pria-
pism is often less dangerous. For example, the
sickle cell priapism is often characterized by the
occurrence of previous prolonged erections resol-
ving frequently and spontaneously.
Delay of developoment:
The main danger of the low-flow priapism is the
potential occurrence of an acute ischemia of
cavernous bodies. For this major reason, it is a real
urological emergency. It has been demonstrated in
prolonged pharmacological erections that a caver-
nous hypoxia (mainly acidosis) begins after 4
hours and increases over 24 hours. With time, pO2
and pH of the trapped blood decrease reaching
levels close to anoxia (p02 0-10 mmHg) and seve-
re acidosis (pH about 6.6). Penile pain is a signifi-
cant clinical symptom of tissue hypoxia [6].
Thus, a vicious physiopathological circle (Fig. 3)
occurs self-maintaining the priapism that become
autonomous. The hypoxia as well as the acidosis
cause loss of the contractility of the cavernous
smooth muscle impairing the venous stasis. At the
Figure 2: Pathophysiology venous priapism, mechanisms of cavenous detumescence anomalies

Figure 3 : Pathophysiological mechanisms self-maintaining the venous priapism

561
Table 1: Main causes of venous priapism
1. HEMATOLOGICALCAUSES
HEMATOLOGIC DISORDERS sickle cell disease
thrombocythemia
leukemia
erythrocytosis
thalassemia
fat emboli
IATROGENIC hyperlipidic parenteral
nutrition
MISCELLANEOUS inflammation, infection,
metabolic causes...
2. PATHOLOGIC PROLONGED RELAXATION OF
CAVERNOUS SMOOTH MUSLE
DRUGS anticoagulant
antihypertensive
antidepressant
psychotrophic
androgen (testosterone)
erectogenic (intracavernous
injections and oral)
alphablocker
parasympathometics
cocaine, alcohol
NEUROLOGIC DISORDERS spinal cord lesions
cauda equina compression
autonomic neuropathy
spinal stenosis
INFECTION OR TOSIX rabies, scorpion sting,
malaria
3. IDIOPATHIC
same time, histological changes occur with first
edema of cavernous tissue, then after the 24th
hour, necrosis of cavernous smooth muscle cells
leading to a fibrosis responsible for impotence.
For these reasons, after the 24th hour, the risk of
autonomisation of the priapism becomes major
even if the pathological stimulation stops.
b) Causes
Since the first report of a priapism by Callaway in
1824, a long list of its causes has been developed
(Table 1).
In the past many cases of priapism were classified
562
as idiopathic. The physiopathologic mechanisms
of priapism allow to differentiate priapisms related
either to hematological changes or to ”pathologic
prolonged relaxation” of cavernous smooth
muscle. However, the precise etiological diagnosis
is still often difficult for three reasons:
1) a ”trial-like” investigation is necessary,
2) a multifactorial etiology is a frequent condition
for the initiation of priapism, exactly as for
erectile insufficiency. Thus, the association of
alcohol abuse, use of drugs and hemorrheologi-
cal abnormal conditions are often present in
patients suffering from priapism. The addition
of these favoring factors appears as a stimula-
tion factor.
3) many priapisms still must be classified as idio-
pathic in the absence of evident cause.
• Causes of hematological priapism:
Any pathological condition inducing a blood
hyperviscosity may induce a venous priapism.
The most classical and frequent cause in the
world is sickle-cell disorder particularly in chil-
dren. The most affected are the patients with
homozygous forms who present in about 40 % of
cases with previous recurrent prolonged erection
phases lasting 2 to 6 hours. Hypercellularity
conditions (as leukemia, thrombocytemia, thalas-
semia, erythrocytosis) fat emboli or hyperlipidic
parenteral nutrition are other causes of hematolo-
gical priapism.
• Causes of pathologic prolonged relaxation of
cavernous smooth muscle:
Presently, it is difficult to classify precisely the
causes of this type of priapism. Many classical
causes as neurological, iatrogenic, neoplastic,
infectious, toxic, medications may induce this type
of priapism by (spinal and / or central) stimulation
of erectogenic centers and / or inhibition of anti-
erectogenic centers.
The most frequently accused drugs are antidepres-
sants, antipsychotics (as clozapine), tranquilizers,
antianxiety agents, psychotropics (as chlorproma-
zine), alpha-adrenergic blockers (as prazosin) and
recreational drugs (as cocaine or alcohol) [7].
The recent progress in our understanding of phy-
siology has shown that any drug having the follo-
wing pharmacological effect(s): alpha-adrenergic
blockade, serotoninergic agonist, dopamine ago-
nist, para-sympathetic agonist, may induce a pria-
pism by central and / or peripheral action.
The most frequent and demonstrative the pria-
pism is that induced by erectogenic drug used
either by intracavernous (papaverine chlorydrate,
prostaglandine E1, moxisylite, phentolamine...)
or less often by oral route (trazodone, testostero-
ne, sildenafil...). In most of the cases, the pria-
pism results from an over-dosage or inadequate
consideration of contraindications. Hormones as
testosterone or gonadotropin-releasing hormone
have also been incriminated, likely owing to their
erectogenic action. The mechanisms of anticoa-
gulants (heparin, coumarin) are still little known.
Very likely, the blockage of the cavernous smoo-
th muscle sponge may result from different ori-
gins (neurological, metabolic, inflammatory,
traumatic...). For example, neurological condi-
tions as lumbar stenosis, spinal cord injury or
herniated discs probably either enhance the relea-
se of erection-inducing neurotransmitters from
the parasympathetic nerves or interfere with
tonic discharge from the sympathetic nervous
system.
2. ARTERIAL OR HIGH-FLOW OR NON-
ISCHEMIC PRIAPISM
• Pathophysiology
Following a traumatic (or surgically induced)
defect in the integrity of the cavernous artery,
unregulated arterial inflow bypasses the protecti-
ve, high resistant helicine arteries and enters the
lacunar spaces directly. The lacunar spaces dis-
tend, but compression of the subtunical venous
plexus against the tunica albuginea is incomplete,
due to the absence of neurological stimulation.
Therefore corporal venous outflow is not restric-
ted, thereby preventing pooling of lacunar blood,
obstruction of arterial inflow, ischemia, and pain
to occuring. The net hemodynamic result is a high
inflow, high outflow prolonged penile erection [8
-11].
563
The frequently observed delayed clinical onset,
following the offending event, has been hypothe-
sized to be due to immediate vasospasm and plate-
let aggregation at the site of cavernosal artery lace-
ration. During subsequent nocturnal or sexual
erections, dilatation and stretching of the arterial
wall might displace the unorganized clot and thus
allow direct bleeding into the lacunar spaces, with
the creation of a cavernosinusoidal fistula [8].
The perpetuation of the priapistic state has been
proposed to rely on the generated shear stress from
the continuous high inflow state that would relea-
se endothelium-derived factors, as nitric oxide and
prostacyclin. These substances would act both by
dilating the lacerated cavernosal artery and inhibi-
ting platelet aggregation [8].
Few cases of high-flow priapism without evidence
of cavernosal artery laceration, often developing
after veno-occlusive low flow priapism refractory
to conventional treatments, have been reported [6,
12-15]. This high-flow state characteristically
responds to pudendal artery embolization. It has
been recently proposed that these cases may repre-
sent either a variant of traumatic high flow pria-
pism, or the pathophysiology of recurrent idiopa-
thic priapism. According to the latter hypothesis,
patients with veno-occlusive priapism in whom
conservative treatment fail, should be considered
in the differential diagnosis with high flow states
[15], besides with recurrent low flow priapism as
a sequel a of priapism [16].
3. RECURRENT PRIAPISM
Recurrent, chronic intermittent or stuttering pria-
pism is defined as multiple, brief (less than 3 hour)
episodes several times a week for 4 weeks or
more. It is a rare condition that occurs often in
patients with sickle trait of disease. Its mechanism
is still unknown [17]. It is necessary to look for
hemorrheological anomalies or pharmacological
side-effect of drugs. Dysfunction of spinal or cen-
tral mechanism are also likely partially respon-
sible. This phenomenon has received almost no
attention in the literature. Neither the prevalence,
the ultimate outcome, nor its conversion rate to
low-flow priapism is know.

III DIAGNOSIS
It is extremely important to distinguish low-flow
priapism from high-flow. This is achieved by:
1. H ISTORY
a) Drugs
Drug use would account for up to 80 % of the inci-
dents of priapism. Oral medication for hyperten-
sion, anti-depressant, anti-coagulants would be the
main oral therapies associated with priapism [19,
44]. The anti-hypertensives probably cause pria-
pism because of the alpha adrenergic blocking
function. This may cause some relaxation of the
smooth muscle of the cavernous tissue although
this would not be the major route by which smoo-
th muscle relaxation is normally achieved for nor-
mal erectile function [6].
Tricyclic anti-depressants are probably associated
with priapism through an alpha-adrenergic bloc-
king function acting peripherally. The phenothia-
zines may act centrally blocking the D1 receptor
or again as an alphagrenergic blocking effect
within the cavernous tissue [18].
Anticoagulants commonly used to maintain shunts
in dialysis units provide a recognized source of
priapism. The mechanism of the priapism is not
known but certainly the use of low dose heparin
has been recognized as an associated factor with
the incidence of priapism [19].
Social drugs (legal and illegal) have also been
associated with priapism. Alcohol, marijuana and
cocaine have all been associated with priapism.
Again the mechanism of the priapism is not clear
[6].
The most common cause of prolonged erections is
the use of intracavernosal injection therapy for
erectile dysfunction. The incidence of prolonged
erection is dose related as well as related to the
specific agent injected. The problem is uncommon
with prostaglandin injection but certainly is well
recognized using papaverine and phentolamine.
Such agents should be used with care when used
for diagnostic purposes or when being injected
into a patient suspected of psychogenic or neuro-
genic erectile dysfunction [20].
564
b) Trauma
Trauma to the perineum is generally the cause of a
high flow priapism. The traumatic event characte-
ristically consists in a straddle injury producing
perineal pain and hematoma: cavernous artery
laceration results in fact from the crush-like injury
between the object striking the perineum and the
ischiopubic ramus. Less frequently intracaverno-
sal self-injection needle injury and penile trauma
have been reported. Of note, high flow priapism
has been a frequent complication of early penile
revascularization procedures, where the inferior
epigastric artery was directly anastomosed to a
window in the tunica albuginea [8, 10,13].
c) Time factor
The length of time of the priapism is important
when low flow priapism is suspected. The ische-
mia of low flow priapism will cause replacement
of intracavernosal smooth muscle with collagen
tissue. This pathological change is directly related
to the severity of erectile dysfunction [6].
d) Pain
Low-flow priapism is generally painful and there-
fore is a feature of the history to help establish the
diagnosis.
e) Quality of previous erection
This clearly has some prognostic importance in
predicting the likely quality of erections following
treatment of the presenting priapism.
f) Malignancy
While this is a rare cause of priapism, primary
tumors of the urethra and penis or metastatic
tumors can cause obstruction of the venous out-
flow from the cavernous tissue and therefore esta-
blish a mechanism for low-flow priapism [21].
g) Hemoglobin abnormalities
The importance of such abnormalities will vary in
different parts of the world where there is a racial
prejudice disposition to abnormalities such as
sickle cell anemia and thalassemia. Sickle cell
anemia is the most common cause of pediatric
priapism. Hematological disorders all predispose
to a low flow priapism. The hematological disor-
der causes white cell or platelet sludging in the
sinusoids. Recurrent episodes of priapism have
also been described in patients with hematological
disorders.
h) Metabolic diseases
This is a rare cause of priapism but metabolic
diseases associated or described in association
with priapism include amyloidosis, gout, diabetes,
nephrotic syndrome and renal failure [7].
2. EXAMINATION
The degree of rigidity of the penis is important in
differentiating high and low-flow priapism [12]. In
general a low-flow priapism causes a hard erection
but a normal corpus spongiosum so that the glans
penis remains soft except in very rare cases of tri-
corporal priapism [22]. Tenderness and loss of elas-
ticity of the penis are further points supporting the
diagnosis of a low-flow priapism. In high-flow pria-
pism the clinical picture is characterized by a spec-
trum of persistent erectile status, that ranges from
tumescence to full erection, although the most com-
mon finding is a partial erection. If the erection is
partial, it can be improved with sexual or manual
stimulation, but it seldom reaches full rigidity. Inva-
riably, the erection is painless and the glans is soft.
Color-doppler ultrasonography has recently
emerged as the mainstay diagnostic evaluation of
high flow priapism, confining the role of selecti-
ve internal pudendal arteriography to arterial
priapism treatment, by means of selective embo-
lization [11]. Arteriography shows a typical uni-
lateral cavernous artery blush, consistent with
extravasation of contrast material from the lace-
rated cavernous artery deep into the cavernosal
erectile tissue (Fig. 5).
When compared to selective internal pudendal
arteriography, color-doppler ultrasonography
exhibits a 100 % sensitivity and a 73 % specifici-
ty [11]. Considering the unlikelihood that dop-
pler ultrasound may record turbulence in the
absence of block inflow through the lacerated
cavernous artery, ultrasonography appears more
accurate than arteriography in predicting arterial
priapism [11].

3. INVESTIGATIONS
a) Cavernosal blood
Most important is the aspiration of cavernosal
blood with blood gas analysis (if available). Dark
hypoxic blood (p02 <30 mmHg and pCo2 >70
mmHg) suggests low flow and bright red, normal
blood gases respectively suggests high-flow pria-
pism [23].
b) Color doppler ultrasonography
Figure 4: Color-Doppler imaging in a patient with high-
Doppler ultrasonography at 3 and 9 o’clock posi- flow priapism demonstrates the site of lesion
tion detects strong pulsation of the cavernosal
arteries [8], suggesting high-flow priapism (Fig.
4). The color-doppler probe must be placed in the
perineum, i.e. in the typical location of the caver-
nous artery laceration. In the rare cases of lacera-
tion at the shaft level, the probe should be placed
along the pendulous penis. The characteristic fin-
ding of color-doppler is the detection of a focal,
pseudoaneurysmatic area of high flow turbulence,
along the affected cavernous artery.
The above findings of doppler ultrasound, corporal
aspiration and blood gas analysis do not strictly rule
out veno-occlusive priapism, as they are commonly
found early in prolonged erections following intra- Figure 5: Selective internal pudendal arteriogram shows
cavernosal pharmacological injections. intracorporal contrast material extravasation arising from
deep penile artery.

565
Moreover, in the rare cases of high flow priapism Table 2: Proven methods of using alpha adrenergic agents
without cavernosinusoidal fistula, color-doppler
ultrasonography can detect the high flow states of DRUG PREPARATION METHOD
the cavernosal arteries [15], where arteriography OFUSE
cannot. Color-doppler is presently the gold-stan- PHENYLEPHRINE 10 mg = 1ml + Inject
dard also of follow-up, where it has been shown (INJECTION) 9 ml saline 0.2-0.4ml
to be superior to clinical examination in detecting or 6 mg = 0.6 ml + Inject 1 ml
recurrence of the arteriosinusoidal fistula [11]. 30 ml Saline
Moreover, after treatment by embolization with (-> 1 ml = 200 µg)
absorbable substances, color-doppler can docu- ETILEFRINE 10 mg = 1 ml + Inject 2 ml
ment cavernosal artery recanalization, with (INJECTION) 9 ml Saline
return of antegrade flow. Further advantages of NOREPINEPHRINE 1 ml 1:1000 in Aspirate,
color-doppler over pudendal arteriography are (IRRIGATION) 1000 ml Saline Inject 25 ml
given by absence of invasivity, easy repeatability, of solution
wide availability, and cost-effectiveness. or
2 ml 1:1000 in Inject 5 ml
500 ml 5 % Dextrose

IV. MEDICAL TREATMENT

Prior to any therapy for priapism a detailed,
informed consent that includes the fact that
impotence is a known sequela of priapism
regardless of treatment, read to the patient is
mandatory with the patient or one of his relatives
signing it with appropriate witness. Since
approximately 50 % of patients develop some
degree of erectile failure (regardless of the dura-
tion of priapism or mode of therapy [24], meticu-
lous attention to this matter can prevent unneces-
sary medicolegal litigation.
1. VENOUS OR LOW-FLOW OR ISCHEMIC
PRIAPISM
Low-flow priapism should be treated urgently if
normal erectile function is to be maintained. Initial
treatment is to aspirate blood from the cavernous
tissue ideally to achieve total detumescence. This
can be aided by irrigating the cavernosal tissue
with normal saline. This process should be repea-
ted if the priapism recurs after initial aspiration/
irrigation. Failure to achieve persisting detumes-
cence after the second treatment is an indication
for using injected medication [12].
An alpha-adrenergic agent suitably diluted should
be injected following the aspiration. Available
agents differ around the world. Proven methods of
using alpha-adrenergic agents are listed in table 2:
The injections may be repeated every 5 minutes up
to a maximum number of 10 doses. During this
treatment the blood pressure,pulse and detumes-
cence of the penis should be monitored.
Relative contraindications are heart block and bra-
dycardia. Epinephrine, Norepinephrine and Meta-
raminol all have significant alpha 1 systemic acti-
vity and may cause hypertensive crises and pul-
monary edema. Metaraminol has been responsible
for two deaths and one case of necrosis of penile
skin [7].
The effectiveness of oral drugs such as Terbutali-
ne and Pseudoephedrine remains uncertain [25,
26].
2. ARTERIAL OR HIGH-FLOW OR NON-
ISCHEMIC PRIAPISM
Ice packs and compression are the most conserva-
tive measure addressing arterial high flow pria-
pism. They infrequently allow resolution of the
priapistic state, but, being noninvasive, are none-
theless reasonable as initial attempts [10]. It has
been recently reported that color-doppler guided
compression, by ultrasound probe, of the flow in
the pseudoaneurysm can achieve complete throm-
bosis of the pseudoaneurysmal cavity, with resul-
ting detumescence [27, 28].
Intracavernosal blood aspirations and cavernosal
irrigations with alpha-adrenoreceptor agonists,

566
while highly effective in low flow priapism, repor-
tedly induce only transient detumescence in cases
of arterial priapism [9, 11, 13, 16]. These
approaches, described in detail under treatments of
the veno-occlusive forms, are all aimed, in fact,
chiefly at improving corporal venous outflow, that
in the high flow forms is already not restricted.
The vasoconstriction, and the inhibition of shear-
stress induced nitric oxide (NO) relaxing effects,
have therefore only a temporary effect on the
damaged cavernosal artery, and accordingly can-
not be recommended.
• Selective internal pudendal arteriography
with transcatheter temporary embolization by
means of absorbable material (autologous clot
±gelatine sponge particals) of the bleeding artery
[29] is presently the treatment of choice [8, 11],
allowing an excellent rate of resolution (100 %)
with immediate detumescence of the erect penis,
and of restoration of erectile potency (86 %) [11]
(Table 3).
Table 3: Commonly used embolizing agents
TEMPORORAY PERMANENT
EMBOLIZATION EMBOLIZATION
Autologous clot Polyvinylic
(lasting few hours) alcohol particles
Gelatine sponges i. Ivalon ™
(lasting 3-7 days)
i. Gellfoam ™ ii. Contour ™
ii. Spongostan ™ Acrilic glues
iii. Spongel ™ Ethanol
Should the cavernosinusoidal fistula recur, this
procedure can be repeated. Temporary emboliza-
tion nonetheless should be performed soon after
the traumatic episode, ideally within a month, as
endothelization of the cavernosinusoidal fistula
may jeopardize fistula repair and closure, at absor-
bable material dissolution. In the event of fistula
endothelization, the option of permanent emboli-
zation with non-absorbable agents may be consi-
dered, with the awareness that this approach car-
ries with it the risk of irreversible changes in the
erectile function, should the residual arterial sup-
ply of the contralateral cavernosal vessel not be
adequate to allow rigidity. Patients should therefo-
567
re be informed that watchful waiting is also an
option, as outlined, below.
• Watchful waiting.
Transcatheter embolization of the bleeding artery,
although presently the treatment of choice, carries
nonetheless few drawbacks. A 66 % rate of recur-
rent arterial priapism, together with cases of per-
manent cavernous artery occlusion and persistent
impotence [11], and one case of perineal abscess
with persistent impotence [30], have been repor-
ted. At the same time, it should be noted that spon-
taneous healing of the injured vessel has been
occasionally reported [10], and that non treated
patients have retained partial and sometimes satis-
factory sexual potency for years, despite the per-
sistent painless erection [11]. Watchful waiting
can therefore be included in the treatment
approaches to high flow arterial priapism [10, 11],
and thoroughly discussed with the patient, while
considering that the best chances of successful
treatment with transcatheter embolization by
means of absorbable material, are within a month
after the cavernous artery lesion.
Surgical ligation of the neoarterial inflow source
was the treatment of choice when high flow pria-
pism, resulting from direct anastomosis of inferior
epigastric artery to the tunica albuginea, occurred
in early penile revascularization procedures. Inter-
nal pudendal artery ligation, and resection/ligation
of lacerated cavernosal artery, has also been per-
formed in posttraumatic arterial priapism [6, 10].
In such procedures the vascular pseudocapsule
formed around the site of ruptured cavernous arte-
ry provides an important anatomical landmark for
intraoperative localization [10]. This surgical
approach is effective in resolving the priapistic
state, but the permanent obliteration of the caver-
nous artery determinates an unacceptably high rate
of postoperative impotence.
Corporospongiosal shunting procedures are not
indicated, since, again, the corporeal blood out-
flow is already adequate in arterial priapism [10].
3. RECURRENT PRIAPISM/PROLONGED
ERECTION
Initial management should be undertaken as soon as
possible after presentation. A prolonged erection
following intracavernosal injection therapy should
be treated at 4 hours if the erection is persisting [31, to be considered in cases of nonischemic, high-
32]. Initial management would be to encourage flow priapism. Surgery should be undertaken as
exercise and use a cold shower. This should be fol- soon as possible if priapism persists or recurs after
lowed by oral Pseudoephedrine 120 mg [25] but if initial successful medical treatment to prevent
this simple measure fails treatment should be as ultrastructural damage to the cavernous endothe-
described for a spontaneous low flow priapism. The lium and smooth muscle, which could lead to erec-
effectiveness of oral therapy to gain detumescence tile dysfunction [7]. Surgical intervention is indi-
is approximately 30 % of pharmacologically indu- cated in ischemic priapism of more than 36 hours
ced priapism patients. Oral Terbutaline is not duration [1, 6].
recommended in patients suffering diabetes, hyper- Inherent in all shunt procedures is the concept that
tension, hyperthyroidism or epilepsy [25].
they are temporary with spontaneous closure
Conventional medical therapy of priapism secon- occurring in the majority of cases once normal
dary to sickle cell anemia has relied on a combi- venous drainage patterns have been re-established.
nation of hydration, analgesia and hypertransfu- If after successful shunting, impotence persists
sion [3]. The goal of intravenous fluid therapy is to secondary to veno-occlusive dysfunction a caver-
inhibit sickling by decreasing tonicity and impro- nosogram should be performed to look for conti-
ving circulation. A fluid rate of three times main- nued shunt patency that can be surgically closed.
tenance is recommended. Blood transfusions and The simplest shunt between to corpus spongiosum
partial exchange transfusions are used to increase and the corpora cavernosa was first described by
hemoglobin levels above 10 mg/dl and to decrea-
Ebbehoj [37] and later modified by Winter [38].
se hemoglobin S to less than 30 %. Priapism in
These procedures are now one of the ”first line”
sickle cell anemia in the pediatric population
shunt treatments used throughout the world. Follo-
should be treated medically if possible because of wing corporal irrigation, under local anesthesia
the high recurrence rate and because shunting pro- using Ebberhoj’s technique, a narrow-blade scal-
cedure under general anesthesia in this age group
pel is inserted through the glans dorsal to the mea-
are associated with an increased risk of cardiac
tus, avoiding the urethra, through the tunica albu-
and respiratory complications, which occasionally
ginea and into the corpora cavernosa (Fig. 6).
can be lethal [3, 33].
Treatment of priapism with intracavernous injec-
tions of small amounts of alpha-agonists have
been successful even in children. Intracavernous
autoinjection of phenyllephrine has been recom-
mended for early therapy in recurrent priapism
[16]. Additionally, six patients with sickle cell
anemia were treated with oral phenylpropanolami-
ne, which reduced the frequency and duration of
recurrences [34]. Antisickling agents, including
diltiazem, a calcium-channel blocker, and pentoxi-
fylline, a vasodilator and membrance liquidifier,
may eventually play a preventative or therapeutic
role in the management of sickle cell anemia-
induced priapism [35, 36].

V SURGICAL TREATMENT

Surgical shunting procedures should be conside-
red if the presumptive diagnosis is ischemic pria-
pism and if the medical therapy for ischemic pria-
pism had failed. These shunting procedures are not
Figure 6: The distal end of the corporal body is pierced
through the glans with a No. 11 blade. Both corpora caver -
nosa can be punctured using the same incision site on the
glans. If a larger shunt is necessary the blade can be turned
along its longitudinal axis.

568
Multiple incisions are made by rotating the scalpel
blade 90 degrees in each tunica albuginea of each
corporal body to create multiple fistulas. The same
entry site on the glans is used for all incisions.
Winter’s procedure uses a Travenol Trucut biopsy
needle to remove cores of tunica albuginea to crea-
te fistulous communications between the corpora
cavernosa and the glans penis. During both proce -
dures the penis is mechanically compressed to
remove all dark old blood and replace it with
bright red blood. The glandular defect is closed
with a figure of eight absorbable suture. The
patient is instructed to squeeze and ”milk” the
penis every few minutes. The procedure(s) can be
done at the bedside and repeated in a few hours if
needed.
Another method of creating a glans-cavernosum
shunt is the Al Ghorab procedure [39]. This proce-
dure done under direct vision creates larger shunts.
The glans is incised semicircularly on the dorsum
at the coronal level and the tips of the distal cor-
pora cavernosa are exposed. A circular core of tis-
sue 5 mm in diameter is excised from each corpo-
ra to create a cavernous-glandular shunt. The penis
is squeezed until bright red blood is seen and the
glans is resutured to the penis with absorbable
suture. It is crucially important not to damage the
dorsal neurovascular bundle to prevent hypoaes-
thesia of the glans and distal penis. Intermittent
compression with a pediatric blood pressure cuff
can be applied to the penis for the first 24 hours
post-operatively.
If a corporal-glandular shunt is not successful, the
next simplest and highly successful procedure is
the construction of a formal shunt or communica-
tion between the cavernosa and spongiosal sys-
tems. The principle is to utilize the thickest portion
of the corpus spongiosum to avoid a urethral fistu-
la and this implies performing the shunt as proxi-
mally as possible. The prototype of this procedure
was described by Quackles in 1964 [40]. This pro-
cedure is performed in an operating room usually
utilizing general anesthesia. The skin incision may
be perineal, transverse scrotal or penoscrotal. Fol-
lowing the skin incision, the corpus spongiosum
and the corpus cavernosum are isolated for a dis-
tance of at least 3 cm. A Foley catheter is utilized
to help localize the urethra. Windows of tissue of
approximately 1 cm are removed from both struc-
tures and once bright red corporal bleeding is esta-
569
blished by squeezing the penis, the openings are
joined by two half-circles of running 5-0 absor-
bable suture (Fig. 7). Care is taken not to incise the
urethra. If one shunt does not result in detumes-
cence, a contralateral one can be performed but at
a slightly different level to avoid tension on the
suture line and to prevent stricture formation. No
compression dressing is necessary.
Along with Quackle’s procedure, the saphenous
vein-corpus cavernosum shunt was described by
Grayhack in 1964 [41]. A longitudinal ventral
penile skin incision is made, exposing the tunica
albuginea of the corpus cavernosum. Another inci-
sion is made medial to the ipsilateral femoral arte-
ry 3 to 4 cm below the inguinal ligament. The
saphenous vein is exposed for 10 to 12 cm and
detached proximally so it is long enough to reach
the base of the penis. This isolated segment should
maintain its attachment to the femoral vein. The
saphenous vein is passed through a bluntly dissec-
ted subcutaneous tunnel connecting the thigh inci-
sion with the penile incision. An ellipse of the
tunica, approximately 11/2 times the size of the
lumen of the saphenous vein is excised. The cor-
pus is irrigated to obtain bright red blood and an
end-to-side anastomosis is created between the
spatulated saphenous vein and corpus cavernosum
using a 5-0 nonabsorbable suture (Fig. 8).
One of the major dilemmas of treating priapism is
the frequent recurrence after intervention. Before
any surgical procedure for priapism can be consi-
dered successful, the intracorporeal blood pressu-
re must remain lower than 40 mmHg for more than
10 minutes. If the pressure rises above 40 mmHg
after several minutes, recurrence is likely and lar-
ger shunts are needed. Severe edema and indura-
tion of the corpora frequently are observed for
several days after shunting. The best way to diffe-
rentiate post-operative edema from recurrence is
to measure intracavernous blood gases. Normal
values indicate tissue edema rather than recurrent
priapism.
Circular compressive dressings should be avoided.
After a shunting procedure, the dorsal veins and
the corpus spongiosum temporarily become the
major drainage routes. These types of dressings
may compromise the venous return, trigger recur-
rence, or even cause necrosis of the penile skin
and glans penis. To prevent infection of ischemic
Figure 7: Cavernosospongiosum shunt Figure 8: Cavernososaphenous shunt: The saphenous vein
is divided, drawn through a skin tunnel and anastomosed
using a 5-0 arterial suture. Care must be taken to avoid kin -
king of the vein.

Figure 9: Management of priapism : algorithm

570
tissue, perioperative antibiotics are recommended.
Urethral catheters should be removed as soon as
possible and avoided in cavernosum-spongiosum
shunt procedures.
Complications associates with surgical shunting
for ischemic priapism are unusual. Early compli-
cation includes recurrence of priapism, bleeding,
infection, skin necrosis, abscess, cellulitis, gangre-
ne, urethral damage, urethro-cutaneous or urethro-
cavernous fistulas, urethral stricture and pulmona-
ry embolism [7]. Late complications include fibro-
sis of vascular spaces and failure of venous shunt
to close spontaneously leading to erectile dysfunc-
tion. Corporal fibrosis and scarring may be exten-
sive and not permit intracavernosal pharmacologi-
cal injections or penile vacuum devices, to be
effective therapies. In these patients the implanta-
tion of a penile prothesis, either semirigid rods or
an inflatable device remains the only treatment
option available to allow for sexual function [42,
43]. Penile implants should not be implanted into
the patient at the initial hospitalization of surgical
shunting procedures. The patient should be given
a time period to see if he will have return of any
penile activity and should be given the options of
penile vacuum device or penile injection prior to
determining if the prosthesis should be inserted. If
implants are placed at the same time of the initial
shunting procedures, distal erosion through the
tunica would be very risky while the risk of infec-
tion would be very high secondary to this device
being implanted in poorly vascularized tissue.
Management strategy is summarized by the
algorithm Fig. 9
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________________
 Committee 16

Socio-Cultural, Educational and Ethical

Aspects of Erectile Dysfunction

Chairman
A. MORALES

Members
H. CHOI,
A. GIAMI,
C. GINGELL,
B. JOHNSTON,
W. PASINI,
L. VELA-RODRIGUEZ,
C. SAMKANGE,
A. SCHMIDT,
F. UGARTE,
G. WILLIAMS

573
 CONTENTS

PREAMBLE II. EDUCATIONAL AND ETHICAL

ASPECTS

I. SOCIO-CULTURAL
CONSIDERATIONS 1. INTRODUCTION

2. MATERIALS AND METHODS

1. INTRODUCTION
3. FINDINGS
2. METHODS 4. DISCUSION

3. FINDINGS 5. PUBLIC EDUCATION

6. RECOMMENDATIONS
4. DISCUSSION

5. RECOMMENDATIONS REFERENCES

574
 Socio-Cultural, Educational and Ethical
Aspects of Erectile Dysfunction
A. MORALES,

H. CHOI, A. GIAMI, C. GINGELL, B. JOHNSTON, W. PASINI, L. VELA-RODRIGUEZ,

C. SAMKANGE, A. SCHMIDT, F. UGARTE, G. WILLIAMS

PREAMBLE

The First Consultation on Erectile Dysfunction

initially included two separate committees: Socio-
cultural Aspects and Ethics and Education. Subse-
quent consideration resulted in the amalgamation
of the works of the two committees. This was an
appropriate decision when consideration is given
to the heterogeneity in cultural and professional
backgrounds of the Committee’s membership that,
unavoidably resulted in divergent points of view.
This report comprises two separate sections, each
one addressing, independently, specific aspects Figure 1: United Nations projections of the world popula-
related to male erectile dysfunction (ED) tion from the end to the 21st. century to the middle of the
22nd.

I. SOCIO-CULTURAL
CONSIDERATIONS

1. INTRODUCTION
Over the last 50 years the world population has
increased rapidly. Just 25 years ago there were 4
billions humans while the number is projected to
double to more than 8 billions by the year 2025
(Figure 1). More important, however, is the phe-
nomenon of the aging of humanity. Figure 2 shows
the projections from the United Nations [1] for the
old (>65 years) and old-old (> 85 years) popula-
tion between 1950 and 2050. These demographic
changes are very relevant in the context of the Figure 2: The United Nations estimate a significant decline
socio-cultural aspects of ED. It is well recognized in the under 15 year-old population in the period 1950-
2050. The older population (>65 years) will continue to
that ED is not the result of aging but associated
increase during the same period. The effects of aging in
with many conditions (i.e. diabetes, atherosclero- sexual function will translate in an increasing demands for
services by an aging humanity.

575
sis) frequently developing in aging men. The
extent of the health issues related to aging have not
been defined completely but, population projec-
tions clearly indicate that health problems related
specifically with aging will increase significantly
over the next 25 years.
The overwhelming majority of investigators have
reported the mean age of patients consulting for
ED to be about 55 years. At this stage in life there
is a conjunction of conditions which alone or in
combination may be responsible or may contribu-
te to the establishment or perpetuation of erectile
difficulties. Health care professionals in general,
and urologists in particular, need to look at the
middle age and elderly man as person with more
than a specific complaint such as lower urinary
tract obstructive symptoms, but at other manifes-
tations of aging (loss of libido, tiredness, depres-
sion). It is imperative that quality of life issues are
proactively sought out. In this context, adequate
sexual function is an important item in many
societies. As indicated in the section on Ethics and
Education, there is a dismal performance by medi-
cal and nursing schools curricula throughout the
world in sexual education. The majority of the
world population has very limited factual informa-
tion on sexual health issues and, almost universal-
ly, government agencies either ignore the topic or
neglect it in favor of, what is perceived, as more
important health concerns. However, a recent
publication (2) reporting one the few population-
based assessments of sexual dysfunction in 50
years indicated that “sexual dysfunction remains a
largely uninvestigated yet significant health pro-
blem”. Unfortunately, the perception by govern-
ment agencies [3] and the public is that sexual dys-
functions in general and ED specifically are not
particularly important health issues. The problem
is further complicated by the cost of currently
available treatments and their limited availability
to all sectors of a community.
The complexity of socio-cultural aspects of ED
are clearly illustrated in the findings of high inci-
dence of psychological and social causes of the
condition among young men and men in the lower
economic stratus [2]. These, are the ones with the
less ability to attract the interest of health authori-
ties, particularly in issues of sexual dysfunction.
576
2. METHODS
The Committee found a scarcity of valid docu-
mentation on the subjects assigned to it. Due to
financial and temporal constraints, a properly desi-
gned and validated population survey was not
considered feasible. The Committee is fully aware
of the limitations of an opinion survey and wishes
to emphasize that the results shown here only
represent a majority view of the Committee mem-
bers and the literature, as indicated in the text.
The Committee members responded to a short sur-
vey related to socio-cultural issues with the ans-
wers specifically focused on the region of the
responder. The survey provided the basis for fur-
ther discussion at the three preparatory meetings
and a consensus for the submisson of the written
report. This material was supplemented by com-
ments from opinion leaders strategically located
around the world because many distinctive regions
(i.e. Middle-East, Asia-Pacific) had limited or no
representation on the Committee. It was also dee-
med necessary to perform a limited review of the
literature.
For purposes of reporting and due to the socio-cul-
tural diversity, greatly magnified in the area of ED,
it was considered appropriate to divided the world
following the geographical distribution of the 5
regional societies with a mandate to promote the
investigation and treatment of ED and who are
affiliates of the International Society for Impoten-
ce Research (ISIR):
1. Society for the Study on Impotence (United
States and Canada);
2. Sociedad Latinoamericana de Impotencia (all
Ibero-American countries from Mexico to
Argentina);
3. Asia-Pacific Society for Impotence Research;
4. European Society for Impotence Research and
5. African Society for Impotence Research.
It is clear that within these very large regions there
are enormous social and cultural differences. There-
fore, the Committee, chose information available
from 2 or 3 representative countries in the region in
assessing the socio-cultural aspects of the whole
region and by a review of the pertinent literature.
The Committee relied primarily on the voluminous
International Encyclopedia of Sexuality.
3. FINDINGS
a) The committee
There are evident divergent and, occasionally
conflicting perceptions on ED among health care
professionals. Medical sociology and medical
anthropology make a clear distinction between
disease and illness. Disease represents the condi-
tion as it is defined as perceived by physicians and
scientists, while illness represents it as it is percei-
ved by the sufferer and defined and perceived by
common sense and lay knowledge [4]. This view
is eminently applicable to the concept of ED and
provides an explanation for the misunderstandings
that can, and frequently develop between the
patient and the health provider. The potential for
patient-health provider difficulties can be further
magnified in trans-cultural situations within the
same social universe.
The differences among concepts have a profound
effects in communication between health profes-
sionals and their clients. The currently predomi-
nant approach for the management of a man com-
plaining of impotence (a term still firmly groun-
ded in sociology and anthropology) follows the
medical model in which a set of investigations and
treatments are carried out. The model is presented
in several previous chapters of this volume. Taken
to its therapeutic extreme (insertion of a penile
prosthesis), this approach would invariably result
in “success”: resolution of the man’s inability to
accomplish vaginal penetration. What this
approach does not answer is the patient’s feelings
of humiliation, loss of self-esteem, shame, marital
discord and so on. As it will be discussed below,
the medical model is frequently successful in
resolving the erectile problems. The constellation
of other issues associated with the condition are
not so easily solvable. There are enormous socio-
economic, cultural, educational and professional
difficulties that need to be addressed in order to
provide adequate global care to the couple affected
by sexual inadequacy. The Committee is not opti-
mistic about a resolution of those issues in the for-
seeable future, even in advanced societies.
b) Results of a survey
The survey completed by the Committee and other
individuals working in the field showed different
insights among various regions of the world.
Although ED is a topic not openly discussed in
577
most societies, it is clear that the perception of its
importance is changing. Figure 3 shows that,
according to the responders, in the majority of
societies the public considers it a medical problem
but only a small minority discusses it freely while
a larger proportion considers the topic banned
from open discussion. It was anticipated and reite-
rated by the survey that no one would consider ED
at the same level of relevance as other common
medical conditions (i.e. cancer, cardio-vascular
disease). On the other hand, it is evident that the
population is not indifferent to the issues related to
ED (Figure 4). The responses indicate that, in most
regions, the public is aware of ED as a common
condition but either has limited knowledge or
gives it a low priority in favor of more pressing
health issues. These findings are consistent with
attitude of the health authorities (Figure 5): a large
proportion of them ignore ED or recognizes it as a
health issue; but, like the constituency they serve,
do not take a proactive attitude towards its treat-
ment. No one felt that these authorities are interes-
ted in supporting investigation and treatment of
ED. In regions with a relatively homogeneous reli-
gious orientation, it is evident that ED has not
caught the interest of the religious leadership
(Figure 6). The last 3 questions of the survey focu-
sed on the medical aspects of ED. Most patients
affected by erectile problems initially seek a varie-
ty of treatments ranging from non-medical healers
to conventional medical advice; the survey did not
ask if the healers use non-medical methods, but it
was assumed that this was the case (Figure 7). The
low profile of the medical profession in the treat-
ment of ED is confirmed by the limited number of
scientific societies actively involved in promoting
increased knowledge and understanding of ED.
The largest proportion (67%) indicated that such
societies either do not exist or if present they were
largely ineffective (Figure 8). The absence or irre-
levance of medical societies in the field of ED are
a faithful reflection of the feelings and attitudes of
health authorities and health professionals. Figure
9 indicates that the majority of health professio-
nals feel that the issue of male sexual dysfunction
is either irrelevant or should take a low priority
position in favor of more important health pro-
blems. In this regard, the appearance of easy to
use, effective, safe and readily available treat-
ments (e.g. sildenafil) has created new socio-
medical dimensions which have not yet been
Figure 3: At the end of the millenium the topic of ED is
most often a guarded secret. Attitudes in this regard, howe-
ver, are changing due, in part to the availability of simple
and effective treatments.
Figure 5: Health authorities appear to be overwhelmed with
other issues and devote little attention to the topic of ED.
Figure 7: Almost universally, friends and relatives are ini-
tially consulted by those affected with ED. Traditional medi-
cine is the preferred approach in less advanced societies. A
combination of allopathic and traditional approaches is
used in most regions of the world.
578
Figure 4: The public does not consider ED an important
condition. This is an interesting dichotomy since the demand
for information on the topic is large. As expected, other heal-
th concerns (cancer, cardiovascular) are considered more
significant.
Figure 6: Similarly to health authorities, the different reli-
gious leaderships tend to ignore the relevance and impact
of ED in every day’s life.
Figure 8: Most medical communities consider ED as a low
priority among the medical conditions. The relevance and
impact of ED in the quality of life has been underestimated
by health professionals.

Figure 9: The limited interest by health care providers is
reflected in the scarcity and ineffectiveness of professional
societies dealing with sexual inadequacy.
settled and are incompletely understood. Suffice it
to say that medicine is currently faced with a new
situation in which the therapy of “real” disease is
in tension with the availability of increasing num-
ber of highly successful treatments that are percei-
ved as simply aimed at improving quality of life.
Pharmacological management of ED falls in the
gray zone between the treatment of a medical
condition and the enhancement of quality of life.
c) The literature
As mentioned before, the population projections
clearly point to an aging of all societies in a global
pattern. It is evident, therefore, that over the next
25 years there will be an increased demand for ser-
vices related to sexual dysfunction which is clear-
ly related to the aging process, although not its
unavoidable consequence [5]. The literature is
remarkably sparse in the specific area of socio-
cultural aspects of erectile dysfunction. A PubMed
search found < 30 articles on the subject and the
majority were irrelevant to the objectives set out
by the Committee. On the other hand, there is a
very voluminous body of literature on the topic of
general sexuality, sexual behaviors including pros-
titution, homosexuality and paraphilias. The basic
and clinical sciences dealing specifically with ED
currently enjoy a great deal of attention, not so the
socio-cultural aspects. This appears to be a fairly
universal situation and no region in particular is an
exception, although changing trends are becoming
apparent. In other words, publishing on ED is a
rapidly expanding field, particularly on its physio-
logical mechanisms and diagnostic and therapeu-
tic aspects but with very little research available
on trans-cultural issues.
579
1 NORTH AMERICA.
This region probably offers the most abundant cul-
tural diversity and a large number of publications
on sexuality. It has long been recognized that
sexual dysfunctions cover the entire range regard-
less of the racial or cultural origin of the patients.
Very recently an encyclopedic publication proclai-
ming to promote “understanding our (American)
sexual values and behavior” covered a large num-
ber of aspects of human sexuality. It correctly indi-
cated that most of the “research has been conduc-
ted with samples of white, middle-class clients”. It
further indicated that minority groups generally
lack either the confidence or the financial
resources to seek therapy [6]. To complicate mat-
ters, therapy generally is offered by Anglo-Ameri-
can professionals. Therefore, culturally appropria-
te counseling and therapy appears to be largely
inaccessible for minority groups in the American
scene. Slowinski and Stayton [7] lament on the
“medicalization” of sex therapy. This medicaliza-
tion is also lamented by Francoeur [8] who speci-
fically refers to the use of phosphodiesterase inhi-
bitors in the treatment of ED. These points of view
by authors with the same professional background
are somewhat difficult to reconcile: they believe
that sexual counseling demands socio-cultural
sensitivity but they also recognize that such thera-
pists are very scarce. The counter-point of these
views, of course, is that therapy of ED is in most
cases, primarily a medical problem, affordably and
successfully treated by medical means [9, 10]. In
addition, ED is culturally generic [11]. It appears
that the so called “medicalization” of sex therapy
is not only unavoidable but desirable [1]. This in
no way implies that the resolution of erectile diffi-
culties would in every instance overcome marital
or emotional problems. Germane to this point is a
recent Canadian study which showed that the vast
majority of patients seeking treatment for ED are
not interested in counseling nor are their partners
willing to participate in it [12]. This observation is
relevant because the refusal to accept counseling
was not related to financial issues since the group
of patients in the study all had access to free coun-
seling but not to medical treatment: despite the
cost, patients were only interested in recovering
their ability for vaginal penetration (the study was
conducted in the pre-sildenafil era). Evidently this
is a fairly common universal occurrence as “pro-
fessionals can become fixated on this (the penis)
organ as their patients and forget that it has a mul-
tiplicity of connections within the man’s mind and
body- and, indeed, outside it” [13]. The study,
however, did not address ethno-cultural issues.
Many of the American situations can be easily
accommodated into a Canadian context and vice
versa. There are however, cultural and social dif-
ferences: the American society has been likened to
a melting pot of cultural diversity in which cul-
tures are rapidly assimilated. A cultural mosaic
best described the Canadian situation where diffe-
rent cultures form part of the whole but maintain a
clear identity. Despite these possible differences, it
is difficult to identify significant cultural diffe-
rences among the causes or the results to therapy
of ED in North America regardless of social or
cultural background. In both countries numerous
studies have been conducted on ethno-cultural
variations of sexual attitudes and behaviors. The
Committee was unable to identify any studies on
differences in the specific area of ED. Whether
this simply reflects the view that, from the purely
medical point of view, there are no relevant socio-
cultural issues remains to be investigated.
2 IBERO-AMERICA
Argentina appears to be a microcosm of the urban
centers in the region. Although the public is inter-
ested in knowing more about available treatments
for ED, until recently there was very limited
expertise available. “When people come for advi-
se on sexual problems -like frigidity, impotence,
fast ejaculation, painful sex, sex during pregnancy,
sex among the aging, etc.- gynecologists, obstetri-
cians, urologists and general practitioners find that
they all are confused” [14]. The same author,
however, indicates that evaluation of dysfunctions
such as impotence and premature ejaculation fol-
low the approach of Masters and Johnson and Sin-
ger-Kaplan and complains that “unfortunately few
urologists and gynecologists are informed or pre-
pared to assist in these type of problems". These
views are not shared by urologists in the region
which enjoys active research and modern diagnos-
tic and therapeutic practices in dealing with ED. In
neighboring Brazil a very similar condition exists
in the larger cities where there is abundant reliable
information, modern treatment and research on
ED. However, the situation among aboriginals is
completely different where much of the understan-
ding and treatment of male sexual dysfunction is
580
based on myths, rituals and magic. This cultural
dichotomy is repeated with only small differences
among the various societies of the region. At the
northern end of the area (Mexico) there is a simi-
lar situation although the isolation of rural and
native societies is much less marked than in Cen-
tral American and other South American Countries
like Colombia, Peru and Venezuela. In all these
countries there are two sources of cultural values:
the European Catholic influence and the native
beliefs that existed in the region prior to the Euro-
pean colonization. They co-exist to the present.
Factual, physiologically based concepts about ED
have become popularized only very recently, pri-
marily through the lay media. Contemporary treat-
ment is available to only a limited segment of
society. There is still a pervading reluctance for
men to seek medical advice for erectile problems.
3 ASIA-PACIFIC
According to Hatano and Shimazaki [15] ED is
the most common of the sexual dysfunctions
reported in Japan. As in other countries in the
region, the topic is not discussed freely but the
availability of new therapies has created pressure
to a more open discussion of ED. In a long chap-
ter devoted to sexuality in China [16], the Ency-
clopedia devotes only a short paragraph to sexual
dysfunction. It only indicates that “20 percent of
China’s adult male population” suffers from
sexual dysfunction but fails to mention the inci-
dence of ED. In India, in addition to well develo-
ped understanding and practice of Western-type
concepts on ED, there are also specific Hindu and
Moslem beliefs. The Ayurvedic medicine is still
widely practiced not only in the sub-continent but
also by Indian expatriates [17]. It is interesting that
practitioners of Ayurvedic and Unani medicine (in
a behavior similar to some of their Western coun-
terparts) make exaggerated claims on treatments
based on modern medical approaches. These
claims are advertised in the popular press [18].
4 EUROPE
Although distinct European societies are very
easily identifiable, it is extremely difficult to esta-
blish ethno-cultural variations in the region when
addressing the issues of ED. As advanced socie-
ties, the Europeans enjoy a great deal of sophisti-
cation in the understanding of the pathophysiolo-
gy of erectile problems and as a consequence
maintain a leadership position on its treatment.
European societies rely primarily on a medical
focus for treatment of ED. Modern treatments are
readily available. The International Encyclopedia
of Sexuality (p. 516), in dealing with sexual dys-
functions in Germany, speculates that in the eas-
tern part of the country “men suffer in particular
from mental problems connected with sexual
competence, sexual performance, their own
attractiveness, and frustration in love and sex”.
There is no mention at all of ED and no references
are provided for these opinions. The same Ency-
clopedia in dealing with The Netherlands simply
puts forward unsupported views regarding the
acceptability of treatment by Dutch men (p. 956).
The comments for Spain in the same publication
are equally unhelpful when searching for the
areas of interest to this Committee. It is likely that
the opinions provided for the United Kingdom are
applicable to the rest of western Europe: British
society appears to be having a reemergence of
sexual awareness. After a very conservative atti-
tude towards sex in the first half of the century,
there was an awakening in the 1960s…. One area
where this has become particularly evident is
male erectile disorder, for which a proliferation of
treatment centers, both within the health service
and in the private sector has developed” [19]. Pre-
liminary information from a French survey on
sexology as a profession indicates that 60% of
sexologists are physicians [20]. This survey also
indicates that, most commonly, French sexolo-
gists employ various approaches of psychothera-
py (including sexotherapy, behavioral, cognitive,
psychodynamic and medical relaxation). Howe-
ver, on occasion psychotherapy is used together
with pharmacotherapy. A French working party
on the treatments of ED concluded that “In all
cases the degree of ED as it is experienced by the
subject results from his suffering and is not direct-
ly dependent on the etiology. The evaluation of
the degree of severity is grounded on the evalua-
tion of the subjective suffering felt by the subject
and eventually by his partner”[21]. In a more
general way, the results of the Committee’s sur-
vey is confirmed by a survey on diagnostic atti-
tudes and treatments of impotence that was car-
ried out in six European countries. It concluded
that there was a lack of interest regarding ED
among health care professionals [22].
581
5 AFRICA AND THE MIDDLE EAST
This region offers impossible tasks in an attempt to
summarize the socio-cultural aspects of ED. The
differences between countries in the region are
enormous. For instance, in Ghana where polygyny
was desirable and currently socially accepted, ED is
seen with suspicion and is socially frowned upon.
On the other hand, Ankomah [23] reports that infer-
tility takes priority on sexual problems. Probably its
management applies equally to ED: “Traditional
healers in Ghana, while conceding the superiority
of Western biomedical medicine for certain diseases
insists that infertility and sexually transmitted
diseases are more effectively treated by traditional
than modern medicine. The secret and highly confi-
dential nature of their practice makes traditional
medicine men, herbalists, Mallams, fetish priests,
and others the main source of treatment”. At the
other end of the spectrum in Israel ED is seen more
from the European or North American perspective.
In Iran, it is reported by Drew : “Counseling in all
marital matters is strictly a family affair. There is
strong taboo against discussing family problems of
any kind with a non-family member… Iran is thus
not very fertile ground for any kind of psychothera-
py” [24]. Whether this unsupported opinion applies
to ED, could not be determined reliably by the
Committee.
The Committee felt that South Africa is worth
noting because its diversity in socio-cultural
groups. In this country there is an interesting co-
existence of so-called third, second and first world
socio-cultural conditions. In many ways, therefore,
South Africa is representative of the issues related
to erectile dysfunction in other parts of the world. In
rural areas wives and children perform a great deal
of work. The males exhibit a high sexual drive and
performance. ED in these communities is, primari-
ly related to the inability to achieve multiple
orgasms per night. The majority of cases of impo-
tence are treated by traditional healers with herbal
preparations. Primary care physicians treat them
with androgens and vitamins. In more advanced,
“second world” areas, extensive changes have been
introduced by Christian missionaries and other
immigrants. In these societies, ED is rarely discus-
sed openly and is considered only of procreative
importance. Here, again a good number are treated,
inappropriately, by traditional healers or by primary
care physicians with vitamins and androgens. In the
most advanced areas where “first world” conditions
prevail, ED is still considered mostly of psychoge-
nic origin and treated with androgens. However, the
availability of better treatments has resulted in a
proliferation of “male clinics” which prescribed
intracavernosal injections. Very few are equiped to
treat their complications or to provide integrated
therapy for the couple. A few psychiatrists and
family physicians have developed an interest in
sexual dysfunction and practice as sexologists.
These physicians tend to deal with the problem
mostly in terms of psychogenicity. Urologist are
more eclectic in their approach to the problem but it
is predominantly pharmacotherapeutic in nature.
The males are usually treated without considering
the influence on the couple’s relationship.
4. DISCUSSION
The Committee recognizes that cultural back-
ground exerts enormous influence in the way a
man discusses his sexual function. We further
recognize that there are other important factors in
an individual’s personality and beliefs system.
They include levels of education and economic
class [25]. In addition, we feel that it is important
to emphasize that any profession, including medi-
cine, may operate as a culture and, here again,
socio-cultural influences may affect health profes-
sionals attitudes in terms of both their own back-
grounds and the backgrounds of the people they
interact with [26]. The work of the Committee was
severely impaired by the lack of reliable informa-
tion about regional social views on erectile dys-
function. The literature search disclosed a very
limited number (< 30) of articles specifically dea-
ling with socio-cultural aspects of ED. The volu-
minous International Encyclopedia of Sexuality
was equally disappointing in this regard. In it, an
unspecified selection process, only 32 countries
were considered. Among the numerous authors
there is a scarcity of physicians and few, if any,
urologists or pharmacologists. This translates to a
serious bias when dealing with male sexual dys-
functions: the authors simply ignore them, focus
mostly on emotional aspects and counseling or
lament the “medicalization” of therapy.
The report of this Commitee, therefore, is primari-
ly based on the views of the Committee members
as well as reports from regional opinion leaders.
Again, the financial and temporal limitations,
obviously, did not permit an extensive survey with
582
a more scientific approach. In reality, there are no
major surprises when the different views were
compiled or through discussions at the 3 separate
meetings of the Committee members (unfortunate-
ly, not all members were pressent at all meetings).
It was felt that the public perception of ED is that,
for the most part, it does not constitute a major
health concern. While a small number (20%) felt
that the topic was kept under wraps in their social
environment, the large majority (65%) estimated
that ED is simply not discussed openly. This is
somewhat surprising in western societies where
there has been an overwhelming amount of dis-
cussion in the spoken and written press. Notably
none of the responders felt that sexual dysfunc-
tions are perceived as a topic to be discussed as
freely as any other medical conditions (e.g. heart
disease, diabetes).
A large number of responders (> 70%) indicated
public apathy in regard to ED. This opinion may be
based on the situation prior to the public accessibi-
lity to effective, non-invasive therapy for erectile
problems. The massive exposure of large sectors of
the population to the newer medical treatments has,
undoubtedly created an increased awareness, parti-
cularly in men at or beyond middle age.
Of particular interest to the committee was the
position of the regional health authorities in regard
to ED. As anticipated, it was felt that the vast
majority simply ignores its prevalence and effect
on the quality of life. Equally important was the
finding that when the condition is not ignored, the
same authorities remain inactive in the promotion
of preventive and curative measures for it. A cited
example was the labeling of cigarette packages: all
sort of adverse health effects have been printed in
such products for years. Only recently and in a few
areas, has ED been named as a significant conse-
quence of cigarette smoking. It was felt that this
type of warning would be particularly effective in
the younger population who is the most suscep-
tible to initiate the habit and to respond to a threat
of diminution in sexual capacity.
In areas with limited religious diversity, religious
authorities, for the most part, are oblivious of the
condition. Only a small minority takes a proactive
attitude and promote discussion of sexual issues.
In several regions there is such a variety of beliefs
that the religious influence on ED could not be
reliably determined.
In order to establish, not only the degree of interest
by the community in ED but also the input from
the health care providers, the questionnaire asked
about the availability of lay (i.e. support groups)
or professional (i.e. “impotence” societies) organi-
zations dealing with ED. In most regions (80%)
such societies do not exist and where they do, are
perceived as ineffective. This finding was curious
and worth noting. The International Society for
Impotence Research (ISIR) has regional affiliated
societies that cover the globe. It is evident that its
membership remains, primarily, limited to indivi-
duals with specific interest in the field of erectile
function at an academic level and its activities do
not percolate to either the public or health care
providers in general.
Notable exceptions to the observations mentioned
above exist. In Europe for example the European
Society for Impotence Research (ESIR) has pro-
duced a "Patient's Guide to a Common Medical
Problem: Impotence" and "A Physicians Guide to
the Management of Erectile Dysfunction"; both
publications are simple and practical but not avai-
lable in all languages. The recent "Man's Guide to
Sexual Health" booklet produced by South African
psychiatrist Bernard Levinson and published by
the Erectile Dysfunction Advisory Council
(EDAC) is also very practical and culturally gene-
ric but, at the time of writing exists only in the
English version. Most of these educational mate-
rials are developed by knowledgeable health pro-
fessionals and with the support but without inter-
ference from industry. This important point is fur-
ther elaborated on in the section on Education and
Ethics. Similar publications (and a great deal of
duplication) exist in all regions surveyed although
their quality is inconsistent. The importance of
dealing appropriately with ethnic, cultural and
even gender sensitivities in these materials cannot
be over-emphasized.
Much less successful have been the health profes-
sionals or the public itself in organizing support
groups for men/couples affected by ED. The Com-
mittee fully recognizes that trans-cultural motiva-
tions and connotations associated with ED are
quite different than, for example, a subject such as
prostate cancer where support groups are nume-
rous. ED in most of the world remains an intensi-
vely private matter. Although it is likely than many
583
such groups exist at a local level, the Committee
was able to identify only one with a national man-
date: The Impotence Association of the United
Kingdom. This group publishes a simple review of
the causes and treatment of ED that are not much
different than many other educational materials on
the subject. However, this publication contains a
very notable and crucial difference: on the back
page there are listed (with addresses and telepho-
ne numbers) 4 large groups that offer counseling
and advice (e.g.: Sexual and Personal Relation-
ships of People with a Disability (SPOD),
286 Camden Road, London, Tel. 016078851.
Tuesday to Thursday 10:30 am to 1:30 pm,
Wednesday 1:30 to 4:30 pm).
This type of organizations are of enormous value
to a population reluctant to approach physicians
and other health professionals with a problem rela-
ted to a sexual inadequacy.
An important cultural issue refers to who is provi-
ding the primary care for patients with ED. Not
surprisingly a significant number (20%) of
patients seek advice from friends and other non-
medical people to assist with simple remedies.
While the same number attend a medical profes-
sional regarding his condition, another 10% seeks
non-medical but “professional” advice from sha-
mans, herbalists and other similar persons. While
most (44%) seek help from all these sources. Such
an approach is what one would expect for a non-
life threatening condition such as ED. It is likely
also that the placebo effects from herbs and incan-
tations are significant and will perpetuate the ten-
dency, in many cultures, to rely on traditional
remedies. Other factors of importance in this
regard are the low cost and accessibility of non-
allopathic treatments.
The Committee determined that there are very
large social, economic and cultural discrepancies
among the various regions of the world and among
segments of the population within the same
region. In most areas the public simply lacks the
financial resources to obtain appropriate care for
ED. The problem is compounded further by an
acute absence of a cadre of properly trained health
providers capable of dealing with the condition in
a knowledgeable and sensitive manner. This unsa-
tisfactory situation can be solved only when an
educated public and trained professionals create
the demand and deliver the expertise for adequa-
te management of sexual dysfunctions. Resolu-
tion of such matters is, obviously, complex and not
forthcoming due to very pressing health issues and
the major socio-economic discrepancies facing the
world today.
The final area explored by the Committee was the
perceived interest by the regional medical com-
munity on issues related to ED. The overwhelming
position was that ED is either irrelevant or quite
insignificant in relation to other more pressing
health issues. This is an understandable position
that correlates well with the one expressed in rela-
tion to the health authorities. Undoubtedly, health
authorities and providers will preferentially direct
their energies, budgets and interest to conditions
threatening life, associated with serious physical
sequelae or enjoying an effecting lobbying force.
ED does not score very high here.
The Committee felt that socio-economic issues did
not fall into its mandate and purposely avoid
addressing them. There are enormous discrepan-
cies not only among countries but also between
health agencies and authorities within the same
country. In addition, the rapid development on the-
rapeutics for ED present a rapidly shifting view of
“clinical, equity and cost-effective grounds” [27].
On the other hand, the Committee felt encouraged
by the vigorous debate in Great Britain on the fun-
ding of all treatments for ED regardless if the
patients are considered “deserving” or “undeser-
ving” of such treatment [28]. This sort of debate
and interest by government agencies is an example
for societies in other countries.
5. RECOMMENDATIONS
The Committee believes that the statement of
the Director General of the WHO fits well in
the management of ED. She wrote that “prevai-
ling cultural values have to be observed if
appropriate policies are to be developed.
Indeed health cannot be dissociated from cultu-
ral, social processes or economic forces – all are
interrelated” [29]. With this in mind, we
agreed on the following culturally generic
recommendations:
1. ED needs to be recognized globally as a signi-
ficant health concern and not as a life style
issue.
584
2. Health authorities should promote sexual
health as an important factor in the overall
quality of life. This should take place by edu-
cating not only the public but also health
professionals.
3. It is important to increase the public aware-
ness about the large prevalence of ED in all
regions of the world. Health authorities and
medical organizations need to provide gui-
dance on the material made available to the
public.
4. There is an obvious need, in most countries,
for the creation of lay support groups with
and interest in dealing with sexual (both
male and female) issues.
5. Pertinent scientific societies, when appro-
priate, should promote high standards of cli-
nical practice, research and education in the
field of ED.
6. With deep respect to religious and cultural
sensitivities the topic of sexuality in general
and ED in particular needs to be addressed
at all levels of medical practice.
7. Regardless of socio-economic status, in most
regions of the world the medicalization of
sexuality is a reality. In the specific area of
ED it is not only unavoidable but desirable.
Although most cases of ED have a multifac-
torial etiology, organic factors are frequently
identified. They can be treated promptly,
inexpensively and effectively by pharmacolo-
gical means.
8. The Committee, however, is fully aware that
a "penocentrically" oriented approach has
its own drawbacks. Serious emotional and
psychological issues may be overlooked. In
addition, the treatment of the purely erectile
problem, although successful, in most cases
results in the emergence of new patient’s and
couple’s issues that would interfere with a
fulfilling sexual relationship. Whenever fea-
sible, the investigation and treatment of ED
should be comprehensive and viewed as “a
couple problem”.
9. The therapy of sexual dysfunction in general
and of ED in particular must be sensitive to
ethno-cultural issues

II. EDUCATIONAL AND ETHICAL
ASPECTS
1. INTRODUCTION
There are few, if any, fields in human health that
have been ignored for longer than erectile dys-
function (ED). Similarly, in few has progress been
so rapid in elucidating the physiology of the erec-
tile mechanisms as well as the causes and treat-
ment of ED. Thus, at the basic level, we have evol-
ved, in less than 30 years, from the erroneous
concept of “pollsters” as the system to trap blood
in the corpus cavernosum to our current unders-
tanding of the molecular mechanisms of penile
physiology [30]. Clinically, the opinion [31] that
“With few exceptions, the causes of impotence in
the male are psychic, i.e. based on guilt, anxiety,
jealousy, or frigidity on the part of the wife”, has
been drastically revised as scientifically and poli-
tically incorrect. Therapeutically, in the short span
of 15 years, the sub-specialty has expanded from
no options or only the possibility of an implant to
safe and effective oral medications. The speed of
progress has been astonishing.
However, the rapid pace of discovery on all
aspects of penile physiopathology has not kept
abreast with the dissemination of this wealth of
knowledge outside a relatively small group of
interested health professionals, most commonly
urologists. The gap in the information network is
rooted in a variety of factors which include:
a) the accelerating rate of breakthroughs;
b) the lack of sexual education at the graduate and
undergraduate levels for health professionals;
c) inability and lack of interest by government and
non-government health agencies to invest
resources in the field of sexual dysfunction;
d) reluctance of the lay press to deal with issues of
sexual health in a serious manner;
e) a pervading belief, at all levels of society, that
sexual health issues are of minor importance;
f) deeply rooted socio-cultural convictions that
prevent open discussion of issues in this area and
g) misinformation provided by ignorant and/or
dishonest parties.
585
2. MATERIALS AND METHODS
The Committee was charged with a global assess-
ment of issues on ethics and education concerning
exclusively the field of erectile dysfunction (ED).
For this purpose, members of the Committee and
other health care professionals in leadership posi-
tions, provided information regarding educational
and ethical aspects of ED in their individual
regions. Their opinions were tabulated and the
results supplemented with information available
from government and non-government agencies.
This approach provided a wide geographical pic-
ture of the topics of interest which were then divi-
ded as follows:
1. Public Education
2. Professional Education
3. Professional Ethics
4. Industrial Ethics
The Committee is fully aware of a multitude of
other very relevant ethical issues in the treatment
of ED. However, they appear of secondary impor-
tance to the specifics of ED or are too vast and
complex to be explored within the limited manda-
te of the Committee. These include the concepts of
confidentiality, informed consent, respect for per-
sonal values of the patient. Interested parties are
referred to the early work of Macklin [32].
In regards to education pertinent to ED, we
concentrated our efforts in establishing:
1) the adequacy of public and professional educa-
tion in the field of erectile function
2) the availability and effectiveness of educational
material specifically dealing with the topic of ED.
The Committee focused on 3 ethical issues:
1) the appropriateness of the information provided
by industry to health care professionals and to the
public.
2) conflict of interests that may exist between
industry and physicians in the diagnosis and treat-
ment of ED.
3) ethical concerns regarding false advertising and
questionable practices by health care providers
(both as individuals ans as government and non-
government coporations) in the diagnosis and
treatment of ED were gleaned from the literature
and from information from scientific societies.
3. FINDINGS
a) Public education.
The majority of responders (55%) felt that the
amount of sexual education among the people of
their region of concern was inadequate. Over one-
third indicated that in their region sexual educa-
tion to the public was non existent, while just over
10% found it to be adequate (Figure 10). The
sexual education material was found to be quanti-
tatively and qualitatively inadequate by 55% of
responders, non-existent by 11% and adequate by
33% (Figure 11). Traditional publications (book-
lets and pamphlets) were selected by the majority
(66%), as the most effective educational material
for the public (Figure 12) while audio-visual aids
were most appropriate in the view of a third of the
responders. Public lectures were the medium of
choice for only a minority of responders (11%)
and no one indicated electronic media as first or
second choice in regard to acceptability and effec-
tiveness.
b) Sexual education and health care professio-
nals.
There was a consensus among responders regar-
ding the inadequacy of sex education for health
professionals (physicians and nurses). In addition,
the amount and quality of material available for
sexual education was reported to be adequate by
only one-third of the responders (Figure 13) . A
large majority of responder (77%) indicated that
the needs for sexual education in their region are
best satisfied by enhanced exposure to the topic at
the undergraduate and post-graduate level. The
remaining gave as first option the availability of
conferences and workshops. When asked to provi-
de a second priority for their country or region,
traditional publications (books, professional jour-
nals), audiovisual aids and improved curricula
were given equal value (Figure 14).
Of particular interest are the views of the World
Organization of National Colleges and Academies
of Family and General Practice (WONCA). Fami-
ly physicians are the point of entry in most health
care systems and they have the most intimate
knowledge of the social, family and medical histo-
ry of these patients. At the same time they have
received little or no training in ED during their
under and post-graduate years. It was pointed out
586
that the average consultation time is 12 minutes
which does not give much time for assessment or
counseling of erectile problems.
Another important professional group is nursing.
Nurses are close to patients, can be effective advo-
cates of patients within the health care system and
are well placed to discuss the patient’s physical
problems and partner relationships. It was felt that
nurse educators involved in primary and commu-
nity care nurse training are a fundamental target
audience for educational programs. In addition,
nurses are capable of sharing the load with prima-
ry care physicians.
The Committee believes that family physicians,
nurses and clinical psychologist in their formative
years should be targeted for enhanced training and
understanding of human sexuality in general and
sexual dysfunction specifically. In this regard, it is
important to reiterate the interdependence of the
various fields of expertise which should be able to
work in a harmonious and effective way.
The opinions regarding the information provided by
industry were mixed. It was recognized that before
medical therapy became available there was very
limited dissemination of information by industry. A
trickle began with the appearance of invasive phar-
macotherapy and now there is an avalanche of
information as a result of the availability of new
oral drugs. Comments regarding the efforts by large
companies in providing education in ED were gene-
rally positive. Various correspondents noted the
sensationalistic, frequently erroneous and derogato-
ry comments by the lay media which may have
resulted in a negative view of medical intervention
by patients suffering with ED. It was felt that, on
many occasions, industry has to battle with an
unjustifiably negative media. On the other hand,
concern was expressed about the large amount of
information, from clinical studies, that has been col-
lected by industry but has not yet been published.
There is a suspicion that industry may have delayed
publication of information that could adversely
affect their marketing position.
Regarding conflicts of interest between physicians
and industry, a variety of views were expressed.
They ranged from the inappropriateness of stock
ownership to lectures and workshops in which the
benefits of one product were extolled without pro-
per balance and exposure to alternative products.
Figure 10: The inadequacy of sexual education is a univer-
sal phenomenon. Even advanced and wealthy societies
experience it.
Figure 12: Booklets and audio-visual materials are consi-
dered the most effective means to disseminate educational
material for the public.
Figure 14: Professional education is best accomplished at
the undergraduate level with changes in curricula. These
changes need to emphasize the impact of ED in the quality
of life and the need to consider ED as a significant medical
condition. For practicing health professionals, re-enforce-
ment of those concepts is best accomplished by either work-
shops or standard printed material.
587
Figure 11: Although a great deal of educational material is
available for the public, much of it is inadequate in quality.
Self-serving, inaccurate information is quite prevalent
throughout the world. Health authorities and professional
organizations have been impotent in eliminating the flow of
inaccurate, self-serving or plainly false and misleading
advertising.
Figure 13: The quantity and quality of educational material
for health professionals is deficient in most regions. Only
recently, and mostly though industry support, there has
been an increase in the amount and quality of available
material both printed, electronic and in the form of courses
and lectures.
Behavior of health workers in the area of ED is felt
to offer an enormous potential for ethical conflict
and controversy. Again, the opinions are varied. It
was pointed out that at one end there is the honest
but misinformed clinician who may over-investiga-
te or the equally honest but ignorant one who may
treat without proper assessment of the patient. At
the other end, more serious, and bordering on the
criminal, is the behavior of some health care wor-
kers (it was remarked that physicians do not have
exclusivity on unethical practices) where false
advertising and exaggerated claims are rampant.
Equally serious and widespread is the practice of
inappropriate, experimental or unproved expensive
treatments (i.e. surgery for penile elongation).
4. DISCUSION
An early WHO document [33] stated that “Sexual
health is the integration of the somatic, emotio-
nal, intellectual and social aspects of sexual
being, in ways that are positively enriching and
that enhance personality, communication and
love. Fundamental to this concept are the right to
sexual information (the underlying is ours) and
the right to pleasure.” There is no qualm with this
statement but, at this juncture it should be
emphasized that all humans have a right to fac-
tual and accurate sexual information. The most
vexing educational issue for the Committee was
dealing with the inaccurate and self-promoting
material that is widely disseminated to the public
and health professionals. Although this is not a
phenomenon occurring exclusively in the field of
ED, it is particularly evident here with the recent
availability of relatively simple diagnostic and
therapeutic alternatives.
5. PUBLIC EDUCATION
Although an increasing amount of educational
material is available to increase public awareness
and understanding of the issues related to ED, the
material is not widely disseminated. Most of the
educational information is factual and of good qua-
lity. However, most of the publications are sponso-
red by industry and the potential for ethical conflict
is always present. In this regard the availability of
regional societies with a mandate to revise the accu-
racy of the information passed to the public is of
outmost importance. A relationship between the
health authorities and professional societies is an
obvious way to maintain and enhance public educa-
tion in the field of ED.
588
Traditional educational material (booklets and
videos) appear to be more effective. As the electro-
nic communications become more accessible they
may turn out to be equally effective. However, this
does not appear to be the case at the moment.
The interest of medical organizations in promo-
ting sexual health has grestly increased in the last
few years. The American Foundation for Urolo-
gical Diseases (AFUD) started in 1998 the Impo-
tence Awareness Month (October) and the ESIR
has established help lines in several European
countries. Similar organizations are developing
in Latin America, Africa and the Asia Pacific
region. This developments are a welcomed addi-
tion to the educational aspects of ED. The availa-
bility of information easy to obtain in a nonthrea-
tening situation is important for a public that
generally perceives ED has a terribly embarra-
sing topic to discuss openly.
Currently there is a proliferation of publications
on ED. It appears that every manufacturer of pro-
ducts for the treatment of the condition develops
an urge to publish information similar to the one
from the competitors but with a slant on their spe-
cific product or area of interest. Every regional
professional organization appears to be possessed
by the same informational urge. It would be desi-
rable to have a more centralized informational
office with a great deal of credibility providing
guidance and approval of the educational material.
Naturally, publications and information in general
require a great deal of cultural sensitivity as well
as understanding of the financial limitations expe-
rienced by the society to which such recommen-
dations are aimed to.
The commercial launching of sildenafil (Viagra)
was one of the major media events of 1998. Inter-
nationally the press created a variety of images
about ED and its new simpler orl treatment. On
many occasions, the importance of the primary
objective of treatment (to restore normal sexual
activity) was grossly distorted by the media which
presented Viagra as «the pill for happiness». The
media also frequently and erroneously indicated
that the drug was an effective aphrodisiac. This
image, together with the strident and unjustified
display of safety concerns interfered with the
proper physician-patient dialogue and the ade-
quacy of treatment.
The Committee feels that medical and nursing
schools are largely ignoring the importance of a
significant condition such as ED. In many regions
with health problems of an enormous magnitude
the consequences of ED appear to be secondary.
The Committee agreed with this assessment but at
the same time feels that ED needs to be considered
a significant condition that universally affects the
quality of life and that demands more considera-
tion in the formation of health professionals.
6. RECOMMENDATIONS
Increase awareness of the public on all aspects
of ED and better education of health professio-
nals will translate in an improvement in the
treatment of the condition. The WHO is in a
privileged position to develop a propitious envi-
ronment for an improvement in the prevention,
assessment and treatment of ED. The Commit-
tee feels that health organizations such as the
WHO and professional organizations such as
the the International Society for Impotence
Research should:
1. Promote the development of recommenda-
tions and guidelines, particularly on the
investigation and treatment of ED. This
would increase public confidence on modern,
efficacious, safe and affordable therapies for
ED.
2. Recognize that the development of guidelines
is usually a time consuming process, therefo-
re, international bodies should establish a
Committee for the development of Position
Statements in areas that demand prompt and
decisive action (false claims, unproven
methods) to prevent emotional, physical and
financial injury to sufferers of erectile pro-
blems.
3. Promote better understanding of the issues
related to ED by national health agencies and
authorities.
4. Heighten awareness by regional health
authorities as well as educational leaders on
the need to increase teaching of sexual health
issues in general and ED in particular at the
undergraduate level.
5. Disseminate widely factual, balanced and
truthful information regarding the causes,
investigation and treatment of ED.
589
6. Insist that all educational publications on
ED, including those sponsored exclusively by
industrial concerns, adhere to scientific and
ethical guidelines accepted by major scienti-
fic agencies and professional associations.
7. Denounce in their publications cases of mis-
leading and false advertising.
The Committee recognizes that the above
recommendations represent continued work
and cannot be carried out by groups working
sporadically. The membership of a group with
the mandate listed above requires, in addition
to a multidisciplinary representation, cultural
sensitivity as well as a balanced international
representation.
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___________________
 Committee 17

Neurological Disorders:
Erectile and Ejaculatory Dysfunction

Chairman
P.O. LUNDBERG

Members
N.L. BRACKETT,
P. DENYS,
E. CHARTIER-KASTLER,
J. SØNKSEN,
D. B. V ODUSEK

591
 CONTENTS

A. THE NEUROANATOMY E. ERECTILE AND EJACULA-

AND NEUROPHYSIOLOGY OF TORY DYSFUNCTION IN
ERECTION, EJACULATION SPINAL CORD DISORDERS.
AND ORGASM.
F. ADVERSE SEXUAL
REACTIONS FROM
B. SEXUAL CASE HISTORY IN PRESCRIPTION DRUGS
NEUROLOGICAL DISORDERS.
CLINICAL AND LABORATORY
INVESTIGATIONS. G. TREATMENT OF
NEUROGENIC ERECTILE
DYSFUNCTION
C.SEXUAL DYSFUNCTION IN
BRAIN DISORDERS INCLU-
DING MULTIPLE SCLEROSIS H. TREATMENT OF EJACU-
LATORY DYSFUNCTION IN
MEN WITH NEUROLOGICAL
DISORDERS
D. SEXUAL DYSFUNCTION IN
AMYOTROPHIC LATERAL
SCLEROSIS, POLYNEUROPA-
I. OVERALL CONCLUSIONS
THIES AND MUSCLE DYS-
AND RECOMMENDATIONS
TROPHIES.

592
 Neurological Disorders:
Erectile and Ejaculatory Dysfunction
P.O. LUNDBERG
N.L. BRACKETT, P. DENYS, E. C HARTIER-KASTLER, J. S ØNKSEN, D. B. V ODUSEK
A. THE NEUROANATOMY
AND NEUROPHYSIOLOGY OF
ERECTION, EJACULATION
AND ORGASM.
I. CEREBRAL CORTEX (Fig. 1)
Both thalamic and cortical areas receive sensory
input from the genitalia, and sexual feelings may
be elicited when such areas are stimulated. In the
primary sensory cortex, localised in the parasagit-
tal region of the brain, there is a centre for senso-
ry input from the genitalia. This conclusion is
based mainly on observations from a limited num-
ber of cases of parasagittal tumours. The rhinen -
cephalon, including the limbic cortex, is of impor-
tance for sexual behavior, but also for sexual desi-
re. Lesions of the frontal lobes, the baso-medial
part in particular, may lead to loss of social
control, which may also influence sexual beha-
viour. In a recent PET-study [1] where regional
cerebral blood flow was measured in eight male
subjects during visually evoked sexual arousal, the
following observations were made. The inferior
temporal cortex (a visual association region) was
activated on both sides. The right insula and right
inferior frontal cortex (regions processing sensory
information and motivational state) and the left
anterior cingulate cortex (involved in neuroendo-
crine function) were also activated. In the future
we can hope for many more imaging studies of the
functional anatomy of the human brain during
sexual activity. For clinical data about sexuality
and the cerebral cortex, see Lundberg [2].
593
II. HYPOTHALAMUS (Fig. 2)
In studies using retrograde labelling with pseudo-
rabies virus in the rat, most of the labelling from
the corpus cavernosum at the level of the dience-
phalon was found only in the hypothalmus - the
paraventricular nucleus, the tuber cinereum, the
medial preoptic area and the dorsal hypothalamic
area [3]. The neurons from the paraventricular
nucleus are known to project to thoracic and lum-
bosacral nuclei concerned with erection. Hypo-
thalmo-spinal projections are localised in the
dorsolateral funiculus [4].
The hypothalamus is the part of the human brain
directly controlling the gonadotropin functions of
the pituitary. In such a way both the prenatal and
pubertal development of the genital organs is
regulated. It is well established that in the basal
hypothalamus there is a centre for sexual desire.
Animal experiments have shown that tissue
levels of sex steroid hormones (testosterone,
dihydrotestosterone and estradiol) in the hypo-
thalamus affect desire. Destruction of this centre
by surgery [5] or by a tumour [6] leads to loss of
sexual desire. Animal experiments have proven a
dopaminergic stimulating and a serotoninergic
inhibiting mechanism within the hypothalamus
controlling sexual desire. Aseries of observations
on human beings supports the existence of simi-
lar mechanisms in man [7]. Sexually dimorphic
nuclei are localised in the anterior hypothalamus
- preoptic region. Their importance in humans is
largely unknown but they may play a role in
regulating sexual motivation and performance [8-
9].
 From the Ciba collection with permission

ACG : Anterior Central Gyrus

AG : Angular Gyrus
CS : Central Sulcus (fissure
of Rolando)
FP : Frontal pole
FS : Fissure of sylvius
IFG : Inferior frontal gyrus MTG : Middle temporal gyrus
IPG : Inferior parietal gyrus MTS : Middle temporal sulcus
IPS : IInter-perietal sulcus O : Operculum
ITG : Inferior temporal gyrus OP : Occipital pole SFG : Superior frontal gyrus STS : Superior temporal
LOG : Lateral occipital gyrus PCG : Posterior central gyrus SMG : Supra marginal gyrus sulcus
MFG : Middle frontal gyrus PCS : Pre-central sulcus SPG : Superior parietal gyrus TP : Temporal pole
POCS : Post central sulcus STG : Superior temporal gyrus
Figure 1: Cerebral cortex

Aq
ue
duc
t

From the Ciba collection

with permission
Figure 2: Hypothalanus

594

III. BRAINSTEM AND
SPINAL CORD (Fig. 3 &4)
In studies using retrograde labelling in the rat,
most of the labelling from corpus cavernosum at
the level of the brainstem was found in the pons
and medulla oblongata [3]. Projections from the
brainstem raphe nuclei descend through in the
lateral funiculus. The nucleus paragigantocellula-
ris was shown to have a majority of serotoninergic
neurons projecting to the spinal cord and provided
tonic inhibition of sexual reflexes in the rat [10].
Efferent nerve impulses are conveyed from the
brain stem through the spinal cord mainly via the
paraependymal tract.
Clinical observations support a theory that the cer-
vical spinal cord is of special importance for eja-
culation [11]. At low thoracic level (spinal cord
segments Th10 - L2) there is a centre for emis-
sion and ejaculation. The impulses are conveyed
via the sympathetic nervous system. Cerebral
(psychogenic) erection is also effected through
the sympathetic nervous system as well as inhibi-
tion of erection in a stress situation.
At the sacral level (S2-4) there is a centre with a
parasympathetic nerve outflow. These nerves
regulate reflex erection and changes in blood
flow in the genital area. Also entering the sacral
level are sensory nerve impulses from the sex
organs via both parasympathetic and somatic
nerves.
In the sacral spinal cord there is a nucleus called
Onuf´s nucleus [12]. The upper pole of this
nucleus lies at rostral S1/midcaudal S1 and the
nucleus varies in length between 4 and 7 mm.
There is a high density of neurons at the cranial
and caudal ends but no distinct segmentation.
This nucleus is comprised of alpha-motor neurons
to the pelvic floor muscles. These nerve cells have
special pathophysiological properties. In this
nucleus there are also nerve cells belonging to the
parasympathetic nervous system.
IV. RETROPERITONEAL SPACE
(Fig. 5)
The superior hypogastric plexus is localised retro-
peritoneally anterior to the aortic bifurcation at the
595
level of the fifth lumbar vertebral body and sacral
promontory between the common iliac arteries. It
divides caudally into the right and the left hypo-
gastric nerves. Within the pelvis these nerves
become the inferior hypogastric plexuses. This
plexus is joined on each side by the pelvic nerves,
also called the nervi erigentes. The inferior hypo-
gastric plexus is lateral to the rectum, seminal
vesicle, prostate and the posterior part of the uri-
nary bladder. The internal iliac vessels are lateral
to this plexus.
Most of the sympathetic nerve fibres are
conveyed through the hypogastric nerves and the
parasympathetic fibres through the pelvic nerves.
However, these plexuses contain numerous small
ganglia with nerve cells.
Pregangionic efferent sympathetic fibres originate
in the lower three thorasic and the upper two lum-
bar spinal segments. Preganglionic parasympathe-
tic nerve fibres originate in the second to forth
sacral spinal cord segments.
The vesical plexus is the anterior part of the infe-
rior hypogastric plexus. Branches from here also
supply the seminal vesicles and the deferent ducts
[13]. There are many neurons among the nerve
fibres in the vesical muscular wall [14]. The para-
sympathetic preganglionic efferent fibres are
mainly motor in function and stimulate the detru-
sor muscles as well as inhibit the internal bladder
sphincter. The efferent sympathetic nerve fibres
are also mainly motor in function but have the
opposite effect to the parasympathetic efferent
fibres. The sympathetic nerve fibres also have a
vasomotor function.
The prostate plexus comes from the lower part of
the inferior hypogastric plexus. It supplies the
prostate, the seminal vesicles, the ejaculatory
ducts and the prostatic urethra. It also contains
many neurons.
V. EXTERNAL GENITALIA AND
PELVIC FLOOR (Fig. 6)
From the front of the prostatic plexus there are two
set of nerves on each side: the lesser and the grea-
ter cavernous nerves. The nerve fibres travel
along the posterolateral aspect of the seminal
vesicle and prostate within the lateral pelvic fascia
 3

FI : Inter-peduncular Fossa
CP : Cerebral Peduncle
AS : Aqueduct of Sylvius
LQ : Lamina Quadri-gemina
CPV4 : Choroid Plexus of 4th Ventricle
AMV : Anterior Medullary Velum
F : Fastigium

Figure 3: Brainstem

596
 C1

Cervical Plexus

Brachial Plexus

C8

Dura Mater
Spinalis

T12

Conus Medullaris
L1
Iliohypogastric N.
Ilio-Inguinal N.
Genitofemoral N.
Cauda Equina
Lumbar Plexus
Femoral N.
Communication between
lumbar and sacral plexuses
Filum Terminale
Sacral Plexus
Superior Gluteal N.
Inferior Gluteal N.
Filum durae Matris Spinalis
Coccygeal N.

From the Ciba collection with

Pudendal N.
permission Sciatic N.
Posterior Cutaneous N. of
Thigh

Figure 4: Spinal Cord

597
 White and gray rami
communicantes 2nd Lumbar sympathetic ganglion

Aortic Plexus

Inferior mesenteric ganglion

Gray ramus
communicans

Inferior mesenteric
artery and plexus

Hypogastric plexus

Superior hemorrhoidal
artery and plexus

Right pelvic
plexus
Lumbo-sacral
plexus Vesical
plexus

Pelvic nerves (nervi

erigentes), sacral
parasympathetic Rectal plexus

Prostatic plexus

Cavernous plexus
Pudendal nerve
(somatic) Corpus penis

From the Ciba collection with permission

Figure 5: Retroperitoneal space

598
 T10
Great splanchnic
nerve
T11
Celiac ganglion
Lesser splanchnic
nerve
T12 Superior mesenteric
Least splanchnic ganglion
nerve
L1
Aortico-renal
ganglion

L2
Intermesenteric nerves
(aortic plexus)
L3 Inferior mesenteric
Internal spermatic
artery and plexus ganglion

Key L4

Sympathetic
preganglionics

Sympathetic Internal spermatic

postganglionics artery and plexus
Parasympathetic
postganglionics Hypogastric plexus

Parasympathetic
preganglionics
S1
Afferents and S1
somatic VAS
nerves
S2
S2

Pelvic nerve
Sacral plexus (nervus
S3 S3 erigens)

Sacral
S4 S4 plexus
S5
S5
Pudendal nerve

Pelvic nerve
Dorsal nerve of penis
(nervus erigens)
Vas deferens
Pelvic plexus
Epididymis
Vesical plexus Prostatic
plexus
Testis
Cavernous plexus
From the Ciba collection with permission

Figure 6: External genitalia

599
quite near the rectum [15] and then accompany the
membranous urethra through the genitourinary
diaphragm. These fibres are located on the lateral
aspect of the membranous urethra and ascend gra-
dually to the 1 and 11 o´clock position in the
proximal bulbous urethra [16]. The lesser caver-
nous nerve goes into the proximal part of the penis
to supply the erectile tissue of the corpus spongio-
sus and the penile urethra. The greater cavernous
nerve proceeds on the dorsum of the penis near the
dorsal vein and artery and supplies mainly the
cavernous bodies. The nerves follow the arteries
all the way and innervate the helicine arteries and
the erectile tissue. The nerves of the corpora
cavernosa have anatomical characteristics diffe-
rent from other nerves. The intracavernous nerves
are located in fibrous tunnels into which numerous
fibrous bundles establish attachments. These
bundles are part of a fibrous network. They are
supposed to prevent compression of the intraca-
vernous nerves during erection [17]. Also the peni-
le veins are under neurogenic control [18].
VI. PERIPHERAL SENSORY
MECHANISMS
The sensory input from the glans penis and the
skin covering the penis is conveyed mainly
through the dorsal penile nerve on both sides. The
dorsal penile nerves are branches of the pudendal
nerve. There is also a sensory input from the root
of the penis to the ilioinguinal nerve.
There are three types of nerve endings in the peni-
le area that can record exteroception. The most
superficial layer of skin/mucosa contains free
nerve endings which record pain. Through very
thin nerve fibres the impulses from these nerve
endings are conveyed via somatic peripheral
nerves, and then within the spinal cord, at veloci-
ties of 1-2 m/sec. Beneath the skin and mucosal
layer the so-called genital nerve corpuscles are
localised. These nerve endings look like balls of
yarn and have a central “nucleus”. Different types
of stimuli can regulate these nerve corpuscles so
that the cortical response changes. They react both
for pressure and movement and the impulses are
conveyed via medium-thick, myelinated nerve
fibres with a relative high velocity (40-60 m/sec)
to the cerebral cortex. Finally, along the nerves
and tendons surrounding the cavernous bodies,
600
there are rather large nerve endings which
resemble onions, with thick lamellae and a central
nerve fibre. These nerve endings respond to deep
pressure and vigorous movement. The nerve
impulses are conveyed through thick, myelinated
nerve fibres to the cortex at a very high velocity
(100 m/sec).
The last two types of nerve endings are thus loca-
lised within or near cavernous tissues. The type of
signal going to the brain via the spinal cord is
influenced by the amount of engorgement of
cavernous tissues. Touch may thus be experien -
ced as just touch or as sexual stimuli depending
upon the degree of engorgement.
Motor innervation of the pelvic floor muscles as
well as the ischiocavernosus and bulbocavernosus
muscles is conveyed through pudendal nerve
branches from below. However, there is also a
motor innervation of the pelvic floor muscles
directly from the sacral plexus.
VII. THE SEXUAL RESPONSE
CYCLE FROM THE NERVOUS
SYSTEM POINT OF VIEW
There are several mechanisms through which
erection can be achieved and maintained [19].
Psychogenic stimuli from the brain are at least in
part conveyed through the sympathetic nervous
system and the hypogastric nerves. This explains
why certain paraplegics with lesions to the cauda
and conus that preserve thoracolumbar segments
may still have erections. Somatic sensory affe -
rents deliver information on tactile stimuli mainly
from the genital region via the pudendal nerve.
After synapsing in the sacral spinal cord the effe-
rent arm of this arc travels via the pelvic nerves
producing vasodilatation and giving erection.
Continued parasympathetic activity maintains the
erection [20]. Contraction of some striated pelvic
floor muscles, the ischiocavernosus muscles in
particular, brought about through the pudendal
nerve, are also of importance for maintaining erec-
tion. For detail concerning animal experiments on
the physiology of erection, see Andersson & Wag-
ner [21].
For detail of the vascular mechanisms brought
about by the nervous system as well as about
transmitters, see other parts of this volume.
The sympathetic nervous system also conveys
nerve fibres causing inhibition of erection. These
nerve fibres produce vasoconstriction. This inhibi-
tion is considered part of the flight-alarm reaction
of the body and probably plays an important role
in psychogenic erectile dysfunction.
Continued sexual stimulation triggers seminal
emission through the sympathetic nervous system
already activated during the arousal phase [22].
Ejaculation is effected by an integrated sympa -
thetic outflow from the Th11- L2 segments The
sympathetic nerves cause smooth muscle contrac-
tions in the seminal vesicles, the prostate and the
ejaculatory duct [14]. The components of the
seminal fluid are delivered into the posterior ure-
thra. Sympathetic nervous activity also causes
contraction of the internal bladder sphincter
during ejaculation to prevent retrograde ejacula-
tion. The ejaculation proper, the expulsion of
semen through the urethra, is then brought about
through contractions of the striated pelvic floor
muscles, the bulbocavernosus muscle in particu-
lar. These muscles are under control of somatic
fibres arising from the pudendal nerve (S2-4). The
CNS mechanisms behind emission are not very
well known. Psychogenic factors are of great
importance, both as facilitators and inhibitors.
B. SEXUAL CASE HISTORY IN
NEUROLOGICAL DISORDERS.
CLINICAL AND LABORATORY
INVESTIGATIONS.
I. CASE HISTORY IN PATIENTS
WITH SEXUAL DYSFUNCTION AND
NEUROLOGICAL DISORDERS
1. GENERAL ASPECTS
From the general medical point of view the case
history should include a survey of the patient´s
medical history, particularly concerning cardio -
vascular, endocrine, psychological and psychia -
tric disturbances, neurological disorders, disor -
ders of the sex organs, prior trauma and surgical
procedures, the use of prescription drugs, smo -
king and alcohol habits, and possible drug abuse.
601
2. DETAILED HISTORY RELATED TO SEXUAL
DYSFUNCTION
From the sexological point of view the case histo-
ry should define the patient´s sexual expectations,
needs and behavior and should identify sexual
problems as well as misconceptions. Psychologi-
cal factors are often involved as an emotional reac-
tion to sexual dysfunction or as a consequence of
a socially or physically disabling disease. The
dependence and the lack of acceptance of the
disease by the patient or the partner, feelings of
unattractiveness or reduced self-esteem also play a
relevant role. It is usually important also to inter-
view the partner if the patient has one, and to eva-
luate the quality of marital/partner relationship.
Thus, it is important to clarify the nature and the
characteristics of sexual dysfunction, to disclose
the underlying (and possibly treatable) organic
cause and to evidence the existence of psychologi-
cal factors.
3. DETAILS OF THE CASE HISTORY OF
PARTICULAR NEUROLOGICAL INTEREST:
As always in neurology, temporal aspects are very
important. Has the problem been there all the time,
or did it have an onset at a particular point in time?
Was the development rapid or slow, the course
chronic or episodic?
1. The patient should be asked about sexual desi -
re. Is there a spontaneous desire, a lack of desi-
re but a wish to have a desire or a total sexual
uninterest? Is the desire evoked by specific
visual, tactile or emotional stimuli? Is the desi-
re partner-dependent or not?
2. Sensory aspects of sexual function should be
elucidated. The patient should describe sensory
experiences of sexual arousal in different areas
of the body. Present or past disturbances of sen-
sitivity in the region corresponding to the sacral
segments is of particular interest as well as pain
during sexual arousal or intercourse and pelvic
or superficial dyspareunia.
3. Descriptions of erections are important. Does
the patient have nocturnal erections, morning
erections, erections evoked by visual, auditory
or psychogenic stimuli and erections evoked or
enhanced by genital stimulation? What is the
quality of penile tumescence? Is there a prema-
ture loss of erection during sexual intercourse?
Does the patient have episodes of priapism or
painful nocturnal erections?
4. Ejaculation should be described. Does the
patient have premature or retarded ejacula -
tion, or even absence of ejaculation? Is the
ejaculation dribbling, i. e. is semen passing
through the urethra without contractions of pel-
vic floor muscles? Retrograde ejaculation
means ejaculation into the bladder with presen-
ce of spermatozoa in urine.
The term emission refers to peristalsis of the
ductus deferens with propulsion of semen from
the epidydimis, and smooth muscle contractions
in the ampulla, prostate and seminal vesicles
resulting in collection of seminal fluid in the
posterior urethra. Aspermia means lack of
emission of semen [1]. Both lack of emission
and retrograde ejaculation can be described as
«dry ejaculation». Spontaneous ejaculations
may also occur or ejaculations may be painful.
The fertility history should be investigated.
5. The the capacity to achieve an orgasm and also
the quality of orgasmic sensations and expe-
riences should be analyzed. An orgasm may be
unhedonic, i. e. without pleasurable sensations.
The patient may have orgasms without ejacula-
tions or ejaculations without orgasms.
In sexology, one often talks about the orgasmic
phase. Kaplan [2] has simplified the sexual res-
ponse model into three phases: the phase of Desi -
re, the phase of Excitement and the phase of
Orgasm. (DEO) (Table 1). Thus, the orgasm can
be defined as the sum of all physiological events
that happen in the body during the sexual climax
and how the individual experiences this. Others
define the orgasm in men as just the feeling of
pleasure accompanying ejaculation. However, the
word orgasm should never be used to describe the
ejaculation itself, i. e., the forceful expulsion of
semen from the penis. Unfortunately, in the litera-
ture the terms orgasm and ejaculation are often
Table 1: Sexual response model
1. PHASE OF DESIRE
Sexual stimulation
2. PHASE OF EXCITEMENT
Erection
Further sexual stimulation
3. PHASE OF ORGASM
Emission
Ejaculation
Orgasm
602
poorely defined which makes the interpretation of
data difficult.
Further details about case history can be found in
Fugl-Meyer et al [3]. Formal questionnaires can be
used to obtain standardized information. An often
used form is the «Brief Male Sexual Function
Inventory for Urology» [4]. It has been suggested
that this protocol is helpful in studies of treatment
efficacy in patients with erectile disorders, but not
practical for everyday assessment of patient with
sexual dysfunction [5].
II. THE CLINICAL EXAMINATION
OF THE NEUROLOGICAL PATIENT
WITH SEXUAL DYSFUNCTION
1. GENERAL CLINICAL EXAMINATION
Sexual development, body height and weight,
changes in pigmentation and body hair and the
presence of galactorrhea are looked for. Inspection
of external genitalia for any pathology, evaluation
of the size of the testes (normal 15-25 ml) and the
prostate gland is performed.
Palpation of peripheral pulses (arms, legs, penis),
auscultation of the heart, and blood pressure mea-
surement is mandatory.
2. NEUROLOGICAL EXAMINATION
A standard neurological examination including
assessment of mental state should reveal any signs
of an underlying neurological disease. Such an exa-
mination will always be somewhat tailored to the
particular patient´s data obtained from the history.
In addition, particular care will be given to inspec-
tion of lower back (for naevus, hypertricosis, sinus
etc.) and the feet (for deformity, muscle atrophy).
Special attention should be paid to the nervous
function of sacral segments. The bulbocavernosus
muscles can be palpated, and tested for voluntary
contraction («move the penis»), and reflex contrac-
tion. Anal sphincter and levator ani tone, volunta -
ry and reflex contraction can be examined. In addi-
tion to standard reflexes, the cremasteric reflex (tes-
ting the L1 segment), and the bulbocavernosus and
external anal reflex (testing the S2 to S4-5 seg-
ments) should be tested [6]. The bulbocavernosus
reflex is tested by squeezing the glans and obser-
ving (or palpating) contraction of the anal sphincter
or the bulbocavernosus muscle. The external anal
reflex is tested by repetitive pricking (or a scratch)
delivered to perianal skin (on both sides!) and
observing for anal sphincter contraction. Skin sen-
sitivity is tested for touch and pain perception in the
perineum, perianally and on the genitals in addition
to testing other dermatomes.
Particular laboratory tests (usually classified as
neurophysiological) are direct extensions of clini-
cal examination of the nervous function. Thus, a
controversial reflex response can be recorded with
greater sensitivity electromyographically; perineal
sensation can be quantified using special devices
and algorithms (see below).
3. INVESTIGATIONS
Generally speaking, the investigations will be per-
formed to objectively assess sexual function, and
then to address the questions of etiology. In few
centers and in very selected males with erectile
dysfunction, spontaneous and physiologically
induced erections are examined; the capacity to
obtain pharmacological erection is evaluated rou-
tinely in many centers. Other segments of sexual
function (i. e., ejaculation) are, as a rule, not
directly evaluated. If retrograde ejaculation is sus-
pected, the bladder neck (internal urethral sphinc-
ter) function may be assessed by videourodyna-
mics. Basic blood and urine tests are commonly
recommended for any patient with erectile or eja-
culatory dysfunction. In some patients, further
investigations are performed to evaluate the neu-
rogenic, vascular, endocrinologic and other pos-
sible etiologic factors, but always in view of the-
rapeutic and prognostic considerations.
a) Investigation of erectile function
Although valuable data will be obtained by histo-
ry, objective evaluation of erection is considered
the gold standard to determine its quality. Sponta-
neous and physiologically induced erection can be
studied with a variety of techniques. The sponta -
neous nocturnal penile tumescence and rigidity
can be measured in the sleep laboratory using
mercury strain gauges (measuring penile expan-
sion), visual inspection and measuring the buck-
ling force (for assessment of rigidity), and poly-
graphic confirmation of sleep phases; such a pro-
cedure is considered as the most accurate for
determining erectile function [7-8]. Various low
603
cost screening tests for nocturnal penile expansion
have been proposed, but their validity is questio-
nable [9]. Continuous monitoring of nocturnal
penile tumescence and rigidity can be obtained by
a rigidometer during normal sleeping conditions at
home [10], and also during daytime napping [11]
or in the awake sexually stimulated examinee [12].
The screening tests for nocturnal penile tumescen-
ce have been classified as promising in distingui-
shing psychogenic from other causes of erectile
dysfunction, but insufficient on their own to arrive
at such a conclusion. However, home measure-
ments with the rigidometer have been classified as
a promising screening in establishing presence and
quality of erections. The nocturnal penile tumes-
cence measurement in the sleep laboratory has
been proposed to be reliable in distinguishing psy-
chogenic from other causes [13].
b) Investigation of erectile capacity
In addition for the need to study spontaneous or
physiologically induced erections (to verify histo-
ry data and distinguish psychogenic from organic
dysfunction), the great advancement in diagnos-
tics of erectile failure came with the introduction
of pharmacologically induced erections. Given
that no major vascular problem is present (particu-
larly no significant venous incompetence) an
intracorporeal injection of a vasoactive substan -
ce (papaverine; combination of papaverine and
phentolamine; prostaglandin E1) will lead to an
erection, thus strengthening the suspicion of neu-
rogenic or psychogenic etiology of erectile dys-
function [14]. The combination with self-stimula-
tion is considered to increase the test sensitivity
[15]. Intracorporeal injection of vasoactive agents
has been proposed as an established diagnostic
tool in patients undergoing assessment for pos-
sible neurogenic erectile dysfunction, and if per-
formed by experienced physicians, is considered
to be safe and have an acceptable complication
rate [13].
c) Investigation of nervous system function -
clinical neurophysiological and other methods
In patients with erectile (and occasionally ejacula-
tory) dysfunction and (suspected) neurologic disor-
der, a diagnosis of involvement of neural and mus-
cular structures related to sexual function may be
strengthened, refined and documented by neuro-
physiologic tests. There are several different
methods, and they may be classified according to
the neuroanatomic subsystem whose function they
test. Motor (somatic and autonomic), and sensory
(somatosensory and viscerosensory) tests may be
distinguished (Table 2). Most of the tests are elec-
trophysiological, but quantitative sensory testing
and testing lower urinary tract and anorectal func-
tion (as indices of sacral autonomic function) can be
conveniently discussed under the same heading.
In addition to clinical testing for sensation, special
devices and algorithms can be used for quanti-
fying sensory perception on the genital organs.
Measuring vibratory perception (biothesiometry/
vibrametry) on the penis has been found to corre-
late with results of electrodiagnostic testing [16].
The vibration sense threshold in the penis (glans
and shaft) is in the neurologically healthy man
similar to that of the feet [17]. The test is conside-
red promising in evaluating penile sensation [13,
Table 2: Tests of nervous system function
SOMATIC SENSORY TESTS
• Quantitative sensory testing
• Dorsal penile nerve neurography
• Pudendal somatosensory evoked potentials (SEP)
• Vibrametry
REFLEX LATENCIES
• Bulbocavernosus reflex
• Anal reflex
VISCERAL SENSORY TESTING
• SEPto proximal urethra/bladder neck stimulation
• Testing bladder sensitivity
• Sacral reflex to proximal urethra/bladder neck stimulation
SOMATIC MOTOR TESTS
• Electromyography
• Pudendal motor latency
• Motor evoked potentials (MEP)
(above mentioned reflexes also test the motor part of the
reflex arc).
AUTONOMIC TESTS
• Sympathetic skin response
• Penile (corpus cavernosum) EMG
• Neurocardial tests
• Cystometry
• Anorectal manometry
604
18]. Even more informative on nervous control of
erection should be tests evaluating thin fiber func-
tion, i.e. testing for penile thermal sensation [19].
Electromyography (EMG) may be used to
demonstrate activation patterns of striated muscles
-within the sexual response - kinesiological EMG;
as for instance demonstrating the pattern of pe-
rineal muscle activity during ejaculation [20].
EMG however, is mainly used to differentiate nor-
mal from denervated (reinnervated) muscle.
Concentric needle EMG (Figure 7-8) can identify
changes due to recent denervation, and changes
due to reinnervation, and is considered the method
of choice to diagnose lower motor neuron invol-
vement in the lower sacral myotomes (i. e., in pel-
vic floor, bulbocavernosus and sphincter muscles).
Apart from diagnosing traumatic and compressive
lesions this may be particularly helpful for streng-
thening a diagnosis of multiple system atrophy
(Figure 4) in which erectile dysfunction can prece-
de other symptoms [21]. Different tests involving
stimulation and recording of somatosensory and
motor evoked responses, and sacral reflexes,
reflect the function of defined parts of the motor
and sensory nervous system (Figure 9). These tests
measure conduction through nervous pathways
and are sensitive to demyelinization, but not to
axonal lesions (which predominate in clinical
practice). Tests have been proposed to assess the
lumbosacral sympathetic system (the sympathetic
skin responses) and penile smooth muscle (the
corpus cavernosum EMG). Details of methodolo-
gy and findings are discussed elsewhere [22-23].
Neurophysiological tests provide a safe means of
detecting nerve or muscle pathology and may refi-
ne the diagnosis of nervous system involvement.
In a recent review [22] of such testing for patients
with incontinence (i.e., another group of patients
with possible involvement of the sacral nervous
system and/or its suprasegmental connections) it
has been suggested that tests should be considered
in selected patients with suspected or known
involvement of the peripheral nervous system (i.e.
of the sacral reflex arc). In these patients, concen -
tric needle EMG of pelvic floor muscles and
recording of the bulbocavernosus reflex have
been classified as optional, and all other tests as
investigational. The review further suggested that
testing in patients with suspected central nervous
system involvement would rarely reveal abnorma-
 Figure 7: Concentric needle EMG recording
from right bulbocavernosus muscle of a 49-
years old male. Pathological spontaneous activi -
ty (runs of positive sharp waves) is shown.

Figure 8: Concentric needle EMG recording

from the external anal sphincter from the same
patient as in Fig. 7. A polyphasic motor unit
potential of prolonged duration is shown. Ove -
rall, the percentage of polyphasic potentials was
50%.
The happily married and otherwise healthy man
presented with a one year history of progressive
erectile dysfunction, which became complete
(no erections on attempted intercourse, mastur -
bation; no morning erections). He recently
became aware of slight gait insecurity. Signs of
mild cerebellar ataxia and bilateral Babinski
signs were present on examination, neuroima -
ging was negative. A diagnosis of possible Mul -
tiple system atrophy was given. The diagnosis
was supportod by development of slight parkin -
sonism and urge incontinence at follow up alter
six months.

Figure 9: Different tests involving stimulation

and recording of somatosensory and motor
evoked responses, and sacral reflexes, reflect
the function of defined parts of the motor and
sensory nervous system (Figure 9).

605
lities not already verified by clinical examination;
in such patients the recording of pudendal soma -
tosensory evoked potentials was classified as
optional Although it was initially hoped that neu-
rophysiologic tests would discriminate between
neurogenic and non-neurogenic erectile dysfunc-
tion the correlation of test results and erectile func-
tion has been generally poor. In order to diagnose
erectile dysfunction in a particular patient as neu-
rogenic an abnormal test result should be correla-
ted to erectile failure in absence of any additional
factors which might cause the problem. But abnor-
malities in neurophysiologic tests (EMG, evoked
potentials) have been found in patients with good
erections, and absent erections in a patient with
abnormal test results can still be at least partially
due to other (non-neurogenic) factors. The neuro-
physiologic tests can only be expected to correlate
with the underlying neuromuscular pathology.
Even their correlation to “simple” nerve and
muscle function is not straightforward, and there-
fore very strong correlation to any “complex”
function (such as erection) cannot be expected.
This is not only because most established methods
test somatic elements of the sacral neuromuscular
system, but also because most of the diagnosed
lesions are only partial. Partial lesions may not
necessarily lead directly to obvious dysfunction.
To summarize, neurophysiological tests have a par-
ticular sensitivity and specificity for diagnosing a
neuromuscular lesion (and even that is not well
explored in literature) but not in any general way to
diagnose sexual dysfunction. Also, neurophysiolo-
gic tests cannot in and of themselves define erectile
dysfunction as neurogenic [13]. However, measure-
ment of dorsal penile nerve conduction, the bulbo-
cavernosus reflex, and pudendal SEP have been
suggested as promising tools in evaluating patients
with suspected neurogenic erectile dysfunction
[13]. This may be particularly true if tests are selec-
tively applied in well defined patient groups. The
presence of the bulbocavernosus reflex, for instan-
ce, has been reported to correlate highly with pre-
sence of reflex erection in a group of spinal cord
injured patients [24]. Tests measuring penile auto-
nomic innervation and smooth muscle function
would be of particular diagnostic value, but their
validity is controversial (for corpus cavernosum
EMG) or the clinical experience still scarce (for
perineal sympathetic skin response). Arecent report
606
found correlation of psychogenic erection and sym-
pathetic skin responses in the perineum in spinal
cord injured patients [24].
Cystometry, other urodynamic tests, and anorectal
function tests may strengthen the suspicion of
sacral autonomic dysfunction [25].
After delineating as much as possible the presence
of a neurological deficit by clinical and laboratory
examination, further investigations (neuroradiolo-
gical, cerebrospinal fluid etc) necessary to diagno-
se the neurological disorder are performed.
4. LABORATORY INVESTIGATION OF BLOOD
AND URINE
Basic laboratory data (including sedimentation
rate, blood cell count, fasting blood sugar, serum
lipids, urinanalysis) as well as serum parameters
screening for hepatic, kidney and thyroid function
should be obtained in every patient suspected to
suffer from organic sexual dysfunction. What hor-
mone to be studied is dependent on the circum-
stances (sex, age, onset of symptoms). Prolactin
and testosterone levels in blood should be investi-
gated whenever a hypothalamo-pituitary-gonadal
insufficiency is suspected.
5. INVESTIGATION OF VASCULAR FUNCTION
If intracorporeal injection testing of penile tumes-
cence has strengthened a suspicion of vascular
etiology in the male patient with erectile dysfunc-
tion, further investigations may be contemplated,
and as a rule are performed by urologists. Penile
blood pressure can be measured using a simple
Doppler method and then related to the arm blood
pressure. Vascular competence can be measured
by angiography, color ultra-sonography and dyna-
mic cavernosography. It has been stressed that the
purpose of testing should always be defined: phar-
macotesting may be sufficient for the majority of
patients, and the invasive tests reserved for those
in whom surgery is contemplated [26].
6. A DIAGNOSTIC ALGORITHM (Figure 10)
It has to be acknowledged that the diagnostic pro-
cedure to establish an erectile dysfunction in a par-
ticular patient as neurogenic has at this stage of
our knowledge mostly some relevance for defi-
ning the neurological disease, disorder or trauma -
of which ED is one of the symptoms -, but not yet
much influence on choosing a particular treatment
607
option. In offering an algorithm for diagnostic
decisions in patients with ED of possible neuroge-
nic origin, the fact should be stressed that treat-
ment may be instituted at any stage of assessment
as it will be little influenced by detailed diagnosis.
Nevertheless, many patients and their physicians
will desire a better knowledge of the underlying
pathophysiology of ED; furthermore such know-
ledge may be of prognostic value. The suggested
algorithm (Figure 10) may serve as a basis for
insights how further diagnostic tests - which at
present are classified as investigational, and there-
fore not included - could further improve the defi-
nition of the neuromuscular lesion underlying the
ED, and how further subgroups of patients might
be evaluated. Its is to be expected that better defi-
ned neurological diagnosis of patients with pos-
sible neurogenic ED may prove more relevant in
the future, when treatment options tailored to par-
ticular subgroups of ED will become available.
Futhermore, a better diagnostic definition of
patient subgroups may be important in research
projects on pathophysiology of sexual dysfunction,
and on the effect of different treatment options in
well defined subgroups of neurological patients. A
simplified algorithm is shown in Table 3.
Table 3: Erectile dysfunction and suspicion of a neurologi -
cal disorder
1. Spinal cord injury :
Remit to Spinal Cord Injury Center
2. Other known neurological disorder :
Consult with neurologist treating patient
3. Case history and/or result of neurological examina-
tion indicates central nervous system disorder :
a) Try to make a diagnosis
b) Then : Try oral drugs such as sildenafil at first
4. Case history and/or result of neurological examinat-
ion indicates peripheral nervous system disorder :
a) Try to make a diagnosis
b) Then : Try ICI with prostaglandin E 1 at first
5. No known neurological disorder present nor anything
in case history nor in examination indication nervous
system disorder :
Proceed according to general principles
608
III. CONCLUSIONS AND
RECOMMENDATIONS
Taking a careful case history, performing at
least a focused neurological examination,
including the lumbosacral segments, com-
plemented in very selected patients (particu-
larly those with suspected peripheral ner-
vous system involvement) by neuro-physio-
logical tests, should - in addition to other
indicated investigations - be considered in
patients seeking medical advice because of a
sexual disability.
C. SEXUAL DYSFUNCTION IN
BRAIN DISORDERS INCLU-
DING MULTIPLE SCLEROSIS
I. SEXUAL DYSFUNCTION IN
PATIENTS WITH HYPOTHALAMO-
PITUITARY DISORDERS
Decreased or absent sexual desire is the cardi -
nal symptom in males with hypothalamo-pitui -
tary disorders. In most cases this is the first
symptom to appear. However, males rarely seek
medical advice when experiencing a loss of
sexual desire. Hence, the diagnosis is usually
postponed in men until some other symptoms
appear and it may be as long as a decade after the
onset of the sexual problem before any further
symptom of a pituitary tumour develops. Three-
fourths of hypothalamo-pituitary cases report
decreased or absent sexual desire at the time of
diagnosis. The figures are higher for those with
larger tumours extending into the suprasellar
region than for those with intrasellar tumours. A
highly significant correlation has been found bet-
ween low serum testosterone levels and a decrea-
se in desire [1]. Usually the patients also have an
erectile failure. However, because of reduced
sexual interest, the erectile failure is less proble-
matic to the patient. Decreased sexual desire is
also the first symptom in most men with smaller
pituitary tumours and hyperprolactinaemia [2].
Most of the time a hypothalamo-pituitary dys-
function is caused by a pituitary adenoma. There
are also less common types of tumours in this
region of the brain such as craniopharyngiomas,
meningiomas, optic gliomas, hypothalamic
hamartomas and metastasis [3]. Furthermore,
there are many non-tumour disorders of hypotha-
lamo-pituitary dysfunction with loss of sexual
desire and impotence as cardinal symptoms [4].
There are also a lot of other causes of secondary
hypogonadism (see committee 7). Thus, in a
CT/MRI study of 164 impotent men with low
serum testosterone values significant pathology
of the hypothalamo-pituitary region was found in
only 11 patients [5].
II. SEXUAL DYSFUNCTION IN
PATIENTS WITH BRAIN INJURIES
Disability and cognitive impairment occur rather
often after a traumatic brain injury. Sexual
impairment is not rare either as a consequence
of the cerebral lesion or as a consequence of psy-
chological factors. Both decreased and increased
sexual desire may be seen as well as impotence
and retarded ejaculation [6-7]. Lesions of the
frontal and temporal lobe seem to result more
often in sexual problems than do lesions of the
parieto-occipital part of the brain. Bilateral
lesions of the anterior temporal regions may
result in the so-called Klüver-Bucy syndrome
where pansexuality is a prevailing symptom.
Pansexuality refers to sexual drive that is direc-
ted not only towards humans but also towards
animals and inanimate objects.
III. STROKE AND SEXUAL
DYSFUNCTION
About 3/4 of stroke patients who were sexually
active before the stroke, report an abrupt and per-
manent decrease in coital frequency. The feeling
of an overall change in sexual life is reported more
frequently by male patients. The majority (50-
65%) have erectile dysfunction after a stroke [8-
11]. In one study nocturnal erections two months
609
after their stroke were normal in 45%, and impai-
red in 55% of patients [12]. Orgasmic dysfunction
after stroke was reported in 2/3 of men [8]. Sexual
problems in post-stroke patients are usually
explained in terms of lack of coping. Diminished
sexual contact for post-stroke patients is primari-
ly due to the patient´s overwhelming fears of
inadequacy. Other psychological factors have also
been suggested. Cognitive impairment may dis-
turb the sexual part of a relationship. Sexual pro-
blems are more often seen in cases with aphasia
[13]. In some studies the prevalence of major
sexual dysfunction (decrease in libido and in fre-
quency of intercourse) was significantly greater
after right than after left hemisphere stroke in male
patients with unilateral stroke [14-15]. Other stu-
dies did not confirm this observation [8,16].
Lesions in the non-dominant hemisphere and the
parietal lobe in particular were more often asso-
ciated with a decline of desire. General hemi-
hypoaesthesia is associated with decreased sexual
ability probably due to loss of erogenous zones.
IV. SEXUAL DYSFUNCTION IN
PATIENTS WITH EPILEPSY
Numerous symptoms of sexual dysfunction can be
seen in epileptic patients, during the interictal per-
iod or in relation to seizures.
a) Interictal phenomena.
Many male epileptic patients suffer from loss of
sexual desire, reduced sexual activity, and/or
inhibited sexual arousal [17-20]. The figure
varies in different studies and is generally higher
than those observed in the control population, with
some exceptions. Inability to maintain erection,
more rarely ejaculatory dysfunction, decreased
satisfaction with sexual life, reduced sexual fanta-
sies, dreams and initiatives, are reported in
patients with complex partial epilepsy and mesio-
basal temporal spike focus [21-22]. Sexual interest
seems to be more reduced in patients with right
compared to left temporal lobe epilepsy. Life satis-
faction and sexuality are higher in patients who are
seizure-free compared to non-seizure-free. Prior
surgery for epilepsy does not seem to be a causal
factor [23]. Hypersexual behaviour exists only in a
few reported cases [24]. Social and psychological
factors may also play an important role.
b) Seizures and sexual dysfunction
Epilepsy and sexual behaviour may be connected in
many ways. For example, sexual activity can pro -
voke an epileptic attack, sexual phenomena may be
a part of an epileptic seizure, and the epileptic
patient may display changes in sexual behaviour.
Hyperventilation is weIl-known to provoke gene-
ralised epileptic seizures. Most individuals hyper-
ventilate during sexual intercourse. Thus, it is not
uncommon for sexual activity to provoke an epilep-
tic fit. Certain types of sexual behavior can trigger
a partial epileptic attack by stimulating particular
cortical areas of the brain. Sexual fantasies as well
as genital stimuli (masturbation) or orgasm may
trigger reflex epilepsy. Only few such cases have
been published but the problem is probably not
reported very often by the patients if not explicitly
asked for.
If an epileptic seizure is generated from a genital
sensory cortical area, sensations in the genital
organs may be experienced as a partial epileptic fit
[25]. Motor symptoms such as erection and ejacula-
tion or the sensory experience of an orgasm may
occur during an epileptic fit. Such events may be
experienced by the patients as sexual or as non-
sexual. Pelvic sexual movements, as a part of epi-
leptic automatisms, or compulsive masturbation in
front of other people may occur during or after a
seizure.
In addition to sensory phenomena, other sexual
phenomena may occur during an epileptic seizure
in patients with complex partial epilepsy, most
often in patients with temporal lobe lesions [26].
Sexual automatisms may also occur with frontal
lobe lesions. They are very uncommon in primary
generalised epilepsy of the grand mal or petit mal
type.
Deviate sexual behaviour such as exhibitionism,
fetishism, frotteurism, sadomasochism, transves-
tism, and violent sexual behavior or pansexual
behavior is sometimes displayed by the epileptic
patient. Only a small number of cases have been
reported but the fact that the behaviour in question
may occur episodically and sometimes disappears
after treatment speaks in favour of a causal
connection between the behaviour and the epilep-
sy or the cerebral lesion behind it. In most cases
there were partial complex epileptic seizures and
lesions in one or both temporal lobes. Sometimes
610
the deviate behavior correlated with continuous
epileptic discharges in the EEG (psychomotor sta-
tus). For further details about sexual phenomena in
epileptic patients, see Lundberg [4].
c) Antiepileptic drugs and sexual function
It should be noticed that antiepileptic drugs, espe-
cially the older types (phenytoin, phenobarbital,
primidone and carbamazepine), may influence
both sexual desire and performance [27]. Patients
on phenytoin or carbamazepine monotherapy as
well as those on polytherapy had a significantly
lower free androgen index than controls [28]. In
this study it was also found that those patients
receiving anti-epileptic drugs embraced a stricter
sexual morality and expressed greater satisfaction
with their marriages then untreated patients with
epilepsy.
V. SEXUAL DYSFUNCTION IN
PARKINSON´S DISEASE AND
OTHER MOVEMENT DISORDERS
Decrease in sexual desire is common in Parkin -
son´s disease. Symptoms of sexual dysfunction
are also frequent in their partners [29]. Erectile
dysfunction during sexual intercourse occurs in
half of the males [30-31] and nocturnal and mor-
ning erections are usually absent. Many males are
also unable to ejaculate and to achieve an orgasm.
During sexual arousal tremor is often enhanced
which makes sexual activity more difficult.
Muscle rigidity and akinesia may also contribute
to difficulties in performance of sexual activities.
Patients with Parkinson´s disease are often depres -
sed and have a tendency to isolate themselves
from other people.
The mechanisms behind sexual dysfunction in
parkinsonian patients is not very well understood.
To some extent it may be a similar mechanism as
with other chronic disorders, such as arthritis [32].
But studies of bladder and bowel function have
demonstrated a high frequency of bladder detru -
sor hyperreflexia and paradoxical contractions
of the striated sphincter muscles during defeca-
tion, suggesting that specific autonomic nervous
system involvement may exist in these patients
[33-34].
It is interesting to note that decrease of sexual
desire is not directly coupled to the severity of the
disease. Treatment with dopaminergic compounds
may result in an apparent increase, or rather a nor-
malisation, of sexual desire without corresponding
improvement of the movement disorder. Thus,
increase in desire has been reported as an adverse
reaction to dopaminergic drugs.
The situation is quite different in Huntington´s
disease (HD). Fertility is increased among these
patients: those of the family who are going to
develop the disease have more children than those
who do not. Increased sexual activity is seen in
around 10% of the patients with HD, not seldom in
combination with mania or hypomania. Habitual
promiscuity and marital infidelity may be symp-
toms of onset in HD. However, HD patients may
have difficulty in getting sexually aroused. Para-
philias such as sexual aggression, exhibitionism
and pedophilia have been reported in HD patients
[35].
Disorders of sexual inhibition and some kind of
pansexuality, e.g. copulation with non-living
objects are not infrequent in Tourette´s syndrome
[36-37]. Increased sexual activity is also reported
in patients with Wilson´s disease [38]. Impotence
is almost universal among patients with multiple
system atrophy, both of the striato-nigral type and
the olivo-ponto-cerebellar type [39]. It may be the
presenting symptom.
VI. SEXUAL DYSFUNCTION IN
MULTIPLE SCLEROSIS
Changes in sexual function are rare at the onset
of the disease but become very common during
the evolution of the disease. Impotence is the
most notable sexual dysfunction in men with mul-
tiple sclerosis. Figures given in the literature vary
between 35 and 80% [40-44]. There are no indica-
tions of insufficient arterial inflow or venous out-
611
flow [45]. Problems with ejaculation are also very
frequent, 35-60 % have been reported [41, 43-44].
Decreased desire also occurs, but this problem has
not been studied to a large extent.
Occasionally, increased sexual desire can constitu-
te a problem. Sexual dysfunction correlates with
bladder and bowel dysfunction and mildly with
motor and sensory dysfunction in the lower extre-
mities [42, 46-47]. The correlation is poor with
disability, clinical course and disease duration.
Depression and cognitive impairment may play
an important role. Anorgasmia has been correlated
with MRI brain stem and pyramidal abnormalities
as well as with total area of lesions on MRI [48].
Symptoms related to MS, such as fatigue, muscle
contractions in the lower limbs, urinary distur-
bances and the use of aids to manage incontinen-
ce and paroxysmal motor and sensory distur-
bances triggered by sexual intercourse can indi-
rectly exert a negative effect on sex life as well as
social and physical changes. A comprehensive
review on sexuality and MS has recently been
published [49]
VII. CONCLUSIONS
Sexual disabilities such as erectile dysfunction
and disturbances of ejaculation and orgasm are
very common among patients with disorders of
the central nervous system. Examples of such
disorders of great importance are sequelae
after brain injuries, stroke, Parkinson´s disea-
se, multiple sclerosis and epilepsy. In brain
disorders and after brain injuries sexual desire
may also be reduced and behavioral distur-
bances may occur.
Sexual disabilities may be the presenting symp-
tom or one of the early symptoms of a neurolo-
gical disorder.

D. SEXUAL DYSFUNCTION IN
AMYOTROPHIC LATERAL
SCLEROSIS, POLYNEUROPA-
THIES AND MUSCLE
DYSTROPHIES
Since amyotrophic lateral sclerosis is a rapidly
progressive paralytic disease leading to an almost
total paralysis of the whole body including respi-
ratory muscles, severe sexual problems might be
expected. However, the neurones of Onuf´s
nucleus in the sacral spinal cord innervating the
pelvic floor muscles are spared and the patients do
not have sensory or autonomic symptoms. Thus,
the patients usually have no difficulty with urina-
tion and defecation, and normal sexual functions
are the rule in males [1]. Despite the fact that seve-
re paralysis of all voluntary movements eventual-
ly make intercourse impossible, erection and eja -
culation is possible through partner masturbation
and the sensation of orgasm may be experienced
as normal.
In Kennedy´s syndrome (X-linked bulbospinal
muscular atrophy) gynecomastia is common, and
testicular atrophy, decreased libido and impotence
may occur [2]. In certain types of progressive
muscular dystrophies, the Becker type in particu-
lar, hypogonadism in combination with distur-
bances of potency and reduction of libido have
been described [3]. Early onset of the neuromus-
cular disease, together with rapid disease progres-
sion results in constricted psychosocial and psy-
chosexual development and in severe limitations
on sexual activity [4].
Autonomic dysfunction, including erectile dys-
function, is a common complication in peripheral
neuropathies [5]. Polyneuropathies resulting in
such complications include those due to infec-
tious agents, chemical toxins [6], prescription or
street drugs, vitamin deficiency (Vitamin B1 [7],
Vitamin B12 [8]) as well as parainfectious or
612
paramalignant manifestations. Such is also the
case in Guillain-Barré syndrome. In a study of
341 consecutive impotent patients, neurophysio-
logical evaluation for polyneuropathy revealed
the presence of polyneuropathy in 38 % of the
diabetic cases and in 10 % of the other impotent
cases [9].
For a further description of sexual dysfunction in
diabetic polyneuropathy the reader is referred to
the Chapter on Endocrine and Metabolic Aspects
in this volume as well as to recent reviews [10-
11].
In addition to the neuropathies described above,
there are also a number of hereditary metabolic
polyneuropathies. Very little has been written
about sexual dysfunction in these types of poly-
neuropathies. However, based on physiological
data both impotence, retarded or retrograde ejacu-
lation and difficulty in reaching the orgasm phase
are to be expected. Thus, impotence and ejacula-
tion problems have been observed in patients with
hereditary sensory neuropathy [12], Charcot-
Marie-Tooth syndrome [13], adrenomyeloneuro-
pathy [14-15], Refsum´s disease [16] and primary
amyloidotic polyneuropathy [17-20]. The adreno-
leukodystrophies represent a group of impotent
patients of particular interest since this is a fatal
disease [14]. On the other hand, in a study of
patients with hereditary motor and sensory neuro-
pathy (HMSN) motor pudendal nerve involvement
was reported but the patients did not have any
signs of erectile dysfunction [21].
CONCLUSIONS
Erectile dysfunction is very common among
patients with polyneuropathies, diabetic poly-
neuropathy in particular. This is also the case in
the large group of genetic neurological disor-
ders. However, here our knowledge is insuffi-
cient.

E. ERECTILE AND EJACULA-
TORY DYSFUNCTION IN
SPINAL CORD DISORDERS.
I. INTRODUCTION
In this review concerning spinal cord disorders no
distinction is made between individuals with non-
traumatic spinal cord or cauda equina lesions
(including congenital spina bifida, sequelae after
transverse myelitis, spinal cord tumours, prolap-
sed discs etc.) and traumatic spinal cord injuries as
they have similar erectile and ejaculatory dysfunc-
tions [1-3], however, the traumatic group consti-
tutes the majority of the spinal cord lesioned popu-
lation.
Traumatic spinal cord injury (SCI) is a devastating
medical condition. In an instant of time, an able-
bodied individual experiences extreme changes in
body functions, including paralysis and loss of
sensation below the level of lesion, loss of normal
urinary bladder and bowel functions, and erectile
as well as ejaculatory dysfunction. Another func-
tion that is usually lost in SCI men is the ability to
procreate naturally [1,3].
For several decades it has been a widespread belief
that individuals with SCI are permanently and
completely impotent and infertile. Fortunately,
many investigations demonstrate that this is not
true [2,3]. Comarr & Vigue [4] stated that health
professionals had been guilty of perpetuating the
myth that disabled individuals are asexual, and
according to Anderson & Cole [5] many people
harbor the belief that a body with some degree of
paralysis or deformity is unable to engage in
sexual intercourse at all.
Sexual dysfunction following SCI has fortunately
attracted considerable attention from therapists in
the field, perhaps, because many people affected
by SCI are young, active, and otherwise healthy
[6]. Modern rehabilitation techniques have given
them much greater life expectancy [7-9] and
considerably greater mobility. Preoccupation with
future sexual performance occurs early and is
quite prominent in the mind of persons with SCI
[6]. Even when considerable, it is a common expe-
613
rience that SCI men may more easily accept their
motor deficits than their sexual problems [3].
Some of these patients even indicate that, if they
had the choice, they would rather regain their
sexual life than their motor function [6]; erectile
dysfunction as well as ejaculatory dysfunction are
frustrating conditions.
II. PATHOPHYSIOLOGICAL
PHASES FOLLOWING SPINAL
CORD INJURIES
Following a sudden and complete spinal cord
transsection, three disorders of function become
evident [10]:
1) all voluntary movement below the level of
lesion is immediately and permanently lost;
2) all sensations below the level of lesion are abo-
lished; and
3) reflex function in all segments of the isolated
spinal cord is completely lost (spinal shock). Less
complete lesions of the spinal cord may result in
little or no spinal shock, and the same is true for
lesions that develop slowly. Guttmann [11] distin-
guished between three phases in the pathophysio-
logy of the sexual organs: spinal shock, reflex
return, and readjustment.
a) Spinal shock
The spinal shock phase lasts from a few hours to
several weeks, during which there is a complete or
almost complete suppression of the reflex activity
below the level of the cord lesion. The male geni-
tal reflexes (reflex penile erection, bulbocaverno-
sus and cremaster reflexes) are abolished or pro-
foundly depressed. The erectile and ejaculatory
functions are abolished. In complete lesions, the
penis may become enlarged and semierected,
which is a result of a passive engorgement of the
corpora cavernosa due to the paralytic vasodila-
tion following the interruption of the vasoconstric-
tor fibers in the antero-lateral tracts of the spinal
cord [11]. The spinal shock stage is believed to be
due to the sudden interruption of the supraseg-
mental descending fiber systems that keep the spi-
nal motor neurons in a continuous state of subli-
minal depolarization (ready to respond) [10].
The period of spinal shock is the main reason that
it usually is impossible to predict the sexual func-
tion, including return of erection and ejaculation,
in SCI males within the first weeks after injury.
b) Return of reflexes
When spinal shock subsides, reflex activity and
spasticity may appear in the lower extremities, and
urinary bladder and bowel function may become
reflexogenic. In upper motor neuron lesions, the
erection reflex becomes one of the components of
the autonomic functions of the isolated cord,
taking part in the “mass response”. In fact, it may
appear, independent of cerebral participation,
before the reflex responses of the skeletal muscles
are fully developed. Tactile stimuli of varying type
and intensity, including stimuli of the penis, result
in erection [11].
c) Re-adjustment
Sexual re-adjustment after SCI is very dependent
on the particular person’s wishes, experience, and
sexual habits in pre-SCI life, whether this applies
to love play or actual methods of intercourse. It
may also, to a great extent depend on the coopera-
tion and helpfulness of their partner [11].
Siösteen et al [12] found that sexual readjustment
after injury was closely and positively correlated
to a young age at injury and willingness to experi-
ment with alternative sexual expressions. Physical
and social independence and a high mood level
were further positive determinants of sexual adap-
tation after injury.
III. ERECTILE DYSFUNCTION
Erectile dysfunction is defined as the inability to
achieve and maintain an erection sufficient for
satisfactory sexual performance [13]. The neurolo-
gical level and completeness of the spinal cord
lesion varies considerably, but in general more
than half of all SCI men are unable to achieve
erections that permit successful sexual intercourse
[14]. However, at least three types of erections in
SCI men have been described in the literature
including reflexogenic, psychogenic and mixed
erections [15,16].
Table 4 shows an overview of the percentage of
men with SCI reporting erection (any type) and
successful intercourse without therapeutic assis-
614
tance [12, 14, 17-37]. Several previous reviews
and studies [24,38-44] have stressed the difficulty
in interpreting the various results due to methodo-
logical factors. These include variability in subject
selection and data collection (for instance, infor-
mation may be obtained by mailed questionnaire
or by personal interview), poorly described dia-
gnostic criteria for determining the level and
extent of the SCI, failure to identify variables such
as years of age and duration of SCI, general heal-
th status, possible surgical intervention such as
external sphincter resection, previous sexual expe-
rience, and opportunity for sexual activity. Howe-
ver, the most important factor may be that the vali-
dity of the retrospective reports obtained from
men with SCI is not known. Thus, Kennedy &
Over [43] found that among SCI men who were
studied with straingauge measurement of penile
tumescence when exposed to erotic material, seve-
ral who had anticipated having an erection failed
to do so, whereas others demonstrated penile
tumescence during erotic stimulation despite clai-
ming loss of the capacity for psychogenic erection.
Tsuji et al [24] reported a very low frequency of
successful intercourse as seen in Table 4, but this
was due to the fact that the majority of the SCI
men did not have the opportunity to test their
sexual ability. In contrast, Jackson [29] found that
15 out of 20 SCI males engaged successfully in
intercourse.
The possible influence of the type and level of
lesion is illustrated with the figures in Table 5
from Bors & Comarr’s study [14]. In general it has
been experienced [38] that the frequency of erec-
tion is higher among SCI men with incomplete
than with complete lesions, with upper than with
lower motor neuron lesions (refering to injuries
that do or do not preserve S2-S4), and with high
rather than low levels of SCI. In a recent study
[45] it was noted that normal erectile function was
maintained in men with incomplete but not with
complete spinal cord lesions. However, as pointed
out by Comarr [26] although knowledge about
completeness and upper/lower motor neuron
lesion enables a general prognosis, it does not
necessarily provide an accurate prognosis for futu-
re sexual function in the individual. Siösteen et al
[12] found that the neurological level and comple-
teness of injury showed no significant correlation
with sexual function.
 Table 4: Percentage of men with spinal cord injury reporting erec -
tion (any type) and successful sexual intercourse without therapeu -
tic assistance.

REFERENCE NO. OF ERECTION SUCCESSFUL

MEN % coitus %
Munro et al 1948 [17] 84 74 -
Bors 1948 (cited in ref.14) 157 87 33
Talbot 1949 [18] 200 64 -
Bors et al 1950 [19] 34 88 -
Kuhn 1950 [20] 29 86 -
Talbot 1955 [21 208 69 23
Zeitlin et al 1957 [22] 100 86 26
Bors & Comarr 1960 [14] 529 81 50
Money 1960 [23] 14 79 -
Tsuji et al 1961 [24] 638 54 5
- 46 73 -
Hohmann 1966 [25] 25 72 -
Comarr 1970 [26] 150 82 38
Jochheim & Wahle 1970 [27]
Wahle & Jochheim 1970 [28] 48 58 -
Jackson 1972 [29] 20 85 75
Piera 1973 [30] 100 79 -
Fitzpatrick 1974 [31] 14 86 21
Comarr & Vigue 1978 [32] 153 90 -
Morley et al 1979 [33] 18 83 -
Uyttendaele et al 1979 [34] 18 78 -
Taylor & Coolican 1988 [35] 16 81 69
Slot et al 1989 [36] 38 95 -
Zasler & Katz 1989 [37] 20 70 -
Siösteen et al 1990 [12] 60 83 64

Total 2,719
Range 54%-95% 5%-75%
Median 80% 36%

Table 5: Effects of completeness and upper versus lower motor neuron lesion on erection, ejaculation and successful sexual
intercourse

TYPE OF LESION NO ERECTION EJACULATION SUCC INTERCOURSE

Compl
upper 287 93 % 5% 53 %
Incompl
upper 123 99 % 32 % 63 %
Compl
lower 109 26 % 18 % 23 %
Incompl
lower 10 90 % 70 % 80 %

(After Bors & Comar 1960) [14]

615
 Table 5 shows figures from Bors & Comarr’s
IV. EJACULATORY DYSFUNCTION study [14] illustrating the influence of the type
and level of lesion on the capability of ejacula -
The ability to ejaculate by masturbation or by tion. The frequency of ejaculation is generally
sexual intercourse is impaired in the majority of considered to be higher among SCI men with
men with SCI and, consequently, pregnancies cau- incomplete than with complete lesions and with
sed by SCI men without medical intervention are lower motor neuron than upper motor neuron
rare [1,3,21,46]. The low incidence of fertility can lesions, respectively.
not be completely attributed to ejaculatory dys- Table 6: The percentage of men with spinal cord injury
function because semen obtained from SCI men reporting ejaculation without therapeutic assistance.
by methods of assisted ejaculation is of poor qua-
lity [47-58].
REFERENCE NUMBER EJACULATION
The impact of loss of the ability to proceate is OF MEN %
amplified by the demographics of SCI from USA Munro et al 1948 [17] 84 10
[9]. In this country there are approximately 10,000 Bors 1948 (cited in ref. 14) 157 20
new SCI cases per year. Eighty-two percent occur
Talbot 1949 [18] 200 10
in males. About 80% of new SCI men are 40 years
Bors et al 1950 [19] 34 15
of age or younger.
Kuhn 1950 [20] 25 8
Table 6 shows the reported frequencies of ejacula-
Talbot 1955 [21] 208 15
tion in SCI men without therapeutic assistance.
Zeitlin et al 1957 [22] 100 3
Considerations concerning methodological fac-
tors, similar to those mentioned about erectile dys- Bors & Comarr 1960 [14] 529 15
function, must be made when comparing the lite- Money 1960 [23] 14 0
rature results of ejaculatory capability [24,38,40- Tsuji et al 1961 [24] 638 9
42,44]. An additional problem is to determine - 46 14
what an ejaculation actually is, which can be Hohmann 1966 [25] 25 12
confounded by individual patients perception of
Comarr 1970 [26] 150 11
ejaculation. For example, in some studies drib-
Jochheim & Wahle 1970 [27]
bling emission has been included, but not in other
studies [59]. Another difficulty in determining the Wahle & Jochheim 1970 [28] 48 8
frequency of ejaculation after SCI is the possibili- Jackson 1972 [29] 20 35
ty of retrograde ejaculation especially following Piera 1973 [30] 101 27
transurethral resection of the urinary bladder neck Fitzpatrick 1974 [31] 14 42
or the prostate [60]. Morley et al 1979 [33] 18 33
Despite these objections it is interesting to note Uyttendaele et al 1979 [34] 18 33
that the studies from 1948 to 1970 report ejacula- Slot et al 1989 [36] 38 45
tion frequencies between 0 and 20%, while those Siösteen et al 1990 [12 60 52
from 1972 to 1990 all show frequencies between
27 and 52% (table 6). These findings may reflect
Total 2,527 0%-52%
some differences in the populations studied, inclu- (median 15%)
ding the number of men with incomplete lesions.
Also other external reasons, such as changing atti-
tudes in the surrounding society towards a more V. CONCLUSIONS
permissive and open view of sexuality and disabi-
lity, supported and encouraged by patients’organi-
The majority of men with SCI can obtain some
sations and the media may be important in this res-
type of erection but, in general, less than half of
pect as well [12]. However, this can also imply
all SCI men are able to achieve erections that
that some of these reported ejaculations have been
permit successful sexual intercourse. Only a
induced, for example, by the use of penile vibrato-
minority of SCI men have the ability to ejacu-
ry stimulation at home [30].
late during sexual intercourse.

616

F. ADVERSE SEXUAL
REACTIONS FROM
PRESCRIPTION DRUGS
I. INTRODUCTION
The emergence of genito-urinary symptoms with
antidepressant treatment was already pointed out
by Simpson et al in 1965 [1]. Since then a number
of review articles on adverse reactions affecting
sexual function from prescription drugs have
appeared [2-6]. However, most of these have been
based on case reports. Relatively few clinical drug
trials have sexual dysfunction included in the side
effect check lists. Also, the mechanisms behind the
drug actions in those cases are not very well
known.
Another way to get information about sexual
adverse reactions is to use the WHO data base of
suspected adverse sexual reactions from prescrip-
tion drugs. This data base contained (1968 to
October 1997) 1.7 million reports about adverse
reactions of drugs in 49 countries from all over the
world. Adverse sexual reactions were described in
approximately 1 % of the reports [7-9]. From these
reports two types of drugs can be distinguished as
the most important: the antihypertensive drugs and
neuro-psychopharmacological drugs, antidepres-
sant drugs in particular.
II. ANTIHYPERTENSIVE DRUGS
The greatest number of reports concerned antihy -
pertensive drugs [7-8]. All classes of these drugs
were represented. The different drugs seem to
have few pharmacological effects in common
other than lowering blood preasure, hence, the
erectile dysfunction could be vascular. However,
since decrease in libido was also reported with
these drugs, the effect may be partly central. Ano-
ther possibility for decreased sexual desire is a
psychological feed-back mechanism: loss of erec-
tion provides less sexual stimulation. The quotient
number of cases of erectile dysfunction over the
617
number of cases of decreased libido was of the
same magnitude (2.9 to 5.4) for all these groups,
indicating a similar mechanism. Alpha-adrenore-
ceptor blocking agents as well as alpha-and beta-
adrenoreceptor blocking agents and guanidine
derivatives were associated not only with erectile
dysfunction but also with ejaculation failure.
Alpha-methyldopa has been reported to cause sup-
pression of ejaculation [10] Furthermore, pria -
pism was reported with the alpha-adrenoreceptor
blocking agents (such as prazosin).
III. ANTIDEPRESSANT DRUGS
If the sexual response cycle is divided into three
phases, then 30% of the more than 5.000 reports
(both sexes) concerning antidepressant drugs
related to the phase of desire, 30 % to the phase of
excitement and 40 % to the phase of orgasm [9].
For the non-selective monoamine reuptake inhibi-
tors, erectile dysfunction and problems with ejacu-
lation were the most abundant, whereas problems
with desire were less important. Problems with
ejaculation and orgasm were much more fre -
quently reported for the group of selective seroto-
nin reuptake inhibitors (SSRIs) than for the group
of non-selective monoamine reuptake inhibitors.
The most frequent adverse reaction with SSRIs
concerned ejaculation and orgasm in males, whe-
reas problems with erectile dysfunction were less
often reported. Trazodone was the drug with the
highest number of priapism reports among all
drugs.
Decreased desire and erectile dysfunction are
typical symptoms of depression. Therefore, it is
difficult to determine in each case what symptoms
are caused by the depression itself and what may
be an adverse drug reaction. It is also difficult to
estimate the incidence of sexual dysfunction in
patients taking antidepressant drugs. Most data
regarding non-selective monoamine reuptake inhi-
bitors were from a time when these problems were
not given much respect. The SSRIs belong to a
more recent generation of antidepressant drugs
and therefore reports of sexual dysfunction or
adverse drug reactions may be increased because
they are more common and accepted. If a particu-
lar drug is followed during its post marketing per-
iod, the frequency of reported adverse sexual drug
reactions may vary immensely, for example, with
fluoxetine, reports varied from 2% - 75% [11]. If
only spontaneous reports were counted, the inci-
dence of sexual adverse reactions during treatment
with SSRIs was much lower (14 %) than if direct
questions were asked (58%) [12].
Ejaculatory problems are seldom reported as
symptoms of depression, nor are anorgasmia or
priapism. In the study of Lundberg & Biriell [9] on
adverse effects of antidepressant drugs, orgasm
and ejaculation were impaired to a greater extent
than erection. Reports on adverse drug reaction
reports do not usually allow a critical analysis of
the distinction between “ejaculation” and
“orgasm” in each male patient. The ejaculatory
process is as mentioned earlier very complex.
Probably the most important effect of the non-
selective monoamine re-uptake inhibitors is an
alpha-receptor blockade of emission.
Priapism after trazodone is a very typical sexual
adverse reaction from this drug. The mechanism
for this is thought to be interference with the sym-
pathetic control of detumescence due to alpha-
adrenoreceptor blocking properties of the drug
[13].
To be able to compare different drugs one needs
controlled studies comparing therapeutic doses of
the drugs in question with a proper analysis of any
possible sexual side effects. Few such studies
exist. Harrison et al [14] compared imipramine
and phenelzine and found a high incidence of
adverse sexual reactions. Both amitriptyline and
mianserin significantly decreased the amplitude
and total duration of nocturnal erections [15]. Fei-
ger et al [16] studied nonpsychotic patients with
major depression treated with sertraline or with
nefazodone. 78 % of the men taking sertraline and
59 % of those taking nefazodone reported delayed
ejaculation. 15 % of the men taking sertraline and
52 % of the men taking nefazodone, reported pre-
mature ejaculation.
IV. OTHER TYPES OF DRUGS
do [7]. L-DOPA has such a pronounced positive
effect on sexual function that it has been used in
treatment [17-18]. Antipsychotic drugs with
alpha-adrenoreceptor blocking properties, chlor-
promazine, thioridazine, haloperidol and clozapi-
ne in particular, are reported to give either impo-
tence or priapism as adverse reactions and also
ejaculation failure and changes of quality of
orgasm [2-4, 7]. Increase or decrease in sexual
desire and erectile dysfunction may also occur.
The mechanisms are largely unknown, but there is
a suspiscion that they could be related to the
increase in plasma prolactin levels that is com-
monly seen with these types of drugs [19]. Thiori-
dazine, belonging to a group of antipsychotic
drugs that rarely causes extrapyramidal side
effects, can also lead to painful, retrograde, or
spontaneous ejaculations [4, 20].
Another main group of drugs causing erectile dys-
function are the histamine-2-receptor antagonists,
cimetidine in particular. These drugs are also repor-
ted to cause decreased libido and gynaecomastia.
The mechanism is at least partly an estrogenic/anti-
androgenic effects of the drugs in question [21].
From animal experiments we know that the GABA
agonist baclofen can block penile reflexes on a
spinal level [22]. Erectile dysfunction in men who
were receiving intrathecal baclofen by an implan-
table pump has been reported [23] as well as ane-
jaculation. Oral baclofen can sometimes result in
increase in sexual desire [24].
V. CONCLUSIONS AND
RECOMMENDATIONS
Sexual adverse reactions have been reported
not only with the use of many prescription
drugs acting on the nervous system but also
with many other groups of drugs, such as anti-
hypertensive drugs and drugs acting on the
endocrine system. It is therefore advisably to
enquire all patients with sexual problems about
actual use of prescription drugs.

Dopaminergic drugs (L-dopa, bromocriptine,

selegiline) represent the only group where the
number of reports with increased libido was grea-
ter than the number of reports with decreased libi-

618
 G. TREATMENT OF
NEUROGENIC ERECTILE
DYSFUNCTION
I. INTRODUCTION
Recent advances in the knowledge of physiology,
pharmacology and haemodynamics of erection
have led to the development of new treatments by
transcutaneous, oral, intracavernous or transure-
thral therapies. All such drugs are now available
for neurologically impaired patients. The majority
of publications have focused on spinal cord inju-
red patients except for one on multiple sclerosis
patients [1].
In general, the spinal cord injured population is
young, and probably exempt from vascular
diseases, and this becomes important when consi-
dering dose ranging studies and risk of priapism.
However in the majority of studies very little is
said about the level of the lesion, whether it is
complete or incomplete or whether reflexogenic
erections may be obtained.
II. VACUUM THERAPY
Vacuum constriction devices have been used
since 1917. Initially the results were excellent,
with adequate rigidity for penetration reported in
90% [2,3-5] of the patients with neurogenic erec-
tile dysfunction (ED). Satisfaction of the partners
was also initially high (70%). After six months of
treatment, despite an increase in sexual activity,
only 41% of the patients were satisfied with the
device [3].Similar results have been reported by
Heller [4]. In this study the most common com-
plaint was premature loss of rigidity and difficulty
in placing and removing the constriction bands.
The most common complications were bruises,
petechiae, and skin oedema. Severe complications
such as penile gangrene, severe erosion and cellu-
litis were reported and were associated with pro-
longed constriction band wearing [6, 7].
619
III. INTRACAVERNOUS INJECTION
THERAPY
1. INTRACAVERNOUS INJECTION OF
PAPAVERINE
Since the first report by Virag [8] in 1982, papa-
verine has been used extensively in the treatment
of erectile dysfunction in spinal cord injured men
especially in the USA[9]. Seven studies, focusing
on the efficacy of papaverine for erectile dysfunc-
tion in spinal cord injury, have been published [8,
10-15] and one for multiple sclerosis [1]. All of
them are open trials with the number of patients
ranging from 12 [16] to 101 [13]. The dosage of
papaverine did not relate statistically to the level
or extent of injury [15, 17]. All the authors repor-
ted efficacy around 90%. In this population doses
were lower than in vascular diseases and erection
lasted longer and was of better quality [14]. In a
study in which the dose started at 3 mg and was
increased weekly, [17] 56% of the patients used
doses of 12 mg or less. Priapism and prolonged
erection were the most common acute complica -
tions but were obviously related to the dosage
used in the protocols. Beretta [10] found 31% of
patients reported priapism with 30 mg of papave-
rine and other studies reported 7% with priapism
when the dose was progressively increased [1, 14-
15, 17]. Tunical scarring is a long term treatment
complication and affects from 2% to 8% of
patients after 6 months of treatment. Little is
known about the long term efficacy in this popula-
tion.
2. I NTRACAVERNOUS PROSTAGLANDIN E1
Prostaglandin E1 is used worldwide for self
injection therapy in ED. An extensive review [18]
of the literature on PGE1 and also on papaverine
and a papaverine-phentolamine mixture showed a
efficacy rate of more than 70% in patients with
ED. Complications such as priapism were lower
with prostaglandin (0.25%) than with papaverine
(6.5%) or a papaverine-phentolamine mixture
(6.3%). Furthermore the risk of local long term
complications was lower with prostaglandin
(0.8%) than with papaverine (5.7%) or a papaveri-
ne-phentolamine mixture (12.4%).
In the setting of neurogenic ED, Hirsh [19] repor-
ted that the mean dosage for efficacy was 6.2 mg
for spinal cord injured patients and 8.2 mg for
multiple sclerosis patients or discogenic diseases.
In a long term study 40% of the patients dropped
out the treatment. This is comparable to the rate of
a non selective population of patients with ED
[20]. No priapism or local complication was
observed in this population [19] with a mean fol-
low-up of 28 months. No patients discontinued
treatment because of pain. This could be explained
by the loss of sensations in contrast to the general
population in which 50% of men reported pain
[21, 22]. Similar results in terms of efficacy have
been reported by Tang [23]. In this population of
15 spinal cord injured patients, only two with
incomplete lesions complained of pain at the site
of injection.
3. MOXISYLYTE
Moxisylyte is an alpha-blocking agent. Efficacy
and tolerance have been sudied in a double blind
study against a placebo [24]. In 12 spinal cord
injured patients all the parameters such as rigidity,
abdominal penile angle, and lenght were improved
significantly by moxisylyte. But no significant dif-
ferences were found between the three doses of
10, 20 and 30 mg. Full rigidity was acheived in 7
patients and for 2, partial rigidity sufficient for
vaginal intromission was achieved. Neither pria-
pism nor hypotension occured in this laboratory
assessment. Despite these encouraging results no
long term study in neurogenic ED with intracaver-
nous moxisylyte has been reported.
4. M IXTURE
Different protocols combining papaverine with
phentolamine have been reported to be effective
for the treatment of neurogenic ED [1, 11, 12, 14-
16]. Unfortunately all the protocols were different
regarding doses of papaverine or phentolamine.
There is no double blind controlled study compa-
ring the efficacy of papaverine alone or papaveri-
ne plus phentolamine in this population of
patients. Moreover no comparison of papaverine
and PGE1 has been performed in this population
as in arteriogenic impotence [25] where the super-
iority of PGE1 has been suggested.
620
IV. TRANSDERMAL THERAPIES
Because of the well known complications of intra-
cavernous injections such as corporeal fibrosis or
priapism, local non invasive therapy seems to be
attractive. This is particularly true in a population
of young patients in which it will be used for seve-
ral decades. Claes reported [26] the use of trans -
dermal nitroglycerin for non specific erectile dys-
function with complications such as local pain and
vasodilatory headache, orthostatic hypotension
and dizziness. In a group of 17 patients [27] who
had a good response with intracavernous papave-
rine, Transiderm-Nitro plaster (10 mg/24 h) on the
penis was tested. The plaster was placed 1 or 2
hours and a penile shaft was placed 10 minutes
before removal. An initial test was positive in 12
patients with 5 having a complete and 7 having a
partial response. These 12 patients tried at home.
It appeared that 5 patients obtained an erection
sufficient for vaginal penetration. In this group the
initial response was complete in four. Secondly the
dose of papaverine required for efficacy in this
group was low (between 5-15 mg). The only side
effect was headache in 50% of the patients in the
home study. It seems that this treatment was safe,
efficient, with minor side-effects. In another group
of 28 spinal cord injured men an open randomized
cross over trial [28] compared the efficacy of an
intracavernous injection of papaverine versus
transdermal nitroglycerin. The initial dose of
papaverine was 10 mg. The nitroglycerin patch
was 5 mg/24 h. A rubber band was kept on the
penis for 1 hour with the patch. 93% of the
patients who received papaverine showed a com-
plete response and 61% with the nitroglycerin
patch. This difference was statistically significant.
No significant difference was found between spas-
tic and flaccid patients. The only complication
with nitroglycerin was mild headache in 21% of
the patients. This study demonstrated that a patch
of nitroglycerin can improve erectile dysfunction
in spinal cord injured patients. The better results
obtained in the second study [28] can be explained
by the use of a rubber band for one hour, despite a
lower dosage of nitroglycerin. Chancelor [29]
demonstrated that topical administration of
minoxidil 2% on the glans did not improve the
erectile dysfunction in terms of rigidity in compa-
rison with papaverine or a vacuum device.
Safe and effective local treatment is highly desi-
rable, however topical agents are likely to be deli-
vered via general circulation. The superiority of
local administration on the skin of the penis versus
another place on the body has not been demons-
trated. Placebo controlled studies are needed.
V. ORAL THERAPY
Since 1997 sildenafil has been avaliable for the
treatment of erectile dysfunction. Only two studies
have focused on its efficacy in a population with
neurogenic aetiology of erectile dysfunction [30].
Sildenafil is an active selective inhibitor of cGMP-
specific phosphodiesterase type 5. Sildenafil
improves erection significantly in able bodied
patients [31] with no known organic cause. 27 spi-
nal cord injured patients were randomized in a
double blind placebo controlled study to receive
50 mg of sildenafil or placebo [30]. After 28 days,
improvement of erection was found in 75% of the
sildenafil group and 7% in the placebo group. Fur-
thermore a significant improvement in satisfaction
with their sex life was reported by the patients
under sildenafil. Suprisingly in a sexual function
questionnaire and patient questionnaire, only a
global satisfaction was improved significantly.
Frequency of erection lasting long enough, fre-
quency of erections hard enough for sex, frequen-
cy of stimulated erections and frequency of
waking erections showed an improvement but
without statistical significance. It probably means
that 50 mg is not high enough in this population of
patients to improve more than a global satisfac-
tion. Another placebo-controlled, 20 weeks,
double-blind, flexible-dose, two way crossover
sudy was undertaken to evaluate the efficacy and
safety of sildenafil in a large population (178) of
spinal cord injured men [32]. At the entry 151
patients were reported to have reflexogenic or psy-
chogenic erections and 27 had no residual erectile
function. The proportion of patients classified with
complete or incomplete lesions were similar in the
two groups. 83% of the patients reported improve-
ment in erections and 80% improved the ability ro
have sexual intercourse. All those results were
stastically significant when compared to placebo.
621
Sildenafil was well tolerated with a low disconti-
nuation rate due to adverse events (3%). The
median proportion of succesful attemps at inter-
course was 55% versus 0% for placebo.
VI. INTRAURETHRAL THERAPY
Intraurethral therapy seems to be effective in the
treatment of ED [11, 33, 34]. No specific double
blind studies focusing on neurogenic ED has yet
been reported.
VII. PENILE PROSTHESIS
Penile prostheses are one of surgical treatments
for impotence. They have been described over the
last 50 years and improvements have been made
on prostheses devices and on implantation tech-
niques. General indications have been summarized
by Shabsigh in a recent editorial [35] for patients
with severe dysfunction or organ failure who do
not respond to any pharmacotherapy. Neurogenic
patients represent a special group since their com-
plications may be related to the etiology of erecti-
le dysfunction, and because penile prostheses are
indicated not only for sexual intercourse but also
for appliance maintenance (condoms catheters).
That is why, as for other treatments, spinal cord
injured patients represent the most documented
population for penile prostheses implantation in
neurogenic erectile dysfunction.
The prostheses can be malleable (semirigid) or
inflatable (semi-flexible or flexible). The choice
is made by the patient and the physician after spe-
cific information is exchanged. Inflatable pros-
theses require manual dexterity from the patient
himself or from his partner who must also be
informed. They allow a flacid penis when not
inflated which is more practical for everyday life.
The choice is guided by indications specially for
neurological patients. The maintenance of external
appliances and/or treatment of penile skin lacera-
tion is best treated by a semirigid prosthesis avoi-
ding ventral flexion of the penis. Most of the
reports in the literature are about this type of peni-
le prosthesis. The first important report on infla-
table prosthesis was made by Scott [36], and
concerned 245 patients during a five year multi-
center experience. Seventeen were spinal cord
injured patients and no comments have been given
regarding specific complications or indications.
Since this first report, inflatable prostheses are not
so much indicated for this type of patients (bet-
ween 2 to 6% [37-40]. Among a paraplegic popu-
lation 31% received a flexible or semi-flexible
prosthesis and the others (143/209) had a semi-
rigid one [41].
It is important to distinguish between the use of a
penile prosthesis for the enhancement of a small
retrectable penis versus the enhancement of a nor-
mally-sized penis for the purpose of improving
sexual function. Primary contraindication for
implants is the loss of condom catheters in patients
with a small retractable penis [41, 44]. Infection
rate in such patients has been considered to be
important,with the rates ranging from 2% [43], to
5.6% [41] or 10% [44].
A consensus has to be reached with regards to
meticulous preoperative skin preparation, pro-
phylactic antibiotics, careful choice of type and
size of prosthesis, which depend on indication and
motivation of the patient. The heterogeneity of dif-
ferent patient populations, and the retrospective
studies with non comparable implantation proto-
cols, makes this a difficult comparison. Despite
this fact, use of penile implants in patients with a
neuropathic bladder can be recommended to allow
condom catheter maintenance. It has also been
reported to be useful to facilitate intermittent self
cathetrisation by lengthening and straightening the
penis for selected patients.
Other complications include penile prosthesis
extrusion leading to explantation and prosthesis
failure (reported to be 6.7% [41], 8% [43], and
16.7% [45]). The lack of homogeneity in preope-
rative protocols among various studies and the
622
retrospective methodology in all of them require
that readers critically evaluate the rates. An
attempt was made by Jarow [46] to describe risk
factors for penile prostheses. 24 of the 157 proce-
dures that he described were done on spinal cord
injured patients and no prosthesis became infected
in this group. The factors that seem of high risk for
complications are revisions including associated
reconstruction of the penis or a previous surgery
for penile implant. Penile prosthesis may be used
in diabetic patients [38, 46] but this group seems
to be at higher risk [47].
As it was reported by Green in 1986 [48] and is
still true today, this is not a procedure to be recom-
mended indiscriminately to every patient who
requests it. If an urologic indication is present,
careful information must be given to the patient to
avoid failure of the prosthesis due to lack of local
care of the penis and prosthesis (skin ulcers, use of
vacuum device, permanent urethral catheter). In
terms of sexual satisfaction, levels of satisfactory
sexual intercourse and of subjective improvement
have not been carefully analysed because of the
lack of good standardized methodology and vali-
dated questionnaires in this population.
VIII. CONCLUSIONS
There exsists an arsenal of specific methods,
medical as well as surgical, for treatment of
erectile dysfunction that can be used also in the
neurologic patient. These include testosterone
substitution, vacuum therapy, intracavernous
injection of prostaglandin E1, papaverine or
moxisylyte, transdermal or intraurethral appli-
cation of different drugs, oral administration of
phosphodiesterase inhibitors, and penile pros-
thesis.

H. TREATMENT OF EJACULA-
TORY DYSFUNCTION IN MEN
WITH NEUROLOGICAL
DISORDERS
I. INTRODUCTION
Disorders of the central nervous system that may
lead to ejaculatory dysfunction include: spinal
cord injury, multiple sclerosis, transverse myelitis,
cerebrovascular accidents, and damage resulting
from excision of central nervous system neo-
plasms. Disorders of the peripheral nervous sys -
tem that may lead to ejaculatory dysfunction
include: cauda equina injuries, retroperitoneal
lymph node dissection (RPLND), pelvic and colo -
rectal surgery, and diabetes mellitus. In addition,
congenital disorders, most notably, myelomenin-
gocele, may lead to ejaculatory dysfunction. In
this part of the text, rapid ejaculation will not be
discussed.
Treatment options for neurogenic anejaculation
depend on the origin of the disorder. Diabetes mel-
litus, RPLND, and some pharmacologic agents [1-
3], may render the patient effectively «sympathec-
tomized» leading to failure of seminal emission, or
to retrograde ejaculation. These patients may
respond with varying degrees of success to mana-
gement with sympathomimetic pharmacologic
agents such as imipramine, phenylpropanolami-
ne, pseudophedrine, or ephedrine [4-6]. If these
measures fail to produce any ejaculation (antegra-
de or retrograde), then other procedures are indi-
cated such as electroejaculation (EEJ) [7], or sur-
gical sperm retrieval from testis, epididymis, or
vas deferens [8-12]. If retrograde ejaculation per-
sists, however, sperm retrieval from the bladder is
usually all that is necessary. Such «sympathecto-
mized» patients are usually poor candidates for the
assisted ejaculation procedure of penile vibratory
stimulation (PVS) since they lack the intact sym-
pathetic innervation necessary for seminal emis-
sion.
Treatment options for other conditions of neuropa-
thic anejaculation include assisted ejaculation or
surgical sperm retrieval. The choice of treatment
623
depends on the patient’s ability to respond to
methods of assisted ejaculation and on the quanti-
ty and quality of sperm obtained in the ejaculate.
With surgical methods, the assisted reproductive
technology (ART) of intracytoplasmic sperm
injection (ICSI) will probably be required, due to
the low numbers of sperm obtained with these
methods. Assisted ejaculation methods generally
result in higher numbers of sperm,thus allowing
for more ART options (see Assisted Conception,
page 630).
The majority of reports on treatments for neuroge-
nic anejaculation have focused on men with spinal
cord injury, presumably because they comprise the
largest proportion of neurogenic anejaculators.
Thus, the majority of literature reviewed in this
report, with respect to techniques, results, etc., will
be from studies of men with spinal cord injury.
To retrieve semen from men with neurogenic ane-
jaculation, the methods most commonly used are
PVS or EEJ [7,13,14]. In PVS, a vibrator is placed
against the penis and mechanical stimulation is
delivered to induce ejaculation. In EEJ, a probe
containing electrodes is placed into the rectum and
electrical stimulation is delivered to cause the
release of semen. The term “electroejaculation” is
a misnomer. Semen usually drips from the penis
rather than being forcefully expelled as is typical-
ly seen during a PVS-induced or during a natural
ejaculation. “Electroemission” is a more accurate
term, however, this chapter will use the term
“electroejaculation” since it is a conventional term
in widespread use throughout the world. To retrie-
ve semen from a man with neurogenic anejacula-
tion, it is recommended that EEJ be used only if
PVS fails. The basis for this recommendation is
that PVS is less invasive, is preferred more by
patients [15] and results in better semen quality
than EEJ [15,16].
II. PATIENT SELECTION
1. PENILE VIBRATORY STIMULATION
Almost any man with spinal cord injury, regard-
less of level of injury, is a candidate for PVS
although certain medical conditions are relatively
contraindicated [13]. (Men with peripheral inner-
vation dysfunction may also be given a trial of
PVS although few will be found to respond).
Severe inflammation or irritation of the glans
penis, which sometimes occurs in patients who
wear condom catheters, is a relative contraindica-
tion because PVS may lead to further skin abra-
sion. PVS should not be administered to patients
with untreated hypertension or cardiac disease,
as PVS may cause an increase in blood pressure.
In patients with a penile prosthesis, PVS must be
applied with care, as the pressure of the vibrator
may push the glans onto the distal end of the pros-
thesis. An additional contraindication is the
patient´s inability to comprehend instructions
about the procedure.
2. ELECTROEJACULATION
The above contraindications apply for EEJ, with
the exception that patients with a penile prosthesis
or irritation of the penile skin are of less concern
with EEJ than with PVS. Additional contraindi -
cations for EEJ are the presence of a cardiac
pacemaker, and rectal pathology other than
simple hemorrhoids noted on anoscopic or sig-
moidoscopic exam. As a note of caution, patients
with recent spinal cord injuries (i.e. less than 24
months) may not respond readily to PVS or EEJ.
Often their ejaculatory response becomes apparent
only after 9-24 months.
III. PREPARATION OF PATIENTS
1. O RIENTATION AND MEDICAL HISTORY
Prior to the first trial of PVS or EEJ, it is advisable
that the patient be oriented to the procedure and to
the potential responses he may experience. In men
with spinal cord injury a complete medical history
should be taken with special attention to autono-
mic dysreflexia and attempts at ejaculation since
spinal cord injury, and the neurological level of
injury assessed
2. BLADDER PREPARATION
Once the patient is safely positioned on an exami-
nation table, blood pressure medication is given if
necessary (see Management of Autonomic Dysre-
flexia). Next, the bladder is prepared in patients
likely to have retrograde ejaculation, and/or in
patients likely to ejaculate urine along with semen.
624
(These features will not be known until the
patient´s ejaculation history is established). To
prepare the bladder, first empty the bladder by
catheterization, then instill 25-50 ml sperm
washing buffer into the bladder[16]. The bladder
should be prepared immediately (no more than 10
minutes) prior to PVS or EEJ, to minimize accu-
mulation of urine. In addition to these measures,
some centers recommend restricting fluids for 8
hours prior to the ejaculation procedure, or recom-
mend alkalinizing the urine with the administra-
tion of oral alkalinizing agents such as sodium
bicarbonate. For patients whose bladders are
managed with suprapubic catheters, the following
may be done before a trial of PVS or EEJ. First,
lavage the bladder with aliquots of normal saline
until no sediment is seen in the fluid. Then lavage
again once or twice with the sperm washing
medium of your choice. Finally, leave 25-50 ml of
sperm washing medium in the bladder. The supra-
pubic tube is clamped during the procedure. A col-
lection cup should be held at the meatus since the
suprapubic tube does not preclude antegrade eja-
culation.
3. MANAGEMENT OF AUTONOMIC
DYSREFLEXIA
Patients with injuries at T6 or above are prone to
autonomic dysreflexia, which is an exaggerated
sympathetic response to an afferent stimulus.
Common symptoms include high blood pressure,
sweating, chills, and headache, which if not mana-
ged properly, can lead to dangerously high blood
pressure levels [17]. Autonomic dysreflexia can
occur suddenly by any irritating stimulus introdu-
ced to the body below the level of injury, such as
an overfull bladder or impacted bowel. In some
patients, PVS or EEJ can cause autonomic dysre-
flexia, but with proper medication, symptoms can
be safely managed or avoided altogether [18,19].
Patients at risk (i.e., any patient with an injury T6
or higher, or any patient with a history of autono-
mic dysreflexia) should be given between 10 and
40 mg of nifedipine, sublingually, 15 minutes
prior to PVS or EEJ. A standard protocol is to start
with 20 mg of nifedipine, then increase or decrea-
se the dose on subsequent trials based on the
patients response [13,14]. In patients with a very
labile blood pressure, 0.4 mg nitroglycerin, sublin-
gually may be given in addition to nifedipine. In
these patients, the procedure should be started
within 30 seconds of nitroglycerine administra-
tion. During the procedure, blood pressure should
be monitored every minute, preferably with an
automatic blood pressure cuff.
In a study of 211 men with spinal cord injury ran-
ging between C3-L3, 41% required nifedipine for
autonomic dysreflexia, and in all but three, the
level of injury was T8 or higher. Of those who
received nifedipine, 17.2% also required nitrogly-
cerin during at least one trial [13].
4. P ERSONNEL
It is recommend that 2-3 professionals be present
during PVS or EEJ, depending on the complexity
of the case. One professional administers the PVS
or EEJ, one collects the semen, and a third attends
to the patients´s symptoms, if necessary. In simple
cases of PVS, only one professional may be neces-
sary, as for example, in the case of a patient who
can hold the vibrator or the specimen cup during
PVS, and who does not get autonomic dysreflexia
or severe spasticity during ejaculation.
IV. PVS PROCEDURE
1. VIBRATOR SELECTION
Vibrators have been designed specifically for ejacu-
lation of men with spinal cord injury (FERTI
CARE® clinic or FERTI CARE® personal, Multi-
cept,Denmark). These vibrators have the capability
of delivering an amplitude of 2.5 mm when pres-
sed against the penis, and this amplitude has been
found to significantly increase ejaculatory success
rate compared to lower amplitudes [13,20]. For the
purposes of this paper, such vibrators will be refer-
red to as “high amplitude vibrators” (Fig.11).
Other commercially available devices, while not
specifically designed for ejaculation of men with
spinal cord injury, may be used for this purpose.
Typically called “massagers” in the United States,
such devices are marketed to the general public for
relief of muscle strain. Most of these massagers
deliver an unloaded amplitude of 1.6 mm or less
(Fig. 12). Any type of vibrator may be perceived
as painful when applied to the penis of men with
some degree of intact sensation.
625
2. VIBRATOR PLACEMENT AND TIMING
(FIG. 13)
The patient may be positioned in a supine or in a
reclining position. The vibrator should be placed
on the glans of the penis, either the dorsum or fre-
nulum. The condition of the penile skin in contact
with the vibrator should be constantly monitored
by the operator. In order to monitor the penile skin
during PVS, the following protocol is recommen-
ded. Apply PVS for 5 minutes, then stop for one
minute and inspect the penile skin. Repeat this
step for up to two more times for a total of 15
minutes of PVS. Stop PVS if the penile skin
bleeds or becomes edematous, if the patient’s
blood pressure rises to a dangerous level, if the
patient requests, or if ejaculation occurs. For gene-
ral safety, the PVS procedure should not last lon-
ger than 15 minutes.
3. SOMATIC RESPONSES DURING PVS
A series of somatic responses are typically obser-
ved during PVS in men with spinal cord injury
[13,14,20]. These include: contraction of the abdo-
minal muscles, followed in frequency of occurren-
ce by spasticity below the level of injury, knee
flexion, hip flexion and abduction of the thighs.
During PVS, periurethral contractions can be felt
on most of the trials in which ejaculation occurs.
However, these somatic responses are not predic-
tive of ejaculation with PVS. On many trials, there
are somatic responses but no antegrade or retro-
grade ejaculation. A lack of somatic responses,
however, is usually predictive of no ejaculation
[13]. It is possible for ejaculation to occur without
erection, therefore, erection is not a good predictor
of ejaculation.
In patients who can ejaculate with PVS, the majo-
rity will have an antegrade ejaculate, and some
will also have a retrograde ejaculate. If no ante-
grade ejaculate is observed, the best indicators of
a retrograde ejaculate are a cumulative building of
somatic responses, contraction of the bulbocaver-
nosus muscles, and an increase in blood pressure.
4. USE OF PHYSOSTIGMINE
To facilitate ejaculation in men with spinal cord
injury, the anticholinesterase, physostigmine, has
been used alone and in combination with mastur-
bation or PVS [21-24]. Physostigmine is generally
administered subcutaneously following pretreat-
Figure 11: The FERTI CARE® clinic (left) and the FERTI CARE® personal (right) vibrators (Multicept, Denmark) are medi-
cal devices that have been engineered specifically for ejaculation of men with spinal cord injury. They can deliver an ampli-
tude of 2.5 mm when pressed against the penis. In men with spinal cord injury, this amplitude results in a higher ejaculatory
success rate compared with lower amplitudes.

Figure 12: While not specifically made for ejaculation of men with spinal cord injury, a wide variety of devices may be used
to deliver penile vibratory stimulation. Typically called massagers in the United States, these devices are sold 'off-the-shelf in
drug stores or department stores. They are marketed to the general public for use in muscle massage. Those shown in the pic-
ture deliver an amplitude of 1.6 mm or less, and are not as effective for inducing ejaculation in men with spinal cord injury
as are the high-amplitude vibrators shown in Figure 11. The advantage of these vibrators is that they are usually less expen-
sive and easier to obtain than high-amplitude vibrators.

626
Figure 13: During PVS, the vibrator may be placed on the dorsum or the renulum (shown here) of the glans penis. The peni-
le skin should be monitored during PVS to avoid edema or bleeding.
ment with N-butylhyoscine to reduce the common
side effect of nausea. Criteria for selecting
patients for treatment with physostigmine has not
been established and currently seems to be gui-
ded by clinician preference (personal communi-
cations).
5. FAILURE WITH PVS
In men with spinal cord injury, if there is no eja-
culation with a high amplitude vibrator, a trial with
two vibrators may be attempted, with one vibrator
placed on the dorsum and one on the frenulum of
the penis. Signs of autonomic dysreflexia should
be monitored closely when using two vibrators. If
no ejaculation occurs after three trials of PVS with
one or two high amplitude vibrators, the case
should be considered an ejaculatory failure and
referred for EEJ. Exceptions are patients injured
two years or less. Ejaculation with PVS may occur
once their injury has matured. In non-spinal cord
injured patients, failure with one trial or pain on
application of the vibrator is an indicator for no
further attempts.
V. EEJ PROCEDURE
In the method of EEJ, a probe containing elec-
trodes is placed into the patient´s rectum and direct
current is delivered to cause the release of semen.
627
EEJ was originally developed to retrieve semen
from farm animals for selective breeding [25].
Later, a variety of rectal probes were developed to
harvest semen from a variety of endangered spe-
cies [26,27]. In the mid 1980’s, EEJ equipment
was modified, and became commercially available
for use in humans [7,28]. Although the exact neu-
ral mechanism by which this method works is not
understood, an intact ejaculatory reflex is not
necessary, and thus EEJ is suitable for any patient
with neurogenic anejaculation.
For EEJ, the patient is placed in the lateral decubi-
tus position (Fig. 14 a , b). The bladder is prepared
for retrograde ejaculation, which is common with
EEJ. An anoscopy or sigmoidoscopy should be
performed prior to introducing the probe, to rule
out pre-existing rectal conditions. A probe of
appropriate diameter is selected. Considerations
are the volume and sensitivity of the patient´s rec-
tum, as well as the amount of current required to
obtain semen from the individual. The EEJ proce-
dure is usually performed with a low level of elec-
trical baseline current of 50 to 100 milliamperes
which is maintained between stimulation peaks. In
a recent study it was shown that during EEJ, the
external urinary sphincter contracts during electri-
cal stimulation [29]. Therefore, the common prac-
tice of a continuous electrical baseline may be
counter-productive, since it may lead to a relative

increase of external sphincter tone, and an increa-
se in the retrograde ejaculation fraction. It is sug-
gested that it may be optimal to completely dis-
continue electrical stimulation during seminal
emission leading to an increase in the percentage
of sperm ejaculated in the antegrade direction. As
with PVS, it is important to monitor for symptoms
of autonomic dysreflexia during EEJ.
1. SOMATIC RESPONSES DURING EEJ
During EEJ in men with spinal cord injury, typical
somatic responses, in the order in which they
appear, include: tightening of the abdominal and
intercostal muscles below the level of injury,
abduction of the thighs, tightening of the paraspi-
natis muscles with back arching, and finally, peni-
le erection[30]. As a note of caution, patients may
complain of tightness of the chest and difficulty
breathing if their injury is high enough to compro-
628
Figure 14 a : Electroejaculation equip-
ment.
b: Electroejaculation should be used
when PVS fails. A probe is placed in the
rectum (shown here in sagittal view) and
electricity, delivered via electrodes aimed
ventrally, results in the release of semen.
Ejaculatory success rate is higher with
EEJ compared to PVS, however, PVS
results in better semen quality, is less
invasive, and is prederred more by
patients.
mise a significant amount of the intercostal mus-
culature. In the typical patient, a series of these
somatic responses will occur prior to emission. In
some patients, somatic responses occur with no
accompanying emission. In these instances, the
current may be abruptly turned off, at which point
the patient will then have prolonged extensor
spasms of the lower extremities. Semen will often
drip out of the penis at this point. If none is seen,
a second course of electrical stimulation may be
given.
2. ANESTHESIA DURING EEJ
Non-spinal cord injured men or spinal cord inju-
red men with enough sensation to feel pain or
discomfort may require intravenous sedation or
general anesthesia for EEJ. Generally, such
measures are necessary in fewer than 10% of the
SCI group.

VI. WHEN TO CHECK FOR A
RETROGRADE EJACULATE
1. PVS TRIALS
At the conclusion of a PVS trial, a decision must
be made about the necessity of urinary catheteri-
zation to check for a retrograde ejaculate. Gene-
rally, post-procedure urinary catheterization
should be done on any trial in which somatic res-
ponses but no antegrade ejaculate occurred. On
trials in which an antegrade ejaculate occurred, a
retrograde ejaculate should be checked: on a
patient´s first visit (to establish the volume); if the
volume of antegrade ejaculate is low (<0.5 cc); if
the sperm count is unexpectedly low (i.e., signifi-
cantly lower than previous trials). It is not neces-
sary to perform urinary catheterization if recent
trials of PVS have resulted in no retrograde ejacu-
lation, or if the amount of motile sperm in the
antegrade specimen is sufficient for an intended
assisted conception procedure.
2. EEJ TRIALS
At the end of EEJ, whether or not antegrade semen
has been obtained, the bladder should be catheteri-
zed and lavaged since retrograde ejaculation is very
common with EEJ. The exceptions are patients with
an established history of no retrograde ejaculation,
if sufficient antegrade semen is obtained for an
intended assisted conception procedure, or if urina-
ry catheterization is contraindicated.
3. RETRIEVAL OF RETROGRADE EJACULATES
To check for a retrograde ejaculate, the bladder
contents may be retrieved by first catheterizing the
bladder and emptying by gravity. Then, another
25-50 ml of sperm washing medium is used to
lavage the bladder to extract any residues of eja-
culate that may have fallen to the floor of the blad-
der and were thus not captured easily during the
initial draining.
VII. RESULTS WITH PVS AND EEJ
1. EJACULATION SUCCESS RATES
There have been various reports of the efficacy of
PVS in men with SCI, with ejaculation success
629
rates ranging from 21% to 91% depending on type
of equipment used and patient selection [20,31-
35]. To address this variability, a large scale study
of 653 trials of PVS in 211 patients was perfor-
med. [13] Success rate was dependent on level of
injury. For example, when patients were grouped
by level of injury (C3-7, T1-5, T6-10, and T11-
L3), the success rate of ejaculation with a high
amplitude vibrator was 66%, 54%, 41% and 36%,
respectively. Completeness of injury, as measured
by the University of Miami Neurospinal Index
[36] was not predictive of ejaculatory success.
Ejaculation was quick and reliable, since most
men who ejaculated did so on 100% of trials, and
within two minutes of stimulation onset. The
effectiveness of the high amplitude vibrator has
been verified in other studies which showed about
80% success rate of antegrade ejaculation with
spinal cord lesions above T10 [20, 37].
There has been no definitive study to determine
the interval between ejaculations that optimizes
ejaculatory success rate with PVS. In general,
experience indicates that an interval of one week
or longer results in a higher success rate of ejacu-
lation than shorter intervals. There have been stu-
dies to investigate if repeated ejaculation with
PVS results in improved semen quality in men
with spinal cord injury, with some studies finding
improvement [34,35] and others not[38].
With the method of EEJ, recent studies have
shown that semen can be retrieved in 85% to
100% of men with SCI [7,28,38-41]. As discussed
previously, the success rate may be lower in
patients injured less than two years.
2. SEMEN QUALITY
In summarizing the literature, the most important
points about semen quality in men with spinal
cord injury are: generally, sperm concentration is
normal to high, but sperm motility is abnormally
low [28,39,42-44]; most of the immotile sperm are
dead [45,46]; sperm of spinal cord injured men
lose motility faster than sperm from normal men
[47]; semen quality is better with PVS compared
to EEJ, even in the same patient [15,16]; semen
quality is better in antegrade versus retrograde
specimens [15,16,45,48]; there is little difference
in semen quality with high versus low amplitude
stimulation [13].
The reason for impaired semen quality in spinal
cord injured men is unknown, but evidence sug-
gests that factors in the seminal plasma contribute
to this condition. For example, seminal plasma
from spinal cord injured men inhibits sperm moti-
lity from normal men [49]. Additionally, different
concentrations of biochemical substances are
found in the semen of men with spinal cord injury
compared to that of normal men. These substances
include prostate specific antigen [50,51], somato-
statin [52], reactive oxygen species [53], fructose
[54], and others [55]. The most compelling evi-
dence is that the motility of sperm obtained from
the vas deferens of men with spinal cord injury is
much higher (and in many cases, normal) compa-
red to the motility found in these same men’s eja-
culates [56].
VIII. OTHER METHODS OF SPERM
RETRIVAL
If assisted ejaculation procedures yield insuffi-
cient motile and/or viable sperm for ART, inclu-
ding ICSI, other procedures of sperm retrieval are
indicated. The patient should be evaluated (as if
he had no neurologic dysfunction) for obstructive
versus nonobstructive causes of the problem.
Transrectal ultrasonographic evaluation should be
performed before any other invasive procedure
[57]. A testicular biopsy may provide useful infor-
mation [58].
Sperm may be obtained from the testicle by need-
le aspiration, core needle biopsy, or open biopsy.
Sperm from the epididymis and vas deferens may
be aspirated using microsurgical techniques [8-
12]. Since most of the neurogenic anejaculators do
not have ductal obstruction, percutaneous aspira-
tion of the epididymis may be fruitless. All of
these techniques have the potential of yielding
adequate numbers of motile/viable sperm for ICSI.
The choice of technique is often up to the prefe-
rence of the surgeon and the embryologist who
will process the sperm.
IX. ASSISTED CONCEPTION
The same assisted reproduction techniques
(ART) used to treat male-factor infertility in the
general population may be used to assist couples
630
with male factor infertility due to spinal cord inju-
ry or other neurogenic disorders. Individual cen-
ters have reported their pregnancy success rates
using various forms of ART in couples with a spi-
nal cord injured male partner [43,59-65]. The suc-
cess rates are similar to those obtained in the gene-
ral population, and it appears that for any given
number of motile sperm, those obtained from men
with spinal cord injury offer the same potential for
fertilization and pregnancy as those of noninjured
men.
As with the general population, the decision of
what type of ART to use should be governed by
the number of motile sperm obtainable, and the
ease of obtaining them. Other factors that influen-
ce the selection of an ART include female factors,
whether the couple can financially afford the pro-
cedure, how quickly they want children, and the
couple´s emotional stability in dealing with pos-
sible conception failures. Also to be considered is
the frequent request from couples (based on our
experience) that the most simple methods be used,
particularly methods that require less pharmacolo-
gic manipulation and less invasiveness to the
female partner. Of further consideration in choo-
sing an ART is the coordination of the semen
retrieval procedure with the insemination procedu-
re. If there is a significant gap between these two
procedures, (for example, if the two centers per-
forming these procedures are located a significant
distance from each other) couples may have to rely
on a frozen semen specimen, collected at some
earlier time, for the insemination procedure.
No standard algorithm has been established for
recommending ART to couples with male factor
infertility due to neurogenic anejacualtion. Some
centers report successful pregnancies in couples
using home insemination, with the semen collec-
ted by PVS and introduced intravaginally [62].
The criteria for recommending more advanced
ART, such as intrauterine insemination, in vitro
fertilization, gamete intrafallopian transfer, the use
of ICSI, and the use of stimulation or monitoring
protocols for the female, have not been standardi-
zed for these couples, and to date seem to follow a
particular center´s trend for treating other etiolo-
gies of male infertility. The evaluation of a large
series of patients is needed to establish standard
treatment protocols for couples with male factor
infertility secondary to spinal cord injury.

X. USE OF PVS FOR SEXUAL
PLEASURE
No studies have established guidelines for the use
of home PVS for sexual pleasure in patients with
neurogenic anejaculation. Some self-reports of its
use by men with spinal cord injury have appeared
in lay magazines written primarily for the disabled
population, such as New Mobility, or on websites
devoted to topics of sexual activity in persons with
disability [66,67]. Anecdotally, many of our
patients have reported on the use of PVS as part of
their sexual activity. Although they do not achieve
the same orgasmic responses they achieved prior
to their injury/disorder, they nevertheless report a
sense of pleasure and well-being at being able to
achieve ejaculation during sexual activity with
their partner. Clinicians counseling patients in the
use of PVS for unsupervised use at home should
do so with great caution, since approximately 40%
of all patients with spinal cord injury experience
autonomic dysreflexia with this method (see
Management of Autonomic Dysreflexia [H-III-3]
and Patient Selection [H-II]).
XI. ECONOMIC CONSIDERATIONS
In choosing treatment options for ejaculatory dys-
function in men with neurogenic disorders, econo-
mic considerations may be important, depending
on the health care system in which the patient is
treated. Generally, the more sophisticated ARTs
are the most expensive. For example, in the United
States, ICSI ranges between $12,000 and $15,000,
while intrauterine insemination ranges between
$600 and $800. In Denmark, the prices are about
20% lower than those for the United States, but a
couple may have to wait for up to two years to for
treatment. While these considerations may not
apply to patients in whom full medical benefits are
provided by their health care system, a similar hie-
rarchy in cost borne by the system may have to be
considered. For this reason, we advocate attempts
at assisted ejaculation, combining the motile
/viable sperm from the antegrade and retrograde
fractions for use in the more simple ARTs, before
committing to the various surgical sperm aspira-
631
tion/extraction techniques which essentially com-
mit the patient only to ICSI, and are themselves
more expensive than assisted ejaculation. As tech-
nology and pregnancy rates improve and costs
come down, this philosophy may need to be re-
evaluated.
Some economic considerations are relevant speci-
fically for patients with spinal cord injury.
1. PVS should be attempted before EEJ, espe-
cially in patients with injuries above T10. PVS
is less invasive to the patient and results in bet-
ter semen quality compared to EEJ [15,16] and
may offer the less expensive option (relative to
other ARTs) of home insemination in selected
couples in whom the male has a reasonable
amount of motile sperm and is at low risk for
autonomic dysreflexia, and in whom the female
partner is young and health.[62].
2. In patients who require EEJ, general anesthesia
is not necessary in the majority of cases, and
should thus be avoided unless EEJ is too pain-
ful for the patient.
3. Since there is a controversy over the use of
repeated ejaculation for improving semen quali-
ty, this method should not be routinely advoca-
ted.
4. There is no evidence to support the notion that
sperm cryospreserved shortly after injury offers
a better chance of fertilization and pregnancy
(when thawed) than fresh sperm collected years
after injury. This information should be offered
to patients considering cryopreservation of their
sperm.
XII. CONCLUSIONS
1. Treatments for neurogenic anejaculation for
the purpose of assisting conception depend
on the etiology of the disorder, and may
include sympathomimetic agents, assisted
ejaculation procedures, orsperm retrieval by
surgical removal from the testis, epididymis,
or vas deferens.
2. The same assisted reproductive technologies
used to treat male factor infertility in the
general population may be used to assist
couples with male factor infertility due to
 neurogenic anejaculation. Pregnancy success
rates appear to be similar to those obtained
in the general male factor infertile popula-
tion.
3. Depending on the health care system where
the patient is treated, economic considera-
tions may be of importance when selecting
treatments for anejaculation and when selec-
ting ARTs.
XIII. RECOMMENDATIONS
1. Practitioners treating patients with neuroge-
nic ejaculatory dysfunction should be fami-
liar with the management of such patients,
especially the management of spinal cord
I. OVERALL CONCLUSIONS AND RECOMMENDATIONS
I. OVERALL CONCLUSIONS
1. Sexual disabilities such as erectile dysfunc-
tion and disturbances of ejaculation and
orgasm are very common among patients
with neurological disorders or patients suf-
fering from sequelea from injuries, spinal
cord injuries in particular. In brain disor-
ders and after brain injuries sexual desire
may also be reduced and behavioral distur-
bances may occur. Sexual adverse reactions
have been reported with the use of many
prescription drugs acting on the nervous
system.
2. Sexual disabilities may be the presenting
symptom or one of the early symptoms of a
neurological disorder.
3. All neurological patients should have the
opportunity of sexual counselling. The majo-
rity of them, even those with complete spinal
cord injuries, can be treated for erectile and
ejaculatory dysfunction.
632
injured patients who are at risk for autono-
mic dysreflexia.
2. Practitioners attempting to manage couples
for ART should be familiar with the type of
semen quality usually obtained from men
with neurogenic anejaculation, and how it
may differ from normal semen. They should
be familiar with how to retrieve and utilize
sperm from a retrograde ejaculate.
3. PVS should be used as the first line of treat-
ment for ejaculatory dysfunction of men
with spinal cord injury, due to its safety, effi-
cacy, and reliability, and low investment of
time and money. Compared to EEJ, PVS is
less invasive, is preferred more by patients,
and results in better semen quality. If PVS
fails, patients should be referred for EEJ.
II. OVERALL RECOMMENDATIONS
1. DIAGNOSIS
Taking a more careful case history, performing
at least a focused neurological examination,
including the lumbosacral segments, comple-
mented in very selected patients (particularly
those with suspected peripheral nervous system
involvement) by neuro-physiological tests,
should - in addition to other indicated investi-
gations - be considered in patients seeking
medical advice because of a sexual disability.
2. TREATMENT
1. The first step of the counselling is to open
the mind of the patient to the existence of
sexual disabilities in cases of his type. The
second step is to give the patient proper
information about sexual issues in this parti-
cular type of disorder/injury. A number of
specific suggestions, such as practical infor-
mations about positions and stimulation
techniques and technical aids and devices
could be given.
2 The next step is to use the arsenal of specific
treatments available, medical as well as sur-
gical, for treatment of erectile dysfunction
and ejaculatory dysfunction. These include
testosterone substitution, vacuum therapy,
intracavernous injection of prostaglandin
E1, papaverine or moxisylyte, transdermal
or intraurethral application of different
drugs, oral administration of phosphodieste-
rase inhibitors, and penile prosthesis. Treat-
ment of bladder dysfunction and spasticity
as well as autonomic dysreflexia in SCI is
also important.
3 In spinal cord injuries semen can be retrie-
ved by use of assisted ejaculation methods
such as penile vibratory stimulation (PVS)
or rectal probe electroejaculation (EEJ).
PVS should be used first due to its safety,
reliability and low investment in time and
money. It also results in better semen quali-
ty. If PVS fails, the patient should be refer-
red to a specialist center for EEJ. So far
there are no treatments to normalise semen
quality in men with spinal cord injury.
4. In the neurological patient, it is important to
treat sexual, bladder, bowel and fertility
problems with a global view of the patient.
Different disciplines need to be better infor-
med and to collaborate both in diagnostics
and treatment of patients with complex
sacral dysfunctions.
5. Greater efforts must be aimed at educating
the medical profession about the nature and
treatment of sexual disability problems in
general, and in neurological patients in par-
ticular. This education should especially be
aimed at support personnel, such as nurses,
occupational therapists, and physical thera-
pists, who spend more time with the patient
and are thus more likely to be the recipients
of the patient’s questions.
III. SUGGESTIONS FOR FUTURE
RESEARCH
1. Detailed knowledge of neurocontrol of erec-
tion, orgasm, and ejaculation is as yet rudi-
mentary, particularly as regards functionally
633
important central nervous system areas and
their connections. It is expected that further
research (probably involving also functional
neuroimaging) will reveal and better delinea-
te relevant areas in the central nervous sys-
tem relevant to psychogenic, reflex, and sleep
erections, orgasm and ejaculation.
2. At present the diagnosis of neurogenic ED
can usually only be inferred as possible or
probable on the grounds of association with
particular neurologic diseases or neuroana-
tomic lesions. Better data on association of
particular neurologic conditions/diseases
with ED as well as a better correlation of
sexual dysfunction with localised lesions (the
diagnosis of which is much improved by
modern diagnostic methods) are expected to
improve the diagnostic accuracy.
3. Clinical neurophysiological tests to assess the
function of the sacral parasympathetic sys-
tem and the penile smooth muscles are as yet
controversial. Further research is expected
to clarify the validity, sensitivity and specifi-
city of corpus cavernosum EMG. Generally,
the place of clinical neurophysiological tests
to help establish certain neurological
diseases associated with early and possibly
isolated neurogenic ED (e.g. multiple system
atrophy) or better define the functional neu-
roanatomic deficits caused by lesions (for
instance in spinal cord involvement) should
be better defined.
4. a. Advanced possibilities for diagnosis
should help in more precise definition
of neurologic patient populations, thus-
making studies of effectiveness of parti-
cular therapies more discriminant.
b. Studies are needed to better define opti-
mal algorithms for investigation of diffe-
rent neurological patient populations with
erectile and ejaculatory dysfunction.
c. Studies are needed to better define opti-
mal algorithms for investigation of
patients with isolated ED, suspected to be
organic (neurogenic), and whether inves-
tigations are relevant to make an early
diagnosis of some neurologic diseases
/conditions possible (MSA, MS and so on).
5. a. Detailed information on the applicability
and efficacy of different therapies for ED
in different and better defined neurolo-
gic patient populations is as yet unk-
nown. Long-term follow-up and cost-
efficiency as well as quality of life assess-
ment is expected to give us better data
for a rational choice of individual thera-
pies in particular patient populations.
b. Quality of life assessment tools are nee-
ded to establish the efficacy of treat-
ments and to directly compare studies on
outcomes of treatments for erection and
ejaculation. Cost assessment tools for
erectile and ejaculatory dysfunction are
missing. Future developments are expec-
ted to propose such tools and test them.
6. a. How soon after neurologic injury/disor
der should treatment begin which is
aimed at improving ejaculatory dysfunc-
tion or semen quality? What type and
timing of treatments should be recom-
mended?
b. What is the best treatment for ejaculato-
ry and orgasmic dysfunction for the goal
of improving sexual pleasure in a patient
with neurogenic anejaculation?
c. What is the best ART algorithm for
couples with male factor infertility
secondary to neurologic injury/disorder?
As part of this question, what is conside-
red “good” semen quality in these men,
i.e., how much sperm is needed for ferti-
lization by intravaginal or intrauterine
insemination? What are the pregnancy
rates with home insemination versus
ART? What is causing low sperm motili-
ty in men with spinal cord injury?
7. What is the impact of various urologic treat-
ments (penile prosthesis, sphincterotomy,
stents, etc.) on ejaculatory dysfunction in
patients with neurological disorders?
634
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________________________
646
 Committee 18

Standards for Clinical Trials

in Erectile Dysfunction:
Research Designs and Outcomes Assessment

Chairman
R. ROSEN

Members
A. BENNETT,
D. FERGUSON,
M. HIRSCH,
H. PADMA-NATHAN,
M. WYLLIE

647
 CONTENTS

I. INTRODUCTION V. PROTOCOL DESIGN AND

IMPLEMENTATION

II. RATIONALE AND DESIGN OF 1. BACKGROUND OF THE STUDY

CLINICAL TRIALS
2. STUDY OBJECTIVES
1. P HASE I 3. DESIGN OF THE STUDY
2. P HASE II 4. ADMINISTRATIVE CONSIDERATIONS
3. PHASE III
4. P HASE IV VI. DATAANALYSIS AND
5. DRUG INTERACTION STUDIES REPORTING OF RESULTS

III. STUDY POPULATIONS

VII. ETHICALAND CLINICAL
1. GENERAL PRINCIPLES ISSUES IN ERECTILE
2. DEFINING THE DISEASE STATE AND DYSFUNCTION RESEARCH
PATIENT POPULATION
3. BALANCE BETWEEN “OPENNESS” OF THE VIII. FINAL RECOMMENDATIONS
ENTRY CRITERIA AND PATIENT SAFETY FOR CLINICAL TRIAL DESIGN AND
OUTCOMES ASSESSMENT
IV. OUTCOME ASSESSMENTS

1. PHYSIOLOGICAL MEASURES REFERENCES

2. SELF-REPORT MEASURES
3. DAILY DIARY AND EVENT LOGS APPENDIX A
4. PARTNER ASSESSMENTS
5. QUALITY OF LIFE AND TREATMENT APPENDIX B
SATISFACTION
APPENDIX C
6. ADVERSE EVENT MONITORING

648
 Standards for Clinical Trials in Erectile
Dysfunction: Research Designs and
Outcomes Assessment
R. ROSEN,
A. BENNETT, D. F ERGUSON, M. H IRSCH, H. PADMA-NATHAN, M. W YLLIE
I. INTRODUCTION
Clinical trials of erectile dysfunction (ED) have
proliferated in the past decade, as a wide range of
injectable, transurethral and oral agents have beco-
me available. Critical to the development of these
new treatments has been the design, conduct and
interpretation of clinical trials in selected patient
groups. Along with the development of novel
agents for the treatment of ED, a plethora of new
outcome measures and assessment tools have been
developed. These new measurement approaches
have allowed for more precise and reliable assess-
ment of erectile function in research and clinical
settings. In addition, the use of valid and reliable
outcome assessments in the context of a well-
controlled clinical trial is the sine qua non for
regulatory approval of any new clinical agent.
In this chapter we focus on the design and conduct
of clinical trials in ED, including a review of the
design and methodology of Phase I, II, III, and IV
clinical trials. In particular, we consider such
issues as the choice of study design, duration and
timing of the trial, selection of clinical or non-cli -
nical populations to be studied, outcome assess -
ments or response variables to be measured, and
statistical analyses to be employed. The use of
parallel-design, crossover-design, and combina-
tion clinical trial designs is reviewed. The chapter
also presents practical guidelines in the develop-
ment of clinical protocols for new drug evaluation,
the role of ethical and clinical issues in the conduct
of clinical trials, and guidelines for the preparation
of research reports and publications.
649
A major goal of the chapter is to review current
standards of practice in the design and conduct
of clinical trials. Many of these standards repre-
sent general principles in the design of clinical
trials, although specific issues in the evaluation
of new agents for ED are addressed. These inclu-
de the use of objective (physiological) versus
self-report (questionnaire) measures of sexual
function, reports of the sexual partner, global
patient and physician assessments, and the use of
disease-specific quality of life measures. The
advantages and disadvantages of each of these
assessment approaches are considered. Although
much of the focus in recent years has been on the
development of new oral agents (e.g. sildenafil,
oral phentolamine, sublingual apomorphine),
similar standards of research must be applied in
the evaluation of other drug delivery systems or
mechanical devices for the treatment of erectile
dysfunction.
Summary points:
• This chapter focuses on the design and
conduct of clinical trials for erectile dys -
function. Issues such as the choice of study
design and methodology, selection of the
study population, and outcome variables to
be measured are considered in depth.
• The development of new agents for treat -
ment of ED has been associated with
advances in clinical trial methodology, parti -
cularly the development of new outcome
measures for assessing sexual functioning
and quality of life. The use of validated and
reliable outcome measures is a necessary
component in all clinical trials.
 dicted threshold efficacy dose in man. Should this
II. RATIONALE AND DESIGN OF be well tolerated, additional doses will usually be
CLINICAL TRIALS evaluated at dose increments of 2x to 3x. Signs of
poor toleration or reaching a pre-determined
dose level will normally conclude this stage of
The process of development and/or regulatory development. Where possible, these studies are
approval for new treatments for ED can be broken accompanied by concomitant assays of plasma
down into several discrete phases. This process is drug levels.
usually described as occurring in four phases
(Phases I, II, III, and IV), each of which is descri- To ensure that tolerability is not affected by admi-
bed in detail below. Beyond the immediate goal of nistration of subsequent doses of the drug, mul -
attaining regulatory approval, clinical trials are tiple dose studies should be undertaken. The fre-
also intended to be predictive of the likely quency of dosing will depend on the predicted
risk/benefit outcomes when the drug or device dosing regimen of the novel agent. Again, plasma
enters widespread clinical use. drug levels should be monitored provided that the
basic assessment of drug tolerability is not com-
1. P HASE I promised.
Formal pharmacokinetic and drug metabolism stu-
These studies represent the first exposure in man
dies are usually initiated following single and mul-
of the novel agent or device and are typically
tiple dose tolerability studies. It is important to
conducted in healthy individuals. Unless there is a
ensure that there is no dose-dependent tissue
particular need at this stage, women of child-bea-
drug accumulation, and that the metabolic path -
ring age are generally excluded. The full range of
way and potential for major drug interactions are
phase I studies potentially relevant to ED is shown
known.
in Table 1.
Limited efficacy information can be obtained
Initial studies in volunteers typically involve from Phase I clinical pharmacology studies in
administration of a single dose of the new agent. healthy volunteers that may expedite dose selec-
The first dose is selected on the basis of acute and tion and the overall drug development process. In
chronic animal studies and, if available, data from recent years, surrogate endpoints have been used
human liver metabolism in vitro. The initial dose increasingly in phase I trials for this purpose. For
selected may be 30-100 times lower than the pre- example, this type of study is now used routinely
Table 1: Phase 1 Drug Development in Healthy Volun - in BPH/LUTS drug development, where the effi-
teers cacy of novel alpha-blockers is determined by a
reduction in response to the alpha agonist, pheny-
S TUDY T YPE RATIONALE lephrine [1]. A similar model could potentially be
Single dose Assessment of tolerability developed for dose selection of novel pharmaco -
after single dose administra- logical agents for ED, based upon specific
tion mechanisms of actions of these drugs (e.g. PDE-
Multiple dose Asssessment of tolerability 5 inhibition, alpha-adrenergic blockade).
over likely dosing period
Finally, it is sometimes worthwhile to undertake
Pharmacokinetics Assess if pre-clinical studies phase I studies in specific populations. For
are predictive of kinetics and
example, studies in women or the “supra-elderly”
metabolites.
may be undertaken during phase I if these popula-
Clinical pharmacology Indirect assessment of efficacy. tions are likely to be further studied during phase
Ensure adequate pharmacody-
namic/Pharmacokinetic rela- II or III clinical trials.
tionships. 2. PHASE II
Special populations Women and/or “supra-
elderly” Efficacy assessment is formally begun in phase II.
May display different Outcome assessments during this phase typically
tolerability/Pharmacokinetics. involve a mixture of objective measures (e.g.
Rigiscan) or self-report measures (e.g., daily dia-

650
ries, IIEF) and are likely to be similar to those
used in the more extensive phase III studies (see
below). The primary objective of phase II effica -
cy studies is dose-setting, i.e., the identification of
an effective dose range to be evaluated in phase
III. The range of doses in phase II studies are
usually more limited than in phase I, since the
maximum tolerability of the drug has been establi-
shed. A starting dose of 5-10% of the maximum
tolerated dose may be initially employed. Additio-
nal information on drug tolerability is also obtai-
ned during this stage of clinical development, allo-
wing calculations of potential benefit/risk ratio.
Crossover designs, in which each patient serves as
his own control, are often used in phase II trials.
The major advantage of this design is the availa -
bility of within-subject comparisons and the
associated reduction in patient variability and
increased statistical power - a feature that may
inadvertently result in a bias towards positive out-
comes. As such, this design is generally favored in
early stage clinical studies (phase I and II). Other
potential problems are the likelihood of carryover
effects from one treatment phase to the next and
susceptibility to patient drop-outs. These problems
may be exacerbated if three or more treatment
arms are included in the study design. Despite
these limitations, crossover designs are frequent -
ly preferred in early phase II dose setting studies.
Phase II studies may involve evaluations in spe -
651
cial populations. The high degree of comorbid
hypertension and diabetes associated with ED [2]
may warrant early stage characterization of the
potential cardiac or metabolic effects of novel ED
agents in these patient groups. Additionally, drug
interaction studies may be undertaken during this
phase (see below).
3. PHASE III
Prior to regulatory approval, it is necessary to
conduct two or more large-scale (“pivotal”) out-
come studies in appropriately selected patient
groups. Phase III trials are usually designed as
multi-center, randomized, prospective studies with
two or more doses of the study drug and a double-
blind placebo control condition. Parallel designs
are typically employed in this phase. In the sim-
plest parallel design study, patients are randomly
assigned to two or more parallel treatment arms
for the duration of the study period (usually 12-16
weeks). Each patient is exposed to one treatment
condition only, and comparisons are made bet-
ween treatment groups at various time points.
Treatment-induced changes are assessed by analy-
sis of between-group differences following treat-
ment. Results can also be analyzed relative to
changes in baseline. Baseline assessments are
necessary to ensure that the treatment groups are
equivalent prior to randomization. Mixed paral-
lel-crossover designs have also been used in Phase
III trials with novel ED agents (See Figure 1).
Figure 1: A combination
parallel-crossover design.
This design was used in
recent phase III trials of sub -
lingual apomorphine for
erectile dysfunction. Patients
were randomly assigned to
one of three treatment arms
(2 mg, 4 mg, 6mg apomorphi -
ne SL). Within each treatment
arm, each patient received
active drug or double-blind
placebo for an initial 4-week
treatment period. Following a
brief washout period (24-72
hours), patients received the
alternative drug or placebo
condition during the second
4-week treatment period. The
design is completely counter -
balanced and minimal car -
ryover effects were observed.
The parallel treatment phase, usually double-blind,
is frequently preceded by a single-blind placebo or
“no treatment” run-in phase to establish a reprodu -
cible baseline prior to randomization. This run-in
period can also be used to screen out patients who
are most susceptible to placebo effects. Following
this stage, patients are assigned to the double-blind,
randomized phase of the study.
A comparison drug or treatment may be included,
although these are not essential or required for ini-
tial regulatory approval. All phase III studies
should be prospective and placebo-controlled,
defining in advance inclusion and exclusion cri -
teria and the baseline characteristics of the popu -
lation. Primary and secondary study endpoints
should be clearly specified, as well as key safety
parameters. Phase III studies are typically powe-
red for the primary efficacy endpoints. The dura-
tion of treatment may range from several weeks to
6 months or more, although longer duration trials
may be difficult to complete due to subject attri-
tion. A minimum duration of 8 weeks of treat -
ment is generally recommended. Most phase III
trials of ED include an open-label extension
phase during which additional safety data is col-
lected. Open-label extension phases may last from
6 months to 2 years or more.
4. P HASE IV
Phase IV studies are undertaken either during the
registration process or subsequent to approval.
One component involves “post marketing sur -
veillance” studies designed to provide long-term
tracking of patients on active drug and thereby
expand the safety database. Special population
studies may also be conducted during this phase.
In general, phase IV studies are designed to
increase understanding of the overall treatment
profile in the target population(s). These studies
may not include all of the controls (e.g., placebo-
blinding and baseline assessment) utilized in
phase II/III. On the other hand, comparator agents
and special population groups are more likely to
be included in the trial design during this phase.
Increasingly, the healthcare environment requires
outcome assessment in long-term studies to gene-
rate data on the potential effect of treatment on
healthcare economics. At the earliest, these stu-
dies would be conducted in phase IV.
652
5. DRUG INTERACTION STUDIES
Many patients with ED are likely to be receiving
drug therapy for associated co-morbidities (e.g.
diabetes, hypertension, hypercholesterolemia) or
unrelated disorders (e.g. asthma, gastric ulcer).
Although it is neither practicable or necessary to
determine the impact of a novel agent for ED on
every potential drug taken by the patient, certain
key drug interactions should be examined. The
interaction studies fall into two major categories:
pharmacokinetic and pharmacodynamic interac-
tions.
Pharmacokinetic drug interaction studies are
designed to evaluate acute effects of the new agent
on the plasma levels of other drugs (e.g. antihy-
pertensives, anticholesterolemics) being concomi-
tantly administered. Specific drug interaction stu-
dies may be required should the novel agent be
known to be an inducer or inhibitor of cytochro -
me-dependent liver metabolizing systems.
Equally important is the potential for pharmaco -
dynamic interactions. Of particular relevance is
the potential of novel ED agents to impact positi-
vely or negatively on the efficacy of agents taken
to control comorbidities such as hypertension,
hyperlipidemia or diabetes. An alteration in blood
pressure control in a patient with controlled hyper-
tension, or endocrine control in a diabetic patient
would be undesirable features, and should be care-
fully evaluated during early phase I or phase II stu-
dies. In addition, specific pharmacodynamic inter-
actions relevant to the mechanism of action, e.g.
PDE-5/nitrate interactions in angina patients
should be carefully assessed.
Summary Points:
• The process of new drug or device develop -
ment is categorized into 4 stages. Stage 1
studies are usually performed in healthy
volunteers to evaluate pharmacokinetic
properties and tolerability of new drugs.
Phase II studies provide initial efficacy and
dose ranging assessment. Phase III studies
are large-scale, prospective (“pivotal”) stu -
dies of efficacy and safety. Finally, phase IV
studies are post-approval or special popula -
tion studies.
• Among the available research designs, cros -
sover designs are usually employed in Phase
II studies. This design has the advantage of
controlling for subject variability and pro -
vides increased statistical power. Parallel or
combination parallel-crossover designs are
preferred in Phase III or IV studies. Phase
III studies should always be double-blinded
and placebo controlled with careful assess -
ment of baseline functioning prior to rando -
mization. The minimum duration of treat -
ment is usually 12-16 weeks in these studies.
• Drug interaction studies are important in
evaluating possible phamacokinetic and
pharmacodynamic interactions between ED
agents and other drugs used in the treatment
of common comorbidities, such as hyperten -
sion, hyperlipidemia and diabetes. Possible
interactions with other cardiovascular drugs
(e.g. nitrates) are of special concern.
III. STUDY POPULATIONS
1. GENERAL PRINCIPLES
All clinical trials require a precise definition of
which patients are eligible for inclusion and which
patients are not eligible.
The most important underlying principal guiding
this definition is that the study population should
represent the overall patient population for
whom the treatment under investigation is inten -
ded. If the study population is truly representative
of the intended treatment population, then the
results of a well-designed controlled trial are like-
ly to predict the “real-world” effect. On the
contrary, if the study population is too narrowly
defined, then the trial results may not generalize to
the broader population. Therefore, when conduc-
ting “pivotal” phase III trials, it is important for
the investigator to define a group of patients that
will be as representative as possible of the inten-
ded patient population at large. The investigator
accomplishes this by taking into account such fac-
tors as patient age, overall health status, concomi-
tant medications, and the severity and duration of
the disorder. All of these considerations apply in
the selection of patients for clinical trials of ED.
653
A second underlying principle in defining the
study population is that the disease state under
investigation must be well characterized and well
defined. In order for the results of controlled cli-
nical trials to be easily interpreted by practitioners,
it is critical that the entrance criteria clearly define
a patient population with well-recognized disease
manifestations. Although practitioners of clinical
medicine are not limited by the boundaries of a
particular disease category when they treat
patients in the real world, the clinical trial investi-
gator should attempt to control these boundaries
relatively strictly. The investigator tries to achieve
this by meticulously defining the particular disea-
se manifestations, using particular signs and
symptoms, and considering symptom severity and
duration. Careful patient selection using unam -
biguous inclusion and exclusion criteria should
be sufficient to delineate a study population that is
easily recognized by all those who assess the study
results.
A third principle is that a logical and reaso -
nable balance must be struck between the safe -
ty of the enrolled patients and the “openness” of
the entrance criteria. Specifically, the trial
population should be sufficiently broad to repre-
sent the larger group of patients who may even-
tually benefit from treatment, although it should
not be so broad so as to include patients who are
clearly at direct high risk of injury from the study
treatment or procedures. Such balance requires
skillful selection of entrance criteria which
comes only with a sound understanding of the
disease process, experience in the management
of such patients, and knowledge of the conduct of
clinical trials. A corollary of this principle is that
exclusion criteria should be sufficiently strict so
as to adequately define the study population and
to safeguard the enrolled population, but should
not be so strict as to significantly impair the abi-
lity of the investigator to recruit the necessary
numbers of patients.
Specific study population issues in erectile dys -
function:
Representative patient population: The phase III
study population should include patients with
erectile dysfunction of varying etiologies and
severities. Such patients will include those with
diabetes, atherosclerosis, hypertension, hyperlipi-
demia, neurologic disorders, genitourinary disor-
ders, appropriately treated endocrinopathies and
depression, tobacco use, and various psychologic
etiologies. The practice of attempting to divide
the population into “organic” and “psychoge -
nic” etiologies appears to create artificial and
unrealistic subgroups. Such a division may serve
to reduce the overall applicability of results.
Alternatively, it may be argued that “too much”
heterogenity of disease can increase inter-patient
variability and may mask or obscure an underlying
treatment effect that would have been observed in
a more homogeneous population.
Regarding disease severity, the phase III study
population should provide a representative mixtu-
re of the various degrees of severity of erectile
dysfunction, as assessed by well-validated and
sensitive instruments. It may be argued that the
inclusion of milder forms of disease could make
the demonstration of a treatment effect more diffi-
cult. In addition, it is also possible that patients
with more severe forms of disease may be more
resistant to treatment. Nevertheless, the principle
of generalizability seems to carry sufficient
weight that it currently appears reasonable to
include the broadest possible range of etiologies
and severities in the “pivotal studies”.
On the other hand, it also appears reasonable, at
this time, to study certain sub-groups of patients in
smaller, “special population” trials. These trials
may include patients with more severe dysfunctio-
nal states, patients who have undergone radical
prostatectomy, and patients with spinal-cord inju-
ry. It may even be reasonable to perform separate
studies in diabetics or depressed patients. Propo-
nents of special population studies argue that
patient-related variability is reduced and that the
likelihood of obtaining a significant treatment
effect is increased. In addition, individual study
reports may be easier to interpret. Regardless,
such studies are capable of providing important
support for the pivotal trials.
2. DEFINING THE DISEASE STATE AND
PATIENT POPULATION
a) Inclusion criteria
Phase III studies in erectile dysfunction are typi-
cally conducted in adult males, 18 years of age and
older. There are usually no upper age limitations.
In most circumstances, males are heterosexual and
654
have a stable, monogamous relationship with a
willing partner. The partner must agree to partici-
pate in the trial. The patient must complain speci-
fically of “erectile dysfunction”; that is, a consis-
tent difficulty in achieving and/or maintaining an
erection sufficient for sexual intercourse. In gene-
ral, the dysfunctional state must negatively
impact on the enjoyment or satisfaction with the
overall sexual experience. The duration of dys-
function is variable in different trials, but in gene-
ral, the problem should be described as a “consis-
tent” one rather than a “transient” one. Currently,
it appears that a duration of at least 3 months is a
generally accepted, minimum period of disease,
although it may be argued that both shorter and
longer duration of dysfunction also constitute true
“erectile dysfunction”. Enrolled patients must be
willing to provide informed consent and must be
willing and able to participate in all necessary and
pre-specified study procedures. In some trials,
inclusion is limited to patients with “mild to
moderate erectile dysfunction”, as assessed by
standardized instruments such as the Internatio-
nal Index of Erectile Function (IIEF) (See
Appendix B). In the design of some trials, patients
who succeed “too often” during a pre-specified
run-in period (e.g. >75% successful attempts) are
excluded from additional study participation.
b) Exclusion criteria
In general, exclusion criteria are used to strictly
define the study population and to provide safe-
guards against enrolling patients who are at inhe -
rent high risk from study participation. In studies
of agents for the treatment of erectile dysfunction, it
has been customary to exclude certain patient
groups. These are shown in Table 2 (following
page).
In some trials, exclusion criteria have been
employed which provide safeguards for a particu -
larly susceptible group of patients from exposure
to a particular physiologic response associated
with the treatment. Such exclusion criteria are
often dependent on the proposed mechanism of
action of the drug. For example, in trials of potent
vasodilator agents, patients with orthostatic hypo-
tension may be excluded. In trials of the phospho-
diesterase inhibitor, sildenafil, patients using nitra-
te therapy are excluded due to the drug’s enhance-
ment of the systemic vasodilating effect of
nitrates.
Table 2: Patients Typically Excluded from Clinical Trials of
ED
1. Patients with untreated hypogonadism.
2. Patients with penile deformities such as Peyronie’s
plaques; patients with penile implants; and patients
with predispositions to priapism, such as those with
sickle cell disease, blood dyscrasias and multiple
myeloma.
3. Patients with significant baseline liver dysfunction,
such as those with baseline SGOT or SGPT > 3 times
the upper limit of normal.
4. Patients with significant baseline renal dysfunction,
such as those with serum creatinine values greater
than 2.5 mg/dl, those on dialysis, and those who are
status post renal transplant.
5. Patients with a history of HIV infection.
6. Patients with drug, alcohol or substance abuse within
6 months of study initiation.
7. Patients who have participated in another study for
the treatment of ED within 30 days of study initia-
tion.
8. Patients who have partners who are nursing, who are
pregnant, or who wish to become pregnant during the
course of the study.
9. Patients who are unable to provide informed consent.
10. Patients with uncontrolled psychiatric disorders, such
as psychosis, manic as is depressive disorders or
chronic depression.
11. Patients with uncontrolled diabetes mellitus, as evi-
denced by elevated hemoglobin A1c levels.
In addition, patients in whom sexual activity itself may
be a risk for cardiovascular events have been excluded
from these trials. The specific exclusion criteria that have
been employed to remove such patients from the study
population have included:
1. Patients with unstable angina.
2. Patients with a history of myocardial infarction
within 6 months of study initiation.
3. Patients with a history of life-threatening cardiac
arrhythmia within 6 months of study initiation.
4. Patients who have suffered a stroke within 6 months
of study initiation.
5. Patients with uncontrolled hypertension, for example,
those with systolic blood pressures above 170 mm Hg
or diastolic blood pressures >100 mm Hg.
655
3. BALANCE BETWEEN “OPENNESS” OF THE
ENTRY CRITERIA AND PATIENT SAFETY
In examining some of these exclusion criteria, it
becomes clear that there is a degree of conflict bet-
ween maintaining the safety of those in the trials
and studying the treatment in a broadly represen-
tative patient population. For example, patients
with extensive cardiovascular disease may not be
appropriate candidates for controlled clinical trials
for safety reasons, yet such patients may become
candidates for treatment once therapy becomes
widely available. As an overview of this problem,
it appears reasonable to state that entry criteria
should allow the broadest pool of patients that
reasonable safety allows. The rapid development
of therapies for erectile dysfunction may help us to
better manage this conflict in the near future.
Summary Points:
• In general, the study population in clinical
trials of ED should be broadly representati -
ve of the overall patient population. Inclu -
sion criteria should define the patient’s
condition as clearly as possible, and should
provide minimal duration and severity crite -
ria. Exclusion criteria should be sufficiently
strict so as to adequately define the study
population and to safeguard the enrolled
population.
• Special population studies may also be of
value in assessing the safety or efficacy of
new treatments in selected sub-populations.
These studies provide valuable complemen -
tary data to the main pivotal trials.
IV. OUTCOME ASSESSMENTS
The outcome of clinical trials in erectile dysfunc-
tion should only be assessed by validated and sen-
sitive instruments which can be used to measure
changes due to treatment from baseline to a pre-
determined follow-up period. Historically, studies
on ED have suffered from the following:
1. Outcomes reported by verbal interactions with
the patient and not by a standardized, written
questionnaire.
2. Follow-up periods of short or indeterminate
length.
3. Pre-treatment and post-treatment clinical status
poorly defined.
4. Quality of life and sexual status questionnaires
not used.
5. Partner verification infrequently used.
For the safety and effectiveness of a drug/device
to be measured and compared to existing thera -
py, both pre-treatment and post-treatment assess -
ments must be standardized and broadly accepted
by the research community.
Response variables are the endpoints or outcomes
to be measured during the course of a clinical trial.
In principle, one or two response variables should
be selected in advance as the primary endpoints of
the trial, although in practice several response
variables are usually reported. In these situations,
special care needs to be taken to correct statistical -
ly for the number of comparisons made, and pos-
sible interrelationships between the response
variables of interest. The choice of primary end -
points in a clinical trial is essential, and response
variables should be clearly defined and justified
prior to initiation of the trial. In the absence of
standardized outcome measures, comparison of
results from one ED trial to another should be vie-
wed with considerable caution. Among the respon-
se variables most frequently used in trials of ED are
physiological measures of penile rigidity or tumes-
cence (e.g. Rigiscan), patient-based questionnaires
or diary reports of sexual function (e.g. IIEF, SEP),
partner assessments, and global ratings of clinical
improvement. Each of these measures has certain
advantages and disadvantages.
1. P HYSIOLOGICAL MEASURES
Several methods for objective measurement of
penile rigidity and engorgement have been descri-
bed [3-5], the most widely used of which is the
Rigiscan system (Timm Medical Systems) (See
Figure 2). This method was first described by Brad-
ley and Timm [6], who recommended use of the
device in the home setting for monitoring of noc-
turnal penile tumescence and rigidity (NPTR). The
device is attached to the patient’s inner thigh, with
two loops placed around the base and tip of the
penis proximal to the coronal sulcus. Measures of
radial rigidity are obtained by application of a pre-
656
determined force to each loop every 3 minutes ini-
tially, and at 30 sec intervals when an increase of
>10 mm at the base is detected. Penile rigidity is
expressed as a function of displacement when the
loop is tightened around the penis, and rigidity is
defined in terms of penile stiffness as determined by
cross-sectional response to radial compression [7].
Although the technique was developed originally
for home monitoring of NPT, Rigiscan recording
has been used extensively for real-time assessment
of penile tumescence and rigidity in response to
pharmacological or visual sexual stimulation
(VSS). For example, in-office Rigiscan measures of
penile rigidity were reported as a primary endpoint
in a pivotal dose-finding study of intracavernosal
alprostadil for ED [8]. Rigiscan changes in respon-
se to VSS (Fig. 3) have similarly been reported in
trials of sildenafil [9] and sublingual apomorphine
[10].
Several potential limitations have been identi -
fied, the most significant of which is the assump-
tion of equivalence between radial and axial rigi-
dity. Although there is limited evidence for this
assumption, at least one study compared measure-
ments of axial and radial rigidity at constant cor-
poral pressures [11]. Axial and radial rigidity
were found to be functionally related, and both
measures were moderately correlated with intraca-
vernous pressure. In a comparison of Rigiscan
with sleep laboratory measures of tumescence
and rigidity, Licht et al. [12] reported that a base
Figure 2: The Rigiscan device (Timm Medical Systems) for
continuous monitoring of penile tumescence and rigidity.
The device can be used for overnight recording of noctur -
nal penile tumescence and rigidity (NPTR) or for provoca -
tive testing of responses to visual sexual stimulation (VSS).
Figure 3: Sample Rigiscan tracing from a provocative testing session with VSS. The onset of stimulation is indicated by the
double vertical lines. The patient achieved near-maximal rigidity for most of the testing session.
rigidity of 55% or more predicted functional erec-
tion with a sensitivity of 85% and specificity of
91%. Other investigators have reported that tip
rigidity of 70% for greater than 5 minutes provides
the best cutoff for diagnostic classification [13].
Additional limitations of the device include lack
of adequate standardization of normal values,
limited time sampling of tumescence and rigidity,
inflexibility of the accompanying software, and
potential intrusiveness of the device for some
patients. Despite these limitations, Rigiscan
recording plays an important role as an objective
and quantifiable measure of erectile response.
Other physiological measures of penile tumescen-
ce and rigidity include volumetric and strain-
gauge plethysmography [14,15], and the erectio-
meter [16]. Volumetric plethysmography provides
a highly sensitive measure of penile engorgement,
which has been used extensively in studies of
sexual preference or paraphilias [17-19]. Howe-
ver, the measurement apparatus is obtrusive and
inconvenient to use, and provides no information
on penile rigidity. Similarly, mercury-in-rubber
and electromechanical strain-gauges provide
sensitive measures of penile circumference change
and have been widely used in laboratory studies of
sexual arousal [20-22]. Again, the lack of rigidity
657
assessment is a major disadvantage of these
approaches in clinical trials of ED.
Finally, the erectiometer provides a crude measu-
re of both rigidity and tumescence (circumference
change). This device consists of a 2 cm wide felt
band with a sliding collar fastened to one end. The
felt band expands with tumescence, but requires a
force of about 250 grams to initiate expansion. In
this way, the device provides a combined assess-
ment of both circumference and rigidity changes
[16]. It has been used to differentiate response pat-
terns in clinical studies with normal and sexually
dysfunctional men [23-24], although the erectio-
meter provides less sensitivity and reliability than
either the Rigiscan or mercury strain gauge
devices [24].
2. S ELF-REPORT MEASURES
Self-report measures of sexual function are divi-
ded into three major categories: self-administered
questionnaires, daily diaries or event logs, and
structured interviews. Each of these approaches
has been used in recent clinical trials, although the
primary emphasis in most validation studies has
been on self-administered questionnaires
(SAQ’s). These measures have the potential
advantage of providing standardized and relative-
ly cost-efficient assessment of current and past
sexual functioning. Patient burden is generally
low, and some measures have been designed spe-
cifically for use in multicenter, clinical trials [25-
26]. Only one structured interview method has
been evaluated to date [27]. At present, the most
widely used measures are as follows.
a) The International Index of Erectile Function
(IIEF)
The International Index of Erectile Function
(IIEF) was designed and developed specifically
for assessment of sexual function in clinical trials
[26] (See Appendix B for sample questionnaire).
The IIEF has been extensively validated and
widely used as a measure of efficacy in clinical
trials of ED agents. The instrument consists of 15
items and assesses sexual functioning in five
domains: erectile function, orgasmic function,
sexual desire, intercourse satisfaction, and overall
satisfaction (See Figure 4). Average scores are cal-
culated in each of the major domains, and a simple
severity algorithm is available for clinical inter-
pretation of scores on the erectile function domain
[28]. A brief, 5-item version of the test has also
been shown to be useful for screening of patients
in clinical settings [29]. Psychometric validation
has demonstrated a high degree of reliability
Figure 4: IIEFDomain scores in untreated and treated ED
patients compared to age-matched controls. The 5 domains
of sexual function are shown (EF, OF, SD, IS, OS), with
near-normalization across each of the domains with silde -
nafil treatment. (Adapted from Dinsmore et al., Urol 1999;
53: 800-805).
658
(internal consistency and test-retest reliability) in
both clinical and nonclinical samples. Discrimi-
nant and concurrent validity are adequate. Sensiti-
vity and specificity (treatment responsiveness) are
excellent, as has been demonstrated in recent cli-
nical trials [30,31]. The IIEF is available in more
than 30 languages, and has been widely adopted
as the “gold standard” instrument for efficacy
assessment in clinical trials of ED.
Major advantages of the IIEF are its relative brevi-
ty and ease of use, inclusion of multiple domains of
sexual function, and strong psychometric profile.
Aggregate scores on the Erectile Function (EF)
domain are recommended for use as a primary end-
point in large-scale pivotal trials of ED. Baseline
scores on this domain are also useful for stratifying
patients according to disease severity, or as a poten-
tial baseline covariate. Potential disadvantages of
the measure are the limited assessment of other
domains of sexual function (e.g. sexual desire,
orgasmic function) and restricted time frame (four
weeks). At present, the IIEF is widely used as an
international standard in both clinical and research
assessment of male erectile function. It is highly
recommended for use in clinical trials of ED.
b) The Brief Male Sexual Function Inventory
(BMSFI)
This is an 11-item, questionnaire scale which
assesses several components of male sexual func-
tion, including sexual drive, erection, ejaculation,
sexual problems, and overall satisfaction [25].
Major advantages of this scale are: (a) a relatively
high degree of internal consistency and test-retest
reliability, (b) adequate discriminant validity for
three of the domains (erectile function, problems,
overall satisfaction), and (c) ease of use. Potential
disadvantages are the restricted evaluation of erec-
tile and orgasmic function, and lack of evidence
concerning sensitivity or treatment responsive-
ness. The scale has had limited use in large-scale
clinical trials of ED.
c) The Center for Marital and Sexual Health
Questionnaire (CMSH-SFQ)
This brief 18-item, self-report questionnaire
assesses current sexual function in the areas of
erection, orgasm, desire and satisfaction [32]. Ini-
tial psychometric assessment of the instrument has
been performed, although data regarding sensitivi-
ty and specificity are lacking. In this study, the
measure showed adequate reliability and construct
validity. It has had minimal use to date in clinical
trials of ED.
d) The Derogatis Sexual Function Inventory
(DSFI)
The DSFI is a comprehensive, multidimensional
measure of male and female sexual function [33].
The complete DSFI scale consists of 245 items,
requiring 40-60 minutes to complete. Ten domains
of sexual function are assessed, including infor-
mation, experience, drive, attitudes, psychological
symptoms, affects, gender role definition, fantasy,
body image, and sexual satisfaction, in addition to
a global sexual satisfaction index. The test has
been psychometrically validated, and has been
widely used in studies of normal and dysfunctio-
nal individuals. Its major drawbacks are the
excessive length and complexity of the instru -
ment, which make it generally unsuitable for use
in clinical trials.
3. DAILY DIARY AND EVENT LOGS
Daily diaries or sexual event logs are alternative
measures of sexual function that may be used to
complement the use of structured questionnaires,
such as the IIEF. Event logs or daily diaries typi-
cally include assessment of variables such as inter-
course frequency and satisfaction, quality of erec-
tion, and medication use. The Sexual Encounter
Profile (SEP) is a 6-item event log which has
recently been used in a number of large-scale cli-
nical trials (See Figure 5). In a preliminary valida-
tion study, a high degree of correlation was obser-
ved between erection and intercourse satisfaction
ratings on the SEP and IIEF measures in patients
with mild to moderate degrees of ED [34].
4. PARTNER ASSESSMENTS
Partner assessments of sexual function may be of
value in corroborating the patient’s efficacy
assessment and are generally favored by regula -
tory agencies for inclusion in clinical trials.
Although no standardized or accepted measure of
partner ratings exists, one recent study used a brief
adaptation of the BMSFI for assessment of partner
responses. In this study, a high degree of correla-
tion was observed between patient and partner
ratings of erectile function and intercourse satis-
659
faction [35]. Further studies are needed to eva -
luate the sensitivity and reliability of partner
ratings in comparison to patient ratings of erec -
tile function.
A partner version of the SEP scale is also available
(See Figure 6). This measure has not been psycho-
metrically validated to date.
5. QUALITY OF LIFE AND TREATMENT
SATISFACTION
Quality of life measures, such as physical functio-
ning, mood state, and overall life satisfaction are
routinely used in large-scale clinical trials of car-
diovascular disease, cancer and other chronic ill-
nesses [36-38]. Recent clinical trials of ED have
included quality of life and patient satisfaction
measures as secondary endpoints. Although these
measures provide a potentially broader understan-
ding of treatment effects, several limitations and
problems are evident. First, most quality of life
scales are designed for use in medically ill
patients, whose disease or treatment has a noti-
ceable impact on physical or psychological func-
tioning. Although ED patients in the general popu-
lation may have deficits in some areas [39], clini-
cal trials of ED typically exclude patients with
major medical or psychiatric disease. Additionally,
most domains of quality of life assessment, such
as physical functioning, cognitive performance,
and global health perceptions, are unlikely to be
affected by the symptoms of ED or its treatment.
In response to the need for a more “disease-speci -
fic” approach, two new instruments for quality of
life assessment in ED trials have been developed.
Wagner et al. [40] report the development of a 19-
item scale (QOL-MED), based on semi-structured
interviews with a representative sample of ED
patients. This measure has a high degree of repro-
ducibility and internal consistency, but has recei-
ved little validation in ED patients or controls.
More recently, Fugl-Meyer et al. [39] have descri-
bed the use of a brief, 8-item life satisfaction
checklist for specific quality of life assessment in
ED trials (See Figure 7). This measure was found
to differentiate between ED patients and controls
on several dimensions. Significant improvements
on two scale dimensions (sexual life and overall
life satisfaction) were found following successful
treatment with prostaglandin E1 injections. This
Figure 5: The Sexual Encounter Profile (SEP). This sexual event log measure is widely used in clinical trials of ED.

SEXUAL ENCOUNTER PROFILE (SEP)

Date of Sexual Encounter _________/_______/_______ (month/day/year)

Time of Sexual Encounter ________________________

1. Were you able to achieve at least some erection (some enlargement of the penis)? [ ]
If yes, place 1 in the box and CONTINUE. If no, place 0 in the box and STOP.
2. Were you able to insert your penis into your partner’s vagina? [ ]
If yes, place 1 in the box. If no, place 0 in the box.
3. Did your erection last long enough for you to have successful intercourse? [ ]
If yes, place 1 in the box. If no, place 0 in the box.
4. Were you satisfied with the hardness of your erection? [ ]
If yes, place 1 in the box. If no, place 0 in the box.
5. Were you satisfied overall with this sexual experience? [ ]
If yes, place 1 in the box. If no, place 0 in the box.

Figure 6: The Partner Sexual Encounter Profile (PSEP). This is a partner version of the sexual event log measure used by
male patients in clinical trials of ED.
PARTNER SEXUAL ENCOUNTER PROFILE (PSEP)

Date of Sexual Encounter _________/_______/_______ (month/day/year)

Time of Sexual Encounter ________________________

1. Was your partner able to achieve at least some erection (some enlargement of the [ ]
penis? If yes, place 1 in the box. If no, place 0 in the box.
2. Was your partner able to insert his penis into your vagina? [ ]
If yes, place 1 in the box. If no, place 0 in the box.
3. Were you satisfied overall with this sexual experience? [ ]
If yes, place 1 in the box. If no, place 0 in the box.

Figure 7: The Fugl-Meyer Life Satisfaction Scale. This simple measure of life satisfaction has been used for assessing quality of
life outcomes in epidemiological and clinical studies of ED (From: Fugl-Meyer AR et al., Intl J Impot Res 9:141-148, 1997.)
FUGL-MEYER LIFE SATISFACTION SCALE
How satisfactory are these different aspects of your life?
1 = Very dissatisfying 4 = Rather satisfying
2 = Dissatisfying 5 = Satisfying
3 = Rather dissatisfying 6 = Very Satisfying
Life as a whole is ………………………………… 1 2 3 4 5 6
My sexual life is …………………………………. 1 2 3 4 5 6
My partnership relation is ……………………….. 1 2 3 4 5 6
My family life is …………………………………. 1 2 3 4 5 6
My contacts with friends and acquaintances are… 1 2 3 4 5 6
My vocational situation is………………………… 1 2 3 4 5 6
My leisure situation is ……………………………. 1 2 3 4 5 6
My financial situation is ………………………….. 1 2 3 4 5 6

660
measure provides a broad assessment of quality
of life dimensions of potential interest in ED
patients and may be of value in future clinical
trials.
A treatment satisfaction measure (Erectile Dys -
function Inventory of Treatment Satisfaction –
EDITS) has also recently been described [41]
(Appendix C). This measure assesses patient and
partner ratings of treatment satisfaction across
several domains of treatment efficacy. The measu-
re has had limited psychometric validation and has
been used in recent clinical trials with sildenafil.
6. ADVERSE EVENT MONITORING
An important consideration in clinical trials of ED
is the monitoring and reporting of adverse events.
Evaluation of adverse events is typically conduc-
ted over several stages, ranging from Phase I safe-
ty and toxicology studies in humans and animals,
to large-scale, Phase III trials during which mul-
tiple adverse events are monitored and evaluated.
Post-marketing surveillance studies provide addi-
tional data on side effects associated with long-
term use of the drug or device. Although most
pharmacological agents are extensively evaluated
prior to and following regulatory approval, several
issues and concerns in adverse event monitoring
in ED trials are worth noting.
First, the means by which adverse events are
ascertained can influence the frequency and type
of reports obtained. Checklist or interview
approaches each have certain advantages and
disadvantages. Symptom checklists (see Figure
8) have the major advantage of allowing standar-

Figure 8: Adverse Events – Definitions and Description

ADVERSE EVENTS
All adverse events are to be investigated as to:
DEGREE OF INTENSITY DESCRIPTION
MILD Awareness of signs and symptoms; easily tolerated
MODERATE Discomfort sufficient to interfere, but not prevent daily activity
SEVERE Unable to carry out usual activity
• Seriousness (whether or not the adverse event is fatal or life-threatening, is persistent or permanently disabling, requires or pro-
longs inpatient hospitalization, or is a congenital anomaly, or is medically significant) or unexpected (not listed in the Investiga-
tors Brochure).
• Action taken (whether or not the adverse event caused the subject/patient to be discontinued from the study).
• Causal relationship to test medication, to be graded as follows:

DEGREE DESCRIPTION
DEFINITELY There is evidence of exposure to the test medication, for example, reliable history or
acceptable compliance assessment; the temporal sequence of the AE onset relative to
the medication is reasonable; the AE is most likely to be explained by the treatment
than by another cause; the challenge is positive; rechallenge (if feasible) is positive;
the AE shows a pattern consistent with previous knowledge of the treatment.
PROBABLY There is evidence of exposure to the test medication; the temporal sequence of the AE
onset relative to medication administration is reasonable; the AE is more likely explai-
ned by the treatment than by another cause; the challenge (if performed) is positive.
POSSIBLY There is evidence of exposure to the test medication; the temporal sequence of the AE
relative to the medication administration is reasonable; the AE could have been due to
another equally likely cause; the challenge (if performed) is positive.
PROBABLY NOT There is evidence of exposure to the treatment; there is another more likely cause of
the AE; the challenge (if performed) is negative or ambiguous; rechallenge (if perfor-
med) is negative or ambiguous.
DEFINITELY NOT The subject/patient did not receive the treatment; or temporal sequence of the AE onset
relative to administration of the test medication is not reasonable; or there is another
obvious cause of the AE.

661
dization of reporting between and within trials,
whereas interview methods encourage more in-
depth assessment and recording of unanticipated
adverse events. Some trials use a combination of
these approaches. The number of patients and
duration of the trial can have a significant impact
on the frequency of adverse events reported.
Since sample size is invariably calculated on the
basis of estimated changes in the primary effica-
cy parameter, most trials lack adequate power
for reliably assessing the frequency of adverse
events, particularly in the area of low frequency,
but potentially serious adverse events (e.g. MI).
A related problem is the relatively high rate of
adverse events often observed in placebo control
groups, which could be related to the age and
health status of the patients, or the influence of
placebo effects. Long-term follow up studies of
ED treatment are relatively rare, although such
trials are obviously important for adequate safety
assessment.
With the advent of a wide range of treatment
options for ED, it might be anticipated that safety
issues and reporting of adverse events will assume
even greater significance in the years to come.
Regulatory agencies are likely to place increasing
emphasis on adverse event reporting since ED is
regarded as neither life-threatening nor a serious
medical condition. Pharmaceutical companies are
also tending to pay greater attention to safety issues
in an attempt to differentiate their product from
those of competitors. A positive effect of these
trends is that clinical trials of ED are including
increasingly larger number of patients for longer
periods of time (e.g. 1-2 years).
Summary Points:
• Safety and efficacy endpoints should be clearly
identified in advance. A variety of outcome
measures are available for assessing efficacy,
including physiological (e.g. Rigiscan) and
questionnaire measures (e.g. IIEF). Daily
diary and event log measures are used for
assessing frequency and adequacy of sexual
performance, and partner assessments provide
valuable corroborating data. Patient satisfac -
tion and disease-specific quality of life mea -
sures have recently been developed. Several
complementary outcome measures are recom -
mended in large-scale clinical trials of ED.
662
• Adverse event monitoring is a critical aspect of
safety evaluation for new drugs or devices for
ED. Several methods are available for monito -
ring of adverse events, including symptom
checklists and patient interview methods.
Long-term monitoring of adverse events is
essential in evaluating the long-term safety of
new treatments for ED.
V. PROTOCOL DESIGN AND
IMPLEMENTATION
The conduct of each clinical trial should be based
on a well-designed and carefully implemented
study protocol. The study protocol serves as a
written agreement between the investigator, the
research participant and the scientific community.
It includes the goals and objectives of the trial,
research design and methodology, plans for data
analysis, and overall organization of the trial. Each
of these sections should be described in detail,
with supplemental data or procedural information
contained in a protocol appendix or manual of pro-
cedures. The study protocol should be fully deve -
loped prior to the initiation of the trial and should
remain essentially unchanged, except for minor
updates or amendments during the course of the
trial. The protocol should be agreed to in writing
by each investigator and should be made available
to all study personnel and others involved in the
conduct of the trial. A copy of the study protocol
and informed consent statement should also be
submitted to the Institutional Review Board and
appropriate regulatory agency prior to initiation of
the trial. The study protocol should be organized
as follows:
1. BACKGROUND OF THE STUDY
This section should provide a concise overview of
the epidemiology and clinical significance of the
problem, alternative approaches to treatment, and
proposed mechanism or site of action of the treat-
ment under study. The need for a new therapeutic
agent or device should be addressed, as well as the
potential advantages or disadvantages of the study
intervention. Also included in this section is a
review of previous animal safety or toxicology stu-
dies, in addition to any available data in humans.
2. STUDY OBJECTIVES procedures should be described in detail. The
Each of the study objectives should be stated clear - description should include full details regarding:
ly in advance. Primary and secondary questions (i) the design to be employed (e.g., crossover,
(e.g. effects on quality-of-life or partner relation- parallel), (ii) blinding procedures (e.g., single-
ship) should be delineated, as well as the response blind, double-blind), (iii) type of treatment
variables to be measured in addressing each of these control (e.g. placebo, standard treatment), (iv)
questions. Any planned sub-group analyses (e.g. number and sequencing of treatment periods, (v)
older vs. younger patients, diabetics vs. non-diabe- method of randomization (e.g., complete, strati-
tics) should be specified in advance. The safety fied randomization), (vi) pre-treatment or baseli-
objectives of the study and adverse event monito- ne assessment (e.g. single-blind, open run-in),
ring plans should also be described in this section. (vii) treatment interventions, (viii) and manage-
ment of dropouts (e.g. with or without replace-
Although multiple objectives are possible, care
should be taken not to overcomplicate the study ment). Full details of the patient population
design or conduct of the trial. This can result in should be provided (inclusion, exclusion criteria)
excessive patient burden, diminished quality of and the study endpoints (primary, secondary)
data collection and “data dredging” in the analysis should be clearly defined. Detailed plans for data
of results. Typically, statistical penalties are collection and analysis should be included (See
applied when multiple comparisons are made (See Section VI). Procedures for interim analysis and
Section VI). termination of the study should also be clearly
specified. In addition to a written description, all
3. D ESIGN OF THE STUDY study procedures and visits should be summari-
This section comprises the main body of the pro- zed in the form of a flow-sheet or summary table ,
tocol, and all aspects of the study design and as illustrated in Figure 9.
Figure 9: Sample study flow sheet from a phase III trial of ED. The flow sheet shows all of the study procedures to be conduc -
ted over 5 study visits.
SAMPLE STUDYFLOW SHEET
Schedule of Events
Activity V1 V2 V3 V4 V5
Informed consent X
Sex history X
Medical and medication history X
Physical examination X X X
Height and weight X
ECG X X X
Clinical laboratory tests 1 X X X
IIEF X X X
Dispense medication 1 X
Dispense diaries (SEP) X X
Collect medication 1 X
Collect and review diaries X X
Begin washout period X
End washout period X
Dispense medication 2 X
Collect medication 2 X
Monitor adverse events X X X X X
Monitor use of concomitant medications X X X X X
1 Hematology, serum chemistry, and urinalysis

663
The methods and procedures section should pro-
vide detailed information for each study visit, spe-
cifying all study procedures to be performed, the
response variables to be recorded at each visit, and
the proper order or sequencing of study proce-
dures and data collection. Standardized laborato -
ry procedures (e.g. ECG, blood sampling) should
be employed unless otherwise specified. Detailed
instructions are especially important for in-hospi-
tal recording of erectile responses (e.g. Rigis-
can/VSS protocols), in order to optimize the qua-
lity of recording and to ensure standardization of
data collection across sites. These instructions
may be contained in a protocol appendix or
manual of procedures. The use of concomitant
medications should be carefully monitored throu-
ghout the study and instructions provided for the
recording and management of adverse events (e.g.
serious vs. non-serious; treatment related vs. treat-
ment unrelated). Clear criteria should be provided
for withdrawal of patients from the study or for
study discontinuation. Periodic reviews of the
study by an independent safety committee or
monitoring board are frequently used in other cli-
nical trial areas (e.g. cancer, cardiovascular disea-
se), although these are less common in clinical
trials of ED. The role of the safety committee
should be clearly specified, if relevant.
Finally, this section of the protocol should contain
a clear description of the study materials. The test
article (e.g., drug tablet, solution) should be des-
cribed in terms of its physical and chemical pro-
perties, formulation and packaging. The stability
of the formulation and specific requirements for
storage and handling should be included. Infor-
mation on dosage and administration of both acti-
ve medication and control (e.g. placebo) is neces-
sary, including unit dose, frequency of dosing,
patient instructions and labeling. The protocol
should also specify the investigator’s responsibili-
ties in recording the receipt, dispensing and
return of the study medications.
4. ADMINISTRATIVE CONSIDERATIONS
Issues related to the protection of subjects’rights,
monitoring and documentation of the study
conduct, maintenance and retention of study
records, and publication policies are all covered
in detail in this section. A clear description should
be provided of the level of patient confidentiality
664
to be observed. Access to the study records by the
sponsor, Institutional Review Board, regulatory
agency or others should be clearly specified. Also,
the terms of confidentiality between the sponsor
and the investigator should be defined.
A separate section should be addressed to the role
of the Institutional Review Board and the proce-
dures to be followed in obtaining informed
consent. A copy of the actual informed consent
statement should be included as an appendix to
the protocol. A sample protocol outline for a clini-
cal trial in ED is shown in Appendix A.
Summary Points:
• The study protocol is a written agreement between
the investigator, the research subject and the scien -
tific community. It includes the goals and objec -
tives of the study, research design and methodolo -
gy, plans for data analysis, and overall organiza -
tion of the trial. The study protocol should be fully
developed and agreed upon prior to initiation of the
trial.
• Essential features of the protocol include the back -
ground, study objectives, design and methods, and
administrative considerations. Each of these sec -
tions should be completed in a clear and detailed
fashion, with the entire protocol being reviewed by
the sponsor, the Institutional Review Board and the
relevant regulatory agency.
• Investigators should adhere to the study protocol as
closely as possible throughout the conduct of the
trial. Procedures should be specified in advance for
monitoring of the trial, and for maintenance and
retention of all study documents. Publication plans
and policies should also be clearly specified.
VI. DATAANALYSIS AND
REPORTING OF RESULTS
A variety of data analytic methods have been
employed in recent clinical ED trials. Although a
detailed discussion of these methods is beyond the
scope of this chapter, some general comments and
recommendations can be made. To a large degree,
the type of statistical model employed depends
upon the nature of the research design (e.g. paral-
lel, between-group vs. counterbalanced, crossover
design) and the response variables being analyzed
(e.g. continuous vs. dichotomous variables).
Given the large number of statistical issues and
data analysis considerations, it is essential that a
qualified biostatistician be involved in the design
and analysis of all clinical trials in ED.
Sample power should be calculated in advance,
using the best available estimates of the means and
variances of the primary efficacy variables, and
anticipated changes associated with treatment.
Sample power for phase III trials is traditionally
based on estimates of efficacy, not safety. In this
respect, studies may not be adequately powered
for detection of low-frequency safety problems.
Standard formulae are available for the computa-
tion of sample power for a clinical trial [42].
All subjects randomized to treatment or control
conditions should be included in an “intention-
to-treat” analysis, in which data from dropouts or
withdrawals are included in the final analysis of
treatment outcome. This general rule should not be
applied to the assessment of adverse events, howe-
ver, where it may be preferable to report the fre-
quency of side effects only among those who
actually received the treatment [43]. Covariate
adjustments or stratification techniques can be
used to control for differences between the study
groups in baseline levels of functioning or demo -
graphic characteristics (e.g. age, duration of ill-
ness), although covariance analysis should be per-
formed only when specific statistical assumptions
are met [44,45]. As noted above, a limited number
of sub-group analyses may be conducted, paying
careful attention to the potential lack of power
and possibility of Type II errors associated with
these analyses [43].
Assessing the magnitude of treatment effects is a
potentially thorny issue, which involves both sta-
tistical and clinical considerations. Effect size cal-
culations can be used to provide a statistical esti-
mate of the magnitude of treatment effects,
although this approach has not been used to any
significant degree in clinical trials of ED. Rather,
most investigators report the magnitude of treat -
ment effects in terms of percentages of respon -
ders in the active compared to control groups.
Such comparisons involve prior definition of a
response threshold or cutoff, which may be subject
to criticism. For example, in a multi-center trial of
transurethral alprostadil [46], a treatment respon-
der was defined as any individual who completed
665
sexual intercourse at least once during the study
period. It could be argued that this definition is
overly-liberal, and not in keeping with the usual
clinical criteria for successful treatment.
Unfortunately, normative population data are lac -
king to establish response criteria for adequate
sexual performance at each age group. In the
absence of such data, continued disagreement on
the definition of a treatment responder is likely.
One approach to the problem is to report several
measures of treatment efficacy, including both
quantitative (e.g. number of successful intercourse
attempts) and qualitative (e.g. global satisfaction)
indices. This allows for a more comprehensive
assessment of the magnitude and consistency of
treatment effects.
Finally, meta-analysis is a potentially powerful
statistical technique for assessing the direction and
magnitude of treatment effects over several inde-
pendent trials [47,48]. First, the method requires
careful selection of trials for inclusion in the ana-
lysis, based upon pre-determined criteria for asses-
sing methodological adequacy (i.e. randomization,
double-blinding). Results from all eligible trials
are standardized and combined according to strict
statistical rules. An odds ratio or relative risk ana-
lysis is then performed on the resulting data. Rela-
tively few meta-analyses have been used in the
analysis of clinical trial data in ED, although this
technique offers considerable promise for addres-
sing certain issues. As the number of clinical trials
of ED increases, it is anticipated that meta-analy -
tic studies will play an increasingly important
role in the future.
Several points should be closely attended to in the
final report preparation and publication of all
clinical trials in ED. These are briefly as follows:
1. Authors should be selected for inclusion based
solely on their contributions to the study design,
conduct, analysis and write-up. Individuals who
have not participated substantially in one or
more of these aspects of the study should not be
listed as authors on the final publication.
2. Full disclosure and acknowledgement should be
made of the source of funding for the study.
Additionally, potential conflicts of interest for
each of the study authors or investigators
should be clearly acknowledged.
3. A complete description of the study methods
and procedures is essential, including a detailed
description of the inclusion and exclusion crite-
ria, patient selection and screening procedures,
efficacy and safety assessments, and treatment
protocol. A table of visits and procedures should
be included.
4. Complete reporting of all statistical procedures
and data analyses is necessary. The final report
should clearly indicate negative, as well as posi-
tive findings in the study. Statistical corrections
should be made when multiple analyses are
reported. When possible, effect size calculations
should be included.
5. Potential limitations and weaknesses of the
study should be carefully considered in the Dis-
cussion. This section of the report should also
consider the clinical implications of the study
and relevance of the findings to the broader
development of the field.
Summary Points:
• Due to the number of statistical and data ana -
lysis issues, a qualified biostatistician should be
involved in the design and analysis of all clini -
cal trials in ED. Specific issues include the cal -
culation of sample power for the trial, type of
statistical model and design to be employed, use
of covariate or sub-group analyses, and calcu -
lation of effect sizes.
• Although most ED trials report the number of
treatment responders following treatment,
disagreement exists at present concerning the
criteria and appropriate definition of a treat -
ment responder.
• Meta-analysis is a potentially valuable statisti -
cal procedure which will undoubtedly play an
increasingly important role in the clinical lite -
rature on ED.
• Key considerations in the preparation and
publication of clinical trial data have been
identified. These include criteria for author -
ship, disclosure of financial support and
conflicts of interest, and complete reporting of
the study methods and findings. The limitations
and weaknesses of the study should also be
clearly identified.
666
VII. ETHICALAND CLINICAL
ISSUES IN ERECTILE
DYSFUNCTION RESEARCH
Ethical issues in clinical trials of ED include those
related to (1) informed consent, (2) patient confi-
dentiality, (3) patient safety, and (4) trial design
issues, such as randomization and the use of place-
bo treatments. In each of these areas, it is essential
that the trial be conducted according to the highest
standards of ethical and clinical conduct.
Patient rights and protections in human research
have been fully delineated in the International
Ethical Guidelines for Biomedical Research
Involving Human Subjects (World Medical Asso-
ciation Declaration of Helsinki [49]). This decla-
ration emphasizes that the health of the patient is
the primary concern of all physicians including
those involved in clinical research. The purpose of
biomedical research is to impact and improve on
clinical practice. It is possible in a clinical trial to
address important public and societal health
concerns, without compromising the health of the
individual. The potential benefits, hazards and
risks of a novel intervention or therapy in sexual
medicine must be carefully weighed against the
advantages of the best available therapeutic alter-
natives. Ethical principles of the Declaration of
Helsinki are especially relevant in the study of
“quality of life” disorders such as erectile dys -
function. Specific principles are as follows:
1. Erectile dysfunction research should conform to
the generally accepted scientific principles out-
lined in this chapter, and should be based on
prior laboratory and animal experimentation, as
well as a thorough background knowledge of
the scientific literature.
2. The design and conduct of any experimental
procedure in this field involving human subjects
should be formulated in protocols that are revie-
wed by an independent (of the investigator and
the sponsor) bio-ethical committee, such as an
accredited Institutional Review Board (IRB).
This committee must be constituted in accor-
dance with the laws and regulations of the coun-
try or region in which the research is conducted.
3. Erectile dysfunction trials should only be
conducted by scientifically qualified indivi -
duals under the supervision of a clinically com -
petent medical person(s).
4. There must be a balance between the objectives
of the study and its value to the public, and the
protection of patient’s rights and safety. In quali-
ty of life disorders, such as erectile dysfunction
or other male or female sexual dysfunctions, the
risks to the patient must inherently be exceedin-
gly low. In any study, each potential subject
must be adequately informed of the aims,
methods, anticipated benefits and potential
hazards of the study and any potential discom -
fort or risk it may entail. The employment of
randomization and placebo-controls must be
made clear to the subject prior to participation.
The patient should be informed that he/she is at
liberty to abstain from participation in the study,
and that he/she is free to withdraw his or her
consent to participation at any time. The refusal
of a patient to participate in a study must never
interfere with the physician-patient relation -
ship.
5. Informed consent is a dynamic process that is
ongoing as a study evolves and data is accumu-
lated and analyzed. The physician, or an appro-
priately delegated representative, must obtain the
subject’s freely given informed consent, prefera-
bly in writing. Sexual dysfunction research does
not ethically permit the involvement of minors or
those that are mentally incompetent. Therefore
the issue of consent from a legal guardian is not
strictly relevant to this topic.
6. The right of the patient to safeguard his priva -
cy or anonymity must be respected at all times.
With increasing availability of electronic data
retrieval, the topic of patient confidentiality has
become a major concern in many countries,
with specific legislation being developed to pro-
tect medical records confidentiality. The pro -
tection of personally-identifiable health infor -
mation is especially relevant in the area of
sexual dysfunction, considering the emotional
overtones and social stigma associated with
these disorders.
7. The findings of clinical trials in ED should be
published in peer-review literature, as well as
being made publicly available following regu -
latory review. The broad and general utilization
of any new medical intervention or therapy for
ED should be preceded by proper scientific
scrutiny, such as provided by the editorial board
of an appropriate peer-review journal.
667
The ultimate objective of clinical trials in erectile
dysfunction, as in any new field of medical resear-
ch, is to impact upon the clinical care of the
patient. As such, the design of research protocols,
patient inclusion/exclusion criteria, and endpoint
assessments should all have maximum relevance
to the practicing clinician. The trial design should
ideally be simple and straightforward, with broad
inclusion of patients that mimic the clinical arena.
The endpoints measured and reported should be
readily translated into clinically meaningful
terms (e.g. percentage of successful intercourse
attempts). Although objective measurement via
Rigiscan or other laboratory devices can provide
valuable data, the most relevant information for
the practicing clinician is that provided by self-
report measures such as the IIEF. Additionally,
global efficacy and satisfaction measures, as well
as quality of life assessments are valuable to the
practicing clinician in determining the ultimate
“real world” value of a new intervention or thera-
py in clinical practice. Clinical research is a
dynamic enterprise; as new interventions and
therapies are introduced, they should be tested
not only against the rigors of an experimental
control or placebo group, but also evaluated in
the context of current clinical practice.
Summary Points:
• Clinical trials in ED should always be conducted
in accordance with the highest ethical and clini -
cal standards, as specified in the Helsinki Decla -
ration.
• All clinical trials should be subject to the appro -
val of an independent review board (Institutional
Review Board), which is constituted according to
the laws and regulations of the host country.
• There must be a careful balance between the
potential benefits and risks to the individual
patient. Patients must be fully informed about
the nature of the study, and any potential risks or
discomforts involved. Consent should always be
freely given without compromising the patient’s
access to healthcare or further research involve -
ment. Confidentiality must be protected to the
fullest extent permitted by the law.
• The findings from clinical research in ED should
be made available in a form that is practically
and clinically useful. The ultimate goal of clini -
cal research is to impact positively on the clinical
care of the patient.
 VIII. FINAL RECOMMENDATIONS
FOR CLINICAL TRIAL DESIGN AND
OUTCOMES ASSESSMENT
Clinical trials in erectile dysfunction should be
conducted according to the highest standards of trial
design and should make use of the best available
outcomes measures. Based upon the information
presented and issues considered in this chapter, the
following general recommendations can be made:
1. Novel drugs or devices for treatment of ED
should be systematically evaluated through
a comprehensive series of phase I through
IV clinical trials. Beginning with tolerability
assessments of single and multiple drug
dosages, these studies should carefully eva-
luate the overall safety and efficacy of any
new agent before regulatory approval is
granted and the treatment enters wides-
pread clinical use.
2. Among the available clinical trial designs,
crossover designs are generally recommen-
ded in early phase I or II studies. Parallel or
combination parallel-crossover designs are
preferred in phase III or IV trials. Post-
treatment changes should always be compa-
red to baseline assessments of erectile func-
tion prior to treatment.
3. Study populations in clinical trials of ED
should be broadly representative of the ove-
rall patient population. Inclusion criteria
should define the patient’s condition clearly,
including minimal duration and severity of
disease. Exclusion criteria should provide
adequate safeguards against unnecessary
risk of drug exposure in the study popula-
tion. Special population studies are recom-
mended to evaluate drug efficacy and safety
in selected sub-populations (e.g. diabetic
patients, spinal cord injury).
4. Efficacy and safety endpoints should be spe-
cified in advance. Recommended efficacy
endpoints include self-report questionnaires
(e.g. IIEF), patient and partner diaries (e.g.
SEP), and objective measures of erectile
function (e.g. Rigiscan). Patient satisfaction
or disease-specific quality of life measures
are recommended as secondary endpoints in
phase III or IV clinical trials.
668
5. Adverse events should be carefully monito-
red via symptom checklists or structured
patient interviews. Adverse events should be
classified according to severity, and should
be judged as treatment-related or treat-
ment-unrelated by the investigator. Long-
term monitoring of adverse events is criti-
cally important in assessing the overall safe-
ty of new treatment agents.
6. A detailed study protocol should be develo-
ped and agreed upon by the sponsor, the
investigator, the institutional review board,
and the relevant regulatory agencies prior to
initiation of the study. The study protocol
should include a complete description of the
background and study objectives, design
and methods, plans for data analysis and
overall organization of the trial. All aspects
of the protocol should be strictly adhered to
in the conduct of the study.
7. A qualified biostatistician should be involved
in the design and analysis of all clinical trials
in ED. A lack of agreement exists currently
regarding the definition of a treatment
responder and few studies have reported
effect size calculations. Similarly, meta-ana-
lytic procedures have been used infrequent-
ly to date. All findings in clinical trials of ED
should be accurately reported, and investi-
gators should make full disclosure regarding
financial relationships with the study spon-
sor and funding of the study.
8. All clinical trials should be conducted in
accordance with standards of Good Clinical
Practice, and in accordance with ethical
principles concerning human subjects as
specified in the Helsinki Declaration. All cli-
nical trials should also be approved and
monitored by an accredited human rights
committee (Institutional Review Board).
Patients must be fully informed about the
nature of the study and the potential risks or
hazards involved. Confidentiality should be
protected to the fullest extent permitted by
the law. Finally, the findings from clinical
research should be disseminated in a form
that is clinically useful to practicing physi-
cians, patients and society at large.

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30. GOLDSTEIN I, LUE TF, PADMA-NATHAN H,
ROSEN RC, STEERS WD, WICKER PA: Oral sildena-
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31. DINSMORE WW, HODGES M, HARGREAVES C,
OSTERLOH IH, SMITH MD, ROSEN RC: Sildenafil
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32. CORTYEW, ALTHOF SE, KURIT DM: The reliability
and validity of a sexual functioning questionnaire. J Sex
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Mar Ther 5:244-281, 1979.
34. ROSEN RC: Sexual function assessment in the male:
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DJ, FROMM S, ROSEN RC: A comparison of patient Heading Page
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TABLE OF CONTENTS 2
36. AARONSON NK: Quality of life: What is it? How BACKGROUND OF THE STUDY 3
should it be measured? Oncology 2:69-74, 1988. References 6
37. GILL TM, FEINSTEIN AR: A critical appraisal of the STUDY OBJECTIVES 9
quality of quality-of-life measurements. JAMA STUDY DESIGN 9
272:619-626, 1994.
PATIENT SELECTION 10
38. GUYATT GH, FEENY DH, PATRICK DL: Measuring Inclusion Criteria 10
health-related quality of life. Ann Intern Med 118:622-
Exclusion Criteria 11
629, 1993.
STUDY METHODS 12
39. FUGL-MEYER AR, LODNERT G, BRANHOLM I-B, Visit 1 (Screening) 12
FUGL-MEYER KS: On life satisfaction in male erecti-
Visit 2 13
le dysfunction. Intl J Impot Res 9:141-148, 1997.
Visit 3 14
40. WAGNER TH, PATRICK DL, MCKENNA P, FROESE
Clinical Laboratory Tests 15
PS: Cross-cultural development of a quality of life mea-
sure for men with erectile difficulties. Qual Life Res Concomitant Medications 16
5:443-449, 1996. Withdrawal Criteria 16
Handling of Withdrawals 17
41. ALTHOF SE, CORTY EW, LEVINE SB, LEVINE F,
BURNETT AL, MCVARY K, STECHER V, SEFTEL Study Discontinuation 17
AD: EDITS: Development of questionnaires for evalua- ADVERSE EVENTS 18
ting satisfaction with treatments for erectile dysfunc- Definitions 18
tion. Urol 1999; 53:793-799. Serious Adverse Events 18
42. DAY SJ, GRAHAM DF: Sample size estimation for Medical Monitor 19
comparing two or more treatment groups in clinical Antidote 20
trials. Stat Med 1991; 10:33-43. STATISTICAL ANALYSIS 20
43. COLLINS R, PETO R, GRAY R, PARISH S: Large- Safety Variables 20
scale randomized evidence: trials and overviews. In: Efficacy Variables 21
Weatherall DJ, Ledingham JGG, Warrell DA (Eds). Primary 21
Oxford Textbook of Medicine (3rd ed), Oxford: Oxford Secondary 21
University Press, 1996. Baseline Measurements 22
44. BEACH ML, MEIER P: Choosing covariates in the ana- Statistical Analysis Plan 22
lysis of clinical trials. Controlled Clin Trials 10:161S- Sample Size 24
175S, 1989. Randomization 24
45. CANNER PL:Covariate adjustment of treatment effects MATERIALS 24
in clinical trials. Controlled Clin Trials 12:359-366, Test Article 24
1991.
Dosage and Administration 24
46. PADMA-NATHAN H, HELLSTROM WJG, KAISER, Test Article Accountability 24
FE et al.: Treatment of men with erectile dysfunction
ADMINISTRATIVE CONSIDERATIONS 25
with transurethral alprostadil. N Engl J Med 1997;
336:1-7.
Confidentiality 25
Institutional Review Board 25
47. CHALMERS TC, LEVIN H, SACKS HS et al: Meta-
Informed Consent 26
analysis of clinical trials as a scientific disclipline. Stat
Med 6:315-326, 1987. Monitoring Case Report Forms 27
Study Record Retention 27
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INVESTIGATOR’S STATEMENT 29
348, 1987.
APPENDIX 1: S CHEDULE OF EVENTS 30
49. CIOMS/ WHO: International ethical guidelines for bio- APPENDIX 2: I NTERNATIONAL INDEX OF
medical research involving human subjects. Geneva, ERECTILE FUNCTION (IIEF) 31
1993.

______________________

670
 APPENDIX B

INTERNATIONAL INDEX OF ERECTILE FUNCTION

These questions ask about the effects your erection problems have had on your sex life. Please answer
the following questions as honestly and clearly as possible. In answering these questions, try to base
your answers on how you currently are without any treatment. The following definitions apply:
• sexual activity includes intercourse, caressing, foreplay and masturbation
• sexual intercourse is defined as vaginal penetration of the partner (you entered your partner)
• sexual stimulation includes situations like foreplay with a partner, looking at erotic pictures, etc.•
ejaculate: the ejection of semen from the penis (or the feeling of this)

1. Over the last month, how often were you able to get an erection during sexual activity?
Please check one box only
a. [ ] No sexual activity
b. [ ] Almost always or always
c. [ ] Most times (much more than half the time)
d. [ ] Sometimes (about half the time)
e. [ ] A few times (much less than half the time)
f. [ ] Almost never or never

2. Over the last month, when you had erections with sexual stimulation, how often were your erections
hard enough for penetration?
Please check one box only
a. [ ] No sexual stimulation
b. [ ] Almost always or always
c. [ ] Most times (much more than half the time)
d. [ ] Sometimes (about half the time)
e. [ ] A few times (much less than half the time)
f. [ ] Almost never or never

The next three questions will ask about the erections you may have had during sexual intercourse.

3. Over the last month, when you attempted sexual intercourse, how often were you able to penetrate
(enter) your partner?
Please check one box only
a. [ ] Did not attempt intercourse
b. [ ] Almost always or always
c. [ ] Most times (much more than half the time)
d. [ ] Sometimes (about half the time)
e. [ ] A few times (much less than half the time)
f. [ ] Almost never or never

671
4. Over the last month, during sexual intercourse, how often were you able to maintain your erection
after you had penetrated (entered) your partner?
Please check one box only
a. [ ] Did not attempt intercourse
b. [ ] Almost always or always
c. [ ] Most times (much more than half the time)
d. [ ] Sometimes (about half the time)
e. [ ] A few times (much less than half the time)
f. [ ] Almost never or never

5. Over the last month, during sexual intercourse, how difficult was it to maintain your erection to
completion of intercourse?
Please check one box only
a. [ ] Did not attempt intercourse
b. [ ] Extremely difficult
c. [ ] Very difficult
d. [ ] Difficult
e. [ ] Slightly difficult
f. [ ] Not difficult

6. Over the last month, how many times have you attempted sexual intercourse?
Please check one box only
a. [ ] No attempts
b. [ ] 1-2 attempts
c. [ ] 3-4 attempts
d. [ ] 5-6 attempts
e. [ ] 7-10 attempts
f. [ ] 11+ attempts

7. Over the last month, when you attempted sexual intercourse how often was it satisfactory for you?
Please check one box only
a. [ ] Did not attempt intercourse
b. [ ] Almost always or always
c. [ ] Most times (much more than half the time)
d. [ ] Sometimes (about half the time)
e. [ ] A few times (much less than half the time)
f. [ ] Almost never or never

672
8. Over the last month, how much have you enjoyed sexual intercourse?
Please check one box only
a. [ ] No intercourse
b. [ ] Very highly enjoyable
c. [ ] Highly enjoyable
d. [ ] Fairly enjoyable
e. [ ] Not very enjoyable
f. [ ] No enjoyment

9. Over the last month, when you had sexual stimulation or intercourse how often did you ejaculate?
Please check one box only
a. [ ] No sexual stimulation/intercourse
b. [ ] Almost always or always
c. [ ] Most times (much more than half the time)
d. [ ] Sometimes (about half the time)
e. [ ] A few times (much less than half the time)
f. [ ] Almost never or never

10. Over the last month, when you had sexual stimulation or intercourse how often did you have the
feeling of orgasm (with or without ejaculation)?
Please check one box only
a. [ ] No sexual stimulation/intercourse
b. [ ] Almost always or always
c. [ ] Most times (much more than half the time)
d. [ ] Sometimes (about half the time)
e. [ ] A few times (much less than half the time)
f. [ ] Almost never or never

The next two questions ask about sexual desire. Let’s define sexual desire as a feeling that may inclu -
de wanting to have a sexual experience (for example masturbation or intercourse), thinking about
having sex, or feeling frustrated due to lack of sex.
11. Over the last month, how often have you felt sexual desire?
Please check one box only
a. [ ] Almost always or always
b. [ ] Most times (much more than half the time)
c. [ ] Sometimes (about half the time)
d. [ ] A few times (much less than half the time)
e. [ ] Almost never or never

673
12. Over the last month, how would you rate your level of sexual desire?
Please check one box only
a. [ ] Very high
b. [ ] High
c. [ ] Moderate
d. [ ] Low
e. [ ] Very low or none at all

13. Over the last month, how satisfied have you been with your overall sex life?
Please check one box only
a. [ ] Very satisfied
b. [ ] Moderately satisfied
c. [ ] About equally satisfied and dissatisfied
d. [ ] Moderately dissatisfied
e. [ ] Very dissatisfied

14. Over the last month, how satisfied have you been with your sexual relationship with your partner?
Please check one box only
a. [ ] Very satisfied
b. [ ] Moderately satisfied
c. [ ] About equally satisfied and dissatisfied
d. [ ] Moderately dissatisfied
e. [ ] Very dissatisfied

15. Over the last month, how do you rate your confidence that you can get and keep your erection?
Please check one box only
a. [ ] Very high
b. [ ] High
c. [ ] Moderate
d. [ ] Low
e. [ ] Very low

Source: Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A: The International Index of
Erectile Function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urol 49:822-
830, 1997.

674
 APPENDIX C

The EDITS:
Erectile Dysfunction Inventory
of Treatment Satisfaction
Patient Version
STANLEY E. ALTHOF, PH.D. & E RIC W. CORTY, PH.D.

For permission to use this questionnaire, contact Dr. Althof at:

Center for Marital & Sexual Health
23230 Chagrin Boulevard, Suite 350 Beachwood, Ohio 44122-5402
Phone: (216) 831-2900 Fax: (216) 831-4306

Name or ID number: __________________________________

Date: ____________________

What treatment method are you currently using? ____________________________

The questions in this inventory ask about a sensitive topic, your sexual life with your wife or partner as
well as your attitude towards and expectations from the treatment method you are using to help with your
erection problem. Please answer the questions as honestly and candidly as you can. If any questions or
terms are unclear, please ask for clarification.

1. Overall, how satisfied are you with this treatment?

a. Very satisfied
b. Somewhat satisfied
c. Neither satisfied nor dissatisfied
d. Somewhat dissatisfied
e. Very dissatisfied

2. During the past four weeks, to what degree has the treatment met your expectations?
a. Completely
b. Considerably
c. Half way
d. A little
e. Not at all

675
3. How likely are you to continue using this treatment?
a. Very likely
b. Moderately likely
c. Neither likely nor unlikely
d. Moderately unlikely
e. Very unlikely

4. During the past four weeks, how easy was it for you to use this treatment?
a. Very easy
b. Moderately easy
c. Neither easy nor difficult
d. Moderately difficult
e. Very difficult

5. During the past four weeks, how satisfied have you been with how quickly the treatment works?
a. Very satisfied
b. Somewhat satisfied
c. Neither satisfied nor dissatisfied
d. Somewhat dissatisfied
e. Very dissatisfied

6. During the past four weeks, how satisfied have you been with how long the treatment lasts?
a. Very satisfied
b. Somewhat satisfied
c. Neither satisfied nor dissatisfied
d. Somewhat dissatisfied
e. Very dissatisfied

7. How confident has this treatment made you feel about your ability to engage in sexual activity?
a. Very confident
b. Somewhat confident
c. It has had no impact
d. Somewhat less confident
e. Very much less confident

676
8. Overall, how satisfied do you believe your partner is with the effects of this treatment?
a. Very satisfied
b. Somewhat satisfied
c. Neither satisfied nor dissatisfied
d. Somewhat dissatisfied
e. Very dissatisfied

9. How does your partner feel about your continuing to use this treatment?
a. My partner absolutely wants me to continue
b. My partner generally prefers me to continue
c. My partner has no opinion
d. My partner generally prefers me to stop
e. My partner absolutely wants me to stop

10. How natural did the process of achieving an erection feel when you used this treatment over the
past four weeks?
a. Very natural
b. Somewhat natural
c. Neither natural nor unnatural
d. Somewhat unnatural
e. Very unnatural

11. Compared to before you had an erection problem how would you rate the naturalness of your
erection when you used this treatment over the past four weeks in terms of hardness?
a. A lot harder than before I had an erection problem
b. Somewhat harder than before I had an erection problem
c. The same hardness as before I had an erection problem
d. Somewhat less hard than before I had an erection problem
e. A lot less hard than before I had an erection problem

Source: Althof SE, Corty EW, Levine SB, Levine F, Burnett AL, McVary K, Stecher V, Seftel AD: EDITS:
Development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. Urol
1999; 53:793-799.

677
678
Imaging Atlas

DIMITRIOS G. HATZICHRISTOU

679
 CONTENTS

INTRODUCTION VI. ARTERIOVENOUS FISTULA

I. ANATOMICAL CONSIDERATIONS VII. PRIAPISM

II. NOCTURNAL PENILE VIII. PEYRONIE’S DISEASE

TUMESCENCE AND RIGIDITY
TEST (NPTR)
IX. PENILE FRACTURE
III. PROLACTINOMA

X. PENILE PROSTHESIS
IV. NEUROPHYSIOLOGIC TESTING

XI. FEMALE SEXUAL FUNCTION

AND DYSFUNCTION
V. VASCULAR TESTING

680
 Imaging Atlas
DIMITRIOS G. HATZICHRISTOU,
INTRODUCTION
Male erectile dysfunction has been considered for
many decades a psychologic condition, mainly
due to the lack of methodology to reproduce in a
clinical setting the physiologic events of an erec-
tion. The introduction of pharmacologic erections
led to the development of numerous diagnostic
procedures, as it was possible for the first time to
induce and maintain an erection, independently of
sexual stimulation.
After a decade of debate, it was recognized that
diagnostic procedures for impotence may take
place exclusively in the dynamic state, after intra-
cavernosal administration of vasoactive agents.
Moreover, taking into consideration that vasculo-
genic impotence is the main organic cause of erec-
tile dysfunction, pharmacologic erections became
the cornerstone in the hemodynamic evaluation of
patients with arterial insufficiency and/or corporal
veno-occlusive dysfunction.
681
Despite numerous controversies in the field, seve-
ral methodologies have been described to assess
erectile mechanism integrity. Nowadays, diagnos-
tic work-up has been minimized and specific dia-
gnostic procedures are included in the evaluation
of small subgroups of patients with erectile dys-
function (ED). Although, the imaging techniques
do not constitute a critical aspect, directing
patients’ management strategy in common clini -
cal practice, the images help to understand the
mechanisms involved in erectile function and the
pathophysiology of ED. Without such knowledge
efficient patients’ management seems questio-
nable. The purpose, therefore, of the present atlas
is to be used as an educational document, helpful
for a better understanding of the pathophysiology
of ED, as well as for teaching purposes. Selected
images and diagnostic procedures tracings were
included.
This atlas was made possible through the contri-
butions of ED experts worldwide, who generously
offered the products of long lasting dedicated cli-
nical research in the field.
 I. ANATOMICAL CONSIDERATIONS

Figure 1: Topographic anatomy of a male and a female body befo -

re sexual intercourse. This unique MRI shows a male and a fema -
le body together, while the associated schematic drawing, offers
further information on the anatomy of the genitourinary organs
before intromission.
a) Sagittal MRI sequences showing a male and a female body
before intromission. 1. female, a. female bladder, c. female pubis.
2. male, b. male bladder, d. male pubis.
b) Drawing showing the position of the couple. 1. pubococcygeal
line, 2. vaginal axis, 3. levator ani.
A. Faix, MD, Department of Urology and JF Lapray, MD, A. Mau -
bon, MD. Department of Radiology, Clinique Beausoleil, Montpel -
lier, France

682
 I. ANATOMICAL CONSIDERATIONS

Figure 2: MRI and drawing after insertion of the semi-erect penis

into the vagina, while the female bladder is full. Anatomical
changes include modification of the vaginal axis, moderated
translocation of the uterus upwards and backwards and raising of
the bladder neck and the urethra.
a) 1. Glans penis, 2. Crus of the corpora cavernosa, 3. Female
bladder.
b) 1. Penis and vagina axis, 2. Fornix, 3. Uterus, 4. Pubococygeal
line, 5. Pubis angle, 6. Bladder neck.
A. Faix, MD, Department of Urology and JF Lapray, MD, A. Mau -
bon, MD. Department of Radiology, Clinique Beausoleil, Montpel -
lier, France.

683
 P

Figure 3 : MRI and drawing demonstrating anatomical changes

when the penis is inserted into the vagina, while the female blad -
der is empty.
a) MRI shows that the glans penis is in contact with the anterior
cul-de-sac, while the bladder is pushed forwards and upwards.
1. Glans penis, 2. Female bladder, 3. Fornix, 4. Uterus, 5. Per -
ineum.
b) Schematic drawing demonstrates the modification of vaginal
axis, the translocation of the uterus, while the bladder neck and
posterior bladder wall have been pushed upwards and forwards.
A. Faix, MD, Department of Urology and JF Lapray, MD, A. Mau -
bon, MD. Department of Radiology, Clinique Beausoleil, Montpel - B
lier, France.

684
 I. ANATOMICAL CONSIDERATIONS (Ctd)

Figure 4 : Transverse sections of a nor -

mal penis. The penis includes the 2 cor -
pora cavernosa and the corpus spongio-
sum (Figure 4a). The corpora consist of
A
trabecular smooth muscle and connecti -
ve tissue and are engloved in the tunica
albuginea (Figure 4b: T: trabecular
smooth muscle, C: cavernous space,
*:tunica albuginea). The structure of
the corpora cavernosa is of particular
importance in that, unlike skeletal load
carrying, penile rigidity is asserted
through soft tissue. Corporal structural
changes, such as decrease in the
amount of trabecular smooth muscle
and increase in the amount of collagen
or changes in the fibers of collagen and
elastin, as occur with aging and disea -
se, result in increased tissue stiffness,
reduced capacitance and corporal veno-
occlusive dysfunction.

E. Meuleman, Department of Urology,

University Hospital Nijmegen , The
Netherlands

685
 II. NOCTURNAL PENILE TUMESCENCE AND RIGIDITY TEST (NPTR)

A B

Figure 5a-c : Penile rigidity represents the main characteristic of a functional erection. NPTR, using the Rigiscan® device, beca -
me the most popular method to differentiate organic from psychogenic impotence, based on the assumption that psychological
factors do not influence this form of erectile activity. In 3 consecutive night recordings of a 23-year-old, healthy, potent volun -
teer, several erectile episodes of adequate rigidity and duration were recorded; the results were reproduced, when the test was
repeated twice.
D.G. Hatzichristou, MD, Department of Urology, Aristotle University of Thessaloniki, Greece

686
 II. NOCTURNAL PENILE TUMESCENCE AND RIGIDITY TEST (NPTR) (Ctd)

A B

Figure 6a-c : NPTR is based on the assumption that patients with psychogenic impotence would be expected to exhibit a normal
pattern of nocturnal erections, while patients with organic impotence will show impaired or absent erectile activity. In a 3-night
recording (a,b,c) of a 46 year old male, with a 15-year history of diabetes mellitus and 8-year history of erectile dysfunction,
abnormal NPTR patterns were recorded; few erectile episodes, of inadequate rigidity and duration were noted.
D.G. Hatzichristou, MD, Department of Urology, Aristotle University of Thessaloniki, Greece

687
III. PROLACTINOMA

Figure 7: Brain MRI after gadolinium injection showing a

pituitary microadenoma (6mm diameter). Serum testostero -
ne was 3.2mg/ml (normal values >2.5 ng/ml) and serum
prolactin 130ng/ml (normal values <15ng/ml).
J. Buvat, MD and A. Lemaire, MD, Centre ETPARP, Lille,
France

Figure 8 : Brain MRI demonstrating a pituitary adeno -

ma after gadolinium injection. The 35-year old man was
complaining of decreased libido and erectile dysfunction.
He was treated with intracavernosal injection therapy for
a year, without any previous diagnostic work-up. Hormo -
nal profile revealed hyperprolactinemia, which led to the
diagnosis and treatment of the main disease (surgical
excision of the adenoma). After surgery, restoration of
erectile function was reported by the patient.
D.G. Hatzichristou, MD, Department of Urology, Aristotle
University of Thessaloniki, Greece

688
 IV. NEUROPHYSIOLOGIC TESTING

A B

Figure 9: Pudendal evoked potentials: normal and abnormal findings.

a) Pudendal evoked potential recorded and the average superimposed twice in response to stimulation of the dorsal nerve of the
penis. Recordings were made from electrodes placed over FZ and CZ-2cms using the conventional system scalp measurement for
EEG recording.
b) Absent pudendal evoked potential recorded from a patient with a cauda equina lesion. This patient had perineal sensory loss,
as well as erectile dysfunction.
C. Fowler, MD, Department of Uro-Neurology, The National Hospital for Neurology and Neurosurgery, London, United Kingdom

A B

Figure 10: Normal and abnormal bulbocavernosus reflex recordings.

a) Bulbocavernosus reflex recording from the striated muscle of the urethral sphincter in response to stimulation of the dorsal
nerve of the penis. The first response occurs at 35m/s. Poor sweeps in step display are superimposed.
b) Delayed bulbocavernosus reflex at 60m/s recorded from a man with a spinal angioma and erectile failure.
C. Fowler, MD, Department of Uro-Neurology, The National Hospital for Neurology and Neurosurgery, London, United Kingdom

689
 V. VASCULAR TESTING

Figure 11: Normal power doppler ultrasonography, sho -

wing the cavernosal and the helicine arteries.
F. Montorsi, MD, Department of Urology, San Raffaele Hos -
pital, Milan, Italy

A B
Figure 12: Power doppler ultrasonography in a young healthy volunteer, at the phase of full (a) and rigid (b) erection. When
intracorporal pressure reaches values close to the cavernosal artery pressure, flow in the helicine arteries diminishes (a), while
during rigid erection the arterial flow is interrupted (b).
K. Hatzimouratidis, Department of Urology, 401 General Military Hospital, Athens, Greece

Figure 13: Duplex ultrasonography showing dorsal to

cavernous collaterals, which may be an important source of
inflow in the aging patient. Sacrifice of these intra-arterial
connections, for example during Peyronie’s surgery, may
cause postoperative erectile dysfunction.
G. A. Broderick, MD, Department of Urology, Mayo Clinic,
Jacksonville Florida, USA

690
 V. VASCULAR TESTING (Ctd)

Figure 14: Duplex ultrasonography showing cavernous veno-
occlusive dysfunction: excellent arterial flows with peak systo -
lic velocity > 30 cm/sec, while resistance index is < 0.9.
G. A. Broderick, MD, Department of Urology, Mayo Clinic,
Jacksonville Florida, USA
Figure 15: Duplex ultrasonography showing severe cavernous
arterial insufficiency, with peak systolic velocity < 20 cm/sec
G. A. Broderick, MD, Department of Urology, Mayo Clinic,
Jacksonville Florida, USA

A B

Figure 16: Power doppler ultrasonography allows not only better imaging of the cavernosal arteries, but also demonstration of
the helicine arteries pathology.
a) cavernosal artery insufficiency and
b) helicine arteries deficiency.
F. Montorsi, MD, Department of Urology, San Raffaele Hospital, Milan, Italy

691
 V. VASCULAR TESTING (Ctd)

Figure 17: Pharmacocavernosometry is a more invasive test, which allows to study the hemodynamics of the erectile mechanism
in details.
a) intracavernosal pressure and circumference increase slowly after intracavernosal injection of vasoactive agents; such res -
ponse may be either to incomplete smooth muscle relaxation due to anxiety, or due to arterial insuficiency.
b) normal flow-to-maintain values (<3ml/min), detected at intracavernosal pressures of 60, 90, 120, 150mmHg. Such findings
are associated with normal veno-occlusive mechanism.
c) intracavernosal pressure decay, from an initial value of 150mmHg to a value of 56mmHg, during a 30 secs period. Drop in
intracavernosal pressure more than 45mmHg within 30secs is associated with cavernosal veno-occlusive dysfunction.
D.G. Hatzichristou, MD, Department of Urology, Aristotle University of Thessaloniki, Greece and I. Goldstein, MD, Department of
Urology, Boston University Medical Center, Boston, USA

Figure 18: Normal pharmacocavernosography, showing

absence of contrast media outside the two corporal bodies.
I. Goldstein and R. Munarriz, Department of Urology, Bos -
ton University Medical Center, Boston, USA.

692
 V. VASCULAR TESTING (Ctd)

Figure 19: Abnormal pharmacocavernosography of a bicy -

clist, showing proximal crural leak, due to blunt perineal
trauma.
I. Goldstein and R. Munarriz, Department of Urology, Boston
University Medical Center, Boston, USA.

Figure 20: Spongiography, after contrast media injection in the glans penis.
a) the media is inserted through the glans penis to the deep dorsal vein and the corpus spongiosum.
b) through the glans penis (arrow), the media is inserted in the corpora cavernosa (*), demonstrating communication between
the corpus spongiosum and the corpora cavernosa. Such images explain the mechanism of action of intraurethraly administe -
red agents.
Y. Vardi, MD and A. Engel, MD, Neuro-Urology Unit and Department of Radiology, Ranbam Medical Center, Haifa, Israel

Figure 21: Normal selective internal pudendal arteriogra -

phy, showing both dorsal and cavernosal arteries.
Y. Vardi, MD and A. Engel, MD, Neuro-Urology Unit and
Department of Radiology, Ranbam Medical Center, Haifa,
Israel

693
 V. VASCULAR TESTING (Ctd)

Figure 22: Selective internal pudendal arteriogram showing
accesory pudendal artery which originates from the obturator
artery. Injury of this vessel during radical retropubic prosta -
tectomy can lead to vasculogenic impotence.
I. Goldstein and R. Munarriz, Department of Urology, Boston
University Medical Center, Boston, USA.
Figure 23: Selective internal pudendal arteriogram showing
proximal occlusion of the cavernosal artery and normal dorsal
artery with distal cavernosal branch
I. Goldstein and R. Munarriz, Department of Urology, Boston
University Medical Center, Boston, USA

A B

Figure 24: Penile post-revascularization arteriogram.

a) flush arteriogram showing origin of inferior epigastric artery and anastomosis to the dorsal penile artery.
b) inferior epigastric artery to dorsal artery anastomosis.
I. Goldstein and R. Munarriz, Department of Urology, Boston University Medical Center, Boston, USA.

694
 V. VASCULAR TESTING (Ctd)

Figure 25: Inferior epigastric artery anastomosed to an isolated deep dorsal vein segment. Selective arteriography of the inferior
epigastric artery preoperatively (a), postoperative conventional (b) and digital substractive (c) arteriogram showing patent anasto -
mosis
Y. Vardi, MD and A. Engel, MD, Neuro-Urology Unit and Department of Radiology, Ranbam Medical Center, Haifa, Israel

695
 V. VASCULAR TESTING (Ctd)

Figure 26: Duplex ultrasonography showing patent anasto -

mosis.
E. Meuleman, MD, Department of Urology, University Hospi -
tal Nijmegen, The Netherlands

B
A

Figure 27: The goal of an anastomosis of the inferior epigastric artery to an isolated deep dorsal vein segment is to achieve retro -
grade flow through the emmisary veins to the corpora cavernosa. Whether this is possible remains uncertain.
a) intraoperative arteriogram showing filling of the deep dorsal penile vein. The contrast medium runs through the corpus spon -
giosum collaterals without filling the corpora cavernosa.
b) postoperative superselective magnetic ressonance angiography with catheter tip in inferior epigastric artery: contrast medium
runs through arterialized deep dorsal vein into infrapubic venous plexus.
M. Sohn, MD, Department of Urology, Markus-Krankenhaus, Frankfurt, Germany.

696
 V. VASCULAR TESTING (Ctd)

C D

c) high flow signal intensity in the arterialized deep dorsal

vein.
d) gadolinium-enhanced MR 20 secs later: strong enhance -
ment of the corpus spongiosum, without enhancement of
the corpora cavernosa.
e) histology of corpus cavernosum in HE-staining: vein
valves in emissary vein obstructing retrograde inflow from
the arterialized deep dorsal vein to the corpus cavernosum.

697
 V. VASCULAR TESTING (Ctd)

Figure 28: Selective penile arteriography in a patient with

glans hyperemia, after anastomosis of the inferior epigastric
artery to an isolated deep dorsal vein segment.
Y. Vardi, MD and A. Engel, MD, Neuro-Urology Unit and
Department of Radiology, Ranbam Medical Center, Haifa,
Israel

A B
Figure 29: Erection penogram after audiovisual sexual stimulation. 99mTechnetium (99m Tc) was injected in the antecubital
vein and papaverine intracavernosally. A computerized gamma camera was used to calculate penile blood flow.
a) normal penogram,
b) penogram demonstrating corporeal veno-occlusive dysfunction
H. K. Choi, MD, Department of Urology, Yonsei University College of Medicine, Seoul, Korea.

Figure 30: Schematic drawing demonstrating the 3 factors

affecting penile rigidity: intracavernosal pressure, penile geo -
metry and mechanical properties of the corpora cavernosa and
the tunica albuginea. Impotence, defined as absence of ade -
quate rigidity for vaginal penetration, may therefore be not
exclusively due to decreased arterial inflow or increased
venous outflow (the two determinants of intracavernosal pres -
sure), but also due to geometric or tissue mechanical factors,
as well as due to any combination of these factors (A, B, C, D).
Such data help to explain the frustration and confusion clini -
cians have experienced, when attempting to correlate erectile
potency exclusively based on hemodynamic findings.
D.G. Hatzichristou, Department of Urology, Aristotle Universi -
ty of Thessaloniki, Greece

698
 VI. ARTERIOVENOUS FISTULA

A B

C D

Figure 31: A case of arteriovenous fistula after transurethral

surgery. A 60 year-old male with a bulbar urethral stricture:
a): urethrogram), developed urethral hemorrhage following
uneventful optical urethrotomy, that could not be stopped with
conservative methods. Perineal ultrasonography showed an
arteriovenous fistula
b), which was confirmed by a selective angiogram
(c and d). Angiographic embolization failed
e). Open surgical suture-ligation was successful.
R. Shabsigh, MD, Department of Urology, Columbia Universi -
ty, New York, USA.

699
 VII. PRIAPISM

Figure 32: Penile duplex ultrasonography demonstrating arte -

riolacunar fistula in a patient with arterial, high-flow pria -
pism after blunt perineal trauma.
I. Goldstein and R. Munarriz, Department of Urology, Boston
University Medical Center, Boston, USA

A B
Figure 33: Digital substractive internal pudental arteriography in a patient with arterial priapism (a), treated with embolization of
the internal pudental artery (b).
S. Glina, MD, Department of Urology, Instituto H. Ellis, Sao Paolo, Brazil

Figure 34: A case of arterial priapism in an 11-year-old boy.

Three weeks prior to admission, the young patient fell on his
bicycle, causing a direct trauma to the perineum.
a) colour duplex ultrasonography shows increased flow in the
right cavernous body and the development of the arteriolacu -
nar fistula.
A. Kolbenstvedt, M.D., Ph.D., B. Smevik, M.D., Department of
Radiology and H. Hedlund, MD, PhD, Department of Urology,
National Hospital (Rikshospitalet), Oslo, Norway.

700
 VII. PRIAPISM (Ctd)

Figure 34: b) pelvic arteriography shows widened right puden -

tal artery (straight arrow) and posttraumatic fistula (curved
arrow) between the right cavernosal artery and the right
cavernous body.

Figure 34: c) distal branches of right pudendal artery after

embolization by particles of a size 250-355 microns. Detumes -
cence was achieved and the boy was discharged from the hos -
pital the next day.

A B

Figure 35: A patient with veno-occlusive priapism treated surgically with the Al Ghorab technique. Post-shunt penile duplex
ultrasonography:
a) large filling defects in the distal corpora cavernosa-tunica albuginea consistent with shunt procedure.
b) longitudinal view showing distal corporal-tunical defect.
I. Goldstein and R. Munarriz, Department of Urology, Boston University Medical Center, Boston, USA.

701
 VIII. PEYRONIE’S DISEASE

Figure 36: Excessive tissue scarring in the corpora caverno -
sa, associated with Peyronie’s disease.
E. Meuleman, Department of Urology, University Hospital Nij -
megen, The Netherlands
Figure 37: Preoperative staging of Peyronie’s disease should
include a penile blood flow study to define relationship of
plaques to vessels and assess erectile hemodynamics.
G. A. Broderick, MD, Department of Urology, Mayo Clinic,
Jacksonville Florida, USA

A B

Figure 38: Cavernosographies of patients with Peyronie’s disease.

a) distal circumferencial plaque with site specific leak.
b) mild dorsal penile angulation with distal site specific leak
I. Goldstein and R. Munariz, Department of Urology, Boston University Medical Center, Boston, USA

702
 IX. PENILE FRACTURE

Figure 39: MRI of a 23-year-old male, one day post-penile trauma during sexual intercourse. The penile MRI (a and b) shows
small defect in the tunica albuginea of the left corpus cavernosum, with a very small hematoma. The patient was treated
conservatively and three months later he was potent with no curvature.
R. Shabsigh, MD, Department of Urology, Columbia University, New York, USA

703
 X. PENILE PROSTHESIS

Figure 40: X-ray showing a penile pros -

thesis
a) deflated and
b) inflated.
I. Moncada, MD, Department of Urology,
Hospital General Universitario Gregorio
Maranon, Madrid, Spain.

704
 X. PENILE PROSTHESIS (Ctd)
Figure 41: Pelvic CT in a patient with an inflatable 3-piece
penile implant, showing the prosthesis reservoir intraabdomi -
nally.
Y. Vardi,MD and A. Engel, MD, Neuro-Urology Unit and
Department of Radiology, Rambam Medical Center, Haifa,
Israel

Figure 42: Penile MRI showing an implanted penile prosthe -

sis.
a) axial and b) sagittal view.
I. Moncada, MD, Department of Urology, Hospital General
A Universitario Gregorio Maranon, Madrid, Spain

A B

Figure 43: MRI showing S-shaped deformity and buckling (a and b) of penile implants. Such deformities caused by inappropriate
introperative corpora length measurements and had as consequence post-implantation penile pain.
I. Moncada, MD, Department of Urology, Hospital General Universitario Gregorio Maranon, Madrid, Spain

705
 XI. FEMALE SEXUAL FUNCTION AND DYSFUNCTION

A B

C D

Figure 44: Several studies have shown that the pelvic floor is a muscular structure, pierced by the lower urinary, genital and distal
intestinal tract. This structure is a functional unit , therefore any pathology may be associated with voiding, sexual, genital and defe -
catory dysfunction. Anatomical and imaging studies have given valuable information regarding the function of the pelvic floor
muscles. The figures are part of a study on the role of levator ani in the continence mechanism of women. The same structure may
be implicated in female sexual dysfunction, such as vaginismus. Moreover, such sophisticated technique may be valuable tool in
female sexual function research.
The figure includes MRI images of young healthy volunteers in the transverse plane, corresponded to gross transverse sections
a). MRI are taken with the pelvic floor muscles relaxed
b) and contracted
c). The substraction between the two images shows in dark the location of maximum pelvic floor displacement due to contraction (d).

C.E. Constantinou, PhD, Department of Urology, Stanford University Medical Center, Stanford, California, USA.

706
 XI. FEMALE SEXUAL FUNCTION AND DYSFUNCTION (Ctd)
Figure 45: Duplex ultrasonography in a female pre- and post-
sexual stimulation, showing increased arterial inflow after
sexual arousal.
I. Goldstein and R. Munarriz, Department of Urology, Boston
University Medical Center, Boston, USA.
Figure 47: Duplex ultrasonography of the clitoris in a 45-year
old woman with sexual arousal disorder. Sagittal scan of the
cavernosal artery after audio-visual sexual stimulation sho -
wed PSV 26cm/sec and EDV 11cm/sec.
K. Park, MD, Department of Urology, Chonnam National Uni -
versity School of Medicine, South Korea
707
Figure 46: Duplex ultrasonography of the clitoris in a 28-year
old, healthy female volunteer. Sagital scan of the cavernosal arte -
ry after audio-visual sexual stimulation showed PSV 48cm/sec
and EDV 20cm/sec.
K. Park, MD, Department of Urology, Chonnam National Univer -
sity School of Medicine, South Korea
Figure 48: Duplex ultrasonography of the clitoris in a 53-year
old, post-menopausal woman with sexual arousal disorder.
Sagittal scan of the cavernosal artery after audio-visual sexual
stimulation showed PSV 19cm/sec and EDV 8cm/sec.
K. Park, MD, Department of Urology, Chonnam National Uni -
versity School of Medicine, South Korea
708
 2000 Recommendations of the
1st International Consultation
Co-Sponsored by
World Health Organisation
on Erectile Dysfunction
(WHO)
International Consultation Jardin A., Wagner G.,
on Urological Diseases
(ICUD) Khoury S., Giuliano F.,
Société Internationale Goldstein I., Padma-Nathan H., Rosen R.,
d’Urologie
(SIU)
Andersson K.E., Becher E., Hendry B., Jonas U., Kim Y.C.,
*
In collaboration with
Krane R., Lewis R., Lue T., Lundberg P.O., Mc Aninch J.,
American Urological Melman A., Meuleman E., Morales A., Navratil H.,
Association Sáenz de Tejada I., Schmidt A., Shabsigh R., Stackl W.,
(AUA)
European Association
Tan H.M., Teloken C., Tiefer L., Virag R.
of Urology
(EAU)
African Society of «There exists fundamental rights for the individual, including the right to sexual
Impotence Research health and a capacity to enjoy and control sexual and reproductive behavior in
(ASIR) accordance with a social personal ethic - freedom from fear, shame, guilt, false
Asia Pacific Society for beliefs and other factors inhibiting sexual response and impairing sexual rela-
Impotence Research tionships - freedom from organic disorders, disease and deficiencies that interfe-
(APSIR) re with sexual and reproductive function. »
Confederaçion Americana WHO 1994
de Urologia
(CAU)
European Society for
Impotence Research INTRODUCTION
(ESIR)
International Academy The 1st International Consultation on Erectile Dysfunction was
of Sex Research convened from July 1-3 1999 in Paris, France . Its mission was to
(IASR)
International Society for
develop recommendations for the diagnostic evaluation and
Impotence Research management of erectile dysfunction.
(ISIR)
Société d’Andrologie de The recommendations are based on a thorough review of the avai-
Langue Française lable literature and the subjective opinion of recognized global
(SALF)
experts serving on eighteen focused committees. The individual
Sociedad Latino Americana
para el estudio committee reports were developed and peer-reviewed by open pre-
de la Impotencia sentation and comments. Each committee also provided focused
(SLAI)
recommendations.
Society for Study
of Impotence Final recommendations were then refined by a working group and
(SSI)
World Association of Sexology
discussed by the Scientific Committee, consisting of the Chairmen
(WAS) of each committee and representatives of the associations sponso-
ring the Consultation.
These recommendations, published in 1999, will be periodically
re-evaluated in the light of clinical experience and progress within
the field.

711
 CONTENTS
A. DEFINITION OF ERECTILE DYSFUNCTION
B. THE KEY TO THE DIAGNOSIS AND EVALUATION OF ERECTILE DYSFUNCTION (Algorithm A)
I. HIGHLY RECOMMENDED EVALUATION AND TESTS
1.COMPREHENSIVE SEXUAL, MEDICAL AND PSYCHO-SOCIAL HISTORY
a) Medical and Sexual History
b) Erectile Dysfunction Intensity and Impact Scales
2. FOCUSED PHYSICAL EXAMINATION

II. RECOMMENDED DIAGNOSTIC TESTS

1. FASTING GLUCOSE OR GLYCOSYLATED HAEMOGLOBIN (HBA1C) AND LIPID PROFILE

2. EVALUATION OF THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS WITH A TESTOSTERONE ASSAY
III. OPTIONAL DIAGNOSTIC TESTS
1. PSYCHOLOGICAL AND/OR PSYCHIATRIC CONSULTATION
2. LABORATORY INVESTIGATIONS: (Serum prolactin, LH, TSH, CBC, Urinalysis)
IV. SPECIALIZED EVALUATION AND DIAGNOSTIC TESTS
1. IN DEPTH PSYCHOSEXUAL AND RELATIONSHIP EVALUATION
2. PSYCHIATRIC EVALUATION
3. NOCTURNAL PENILE TUMESCENCE AND RIGIDITY (NPTR) ASSESSMENT
4. VASCULAR DIAGNOSTICS
5. SPECIALIZED ENDOCRINOLOGICAL TESTING
6. NEURO-PHYSIOLOGICAL TESTING
V. CONCLUSION

C. THE KEY TO THE TREATMENT OF ERECTILE DYSFUNCTION (ALgorithm B)

I. ALTER MODIFIABLE RISK FACTORS OR CAUSE

1. LIFESTYLE AND PSYCHOSOCIAL FACTORS

2. SEXUAL TECHNIQUE AND INFORMATION
3. PRESCRIPTION OR NON-PRESCRIPTION DRUG USE
4. HORMONE REPLACEMENT THERAPY

II. DIRECT TREATMENT INTERVENTIONS FOR ERECTILE DYSFUNCTION

1. SEXUAL COUNSELLING AND EDUCATION

2. ORAL AGENTS
a) Sildenafil
b) Apomorphine
c) Phentolamine
d) Other drugs
3. LOCAL THERAPIES
a) Intracavernosal Injection Therapy
b) Intraurethral Therapy
c) Vacuum Constriction Devices
4. SURGICAL THERAPY
a) Vascular Surgery
b) Penile implants

III. REASSESSMENT AND FOLLOW-UP

GENERAL CONCLUSION

712
 A. Definition of Erectile
Dysfunction
The term «erectile dysfunction» is widely used to
refer to the consistent or recurrent inability of a
man to attain and/or maintain a penile erection
sufficient for sexual performance. «Erectile dys-
function» is now used in preference to the more
traditional terms, «impotence» or «male impoten-
ce». These earlier terms were replaced due to their
lack of specificity and pejorative connotations for
the patient.
Erectile dysfunction is a disorder and a symptom
based on the patient’s complaints. Objective tes-
ting (or partner reports) may be used to support
the diagnosis of erectile dysfunction, but these
measures cannot substitute for the patient’s self-
report in defining the disorder or establishing the
diagnosis.
The necessary reliance on patient reports implies
that cultural factors and patient-physician com-
munication will be important determinants in
defining, diagnosing and evaluating the disorder.
Consistency is a part of the definition of erectile
dysfunction. Erectile difficulties must be reported
to occur on a consistent or recurrent basis in
order to qualify for the diagnosis of erectile dys-
function. At present, a 3-month minimum dura-
tion is generally accepted for establishment of the
diagnosis. In some instances of trauma or surgi-
cally-induced erectile dysfunction (e.g. post-pros-
tatectomy), the diagnosis may be given prior to 3
months.
Erectile dysfunction may occur regardless of the
postpubertal age and there are many aetiologic
profiles in erectile dysfunction. It is noteworthy
that erectile dysfunction might not be the primary
complaint and/or may be associated with other
sexual problems.
Sexuality, including erection, is a complex bio-
psychosocial process. The treating physician and
713
collaborating specialists should possess a broad
knowledge about human sexuality. In the case of
erectile dysfunction, problems may be lifelong or
acquired, global or situational. Adequate atten-
tion to these details during the history will educate
the often uninformed patient regarding the
complex nature of sexuality, and prepare him to
understand treatment and outcome realities.
Patient and partner expectations, needs and prio-
rities will be significantly influenced by cultural,
social, ethnic, religious and national/regional
perspectives. The rational selection of therapy by
patients is only possible following appropriate
education, including information about sexuality
and all treatments for erectile dysfunction.
Although not always possible on the first visit,
every effort should be made to involve the
patient’s primary sexual partner early in the the-
rapeutic process.
Erectile dysfunction with its abbreviation ED is a
worldwide accepted term. Although there are
some acceptable synonyms for ED e.g. erectile
insufficiency or failure or impairment, ED refers
to the specific inability to achieve or sustain a
penile erection, and should not be applied to peni-
le curvatures, La Peyronie’s disease, spontaneous
or drug-induced prolonged erections and painful
erections.
ED must also be distinguished from other sexual
disorders in the male such as premature ejacula-
tion, anorgasmia and lack of desire, although ED
may occur concurrently with these other sexual
disorders.
In contrast to most other medical conditions, the
various treatments for ED have to be considered in
the context of traditions, ethnicity and socio-eco-
nomic conditions and also the patient’s and part-
ner’s preference, expectations and psychological
status.
 B. The Key to the Diagnosis and
Evaluation of Erectile Dysfunction
(Algorithm A)
The cornerstone of clinical assessment of all
men with ED is an initial diagnostic work-up
and evaluation. This evaluation should be perfor-
med by a physician knowledgeable in male
sexual function and dysfunction with sensitivity
toward cultural, ethnic and religious factors. It
is anticipated that most men with ED will first be
evaluated by a primary care physician. Basic
knowledge of human sexuality as well as anatomy
and physiology of male sexual function are
essential. A multidisciplinary approach may be
required. Although a male with ED may be refer-
red for psychosexual therapy, the medical treat-
ment including pharmacological and surgical
therapies for ED require the involvement of a
physician.
I. HIGHLY RECOMMENDED EVALUATION AND TESTS
COMPREHENSIVE SEXUAL, MEDICAL
1. AND PSYCHOSOCIAL HISTORY
a) Medical and sexual history
The medical and sexual history (Table 1 gives a
sample of sexual history questions in everyday
practice) are the most important elements in the
evaluation of ED. Such a history should be obtained
by a patient -physician dialogue in all men presen-
ting with complaints consistent with ED.
The essential components of this history should
include an assessment of the following:
• erectile insufficiency (onset, duration, progres-
sion, severity of the problem (see Table 4), evi-
dence of ED as it relates to sex with a partner,
nocturnal/morning erections, self-stimulatory
and visual erotic-induced erections)
• altered sexual desire
• ejaculation
• orgasm
• sexually induced genital pain
• partner sexual function
• lifestyle factors
714
The diagnostic tests utilized in the assessment of
the patient with ED may be stratified as:
u Highly recommended test: is a test that
should be done on every patient
u Recommended test: test of proven value in
the evaluation of most patients. Its use is
strongly encouraged during initial evaluation
u Optional test: test of proven value in the eva-
luation of specific patient profiles, with use
left to the clinical judgment of the treating
physician in general practice
u Specialized test : test of value in selected
patient profiles in specialized settings.
The rationale for testing and the potential impact
of a positive test must be explained to the patient
(e.g. an abnormal fasting glucose result may lead
to the diagnosis of diabetes).
• smoking
• chronic medical illness:
- hypertension
- diabetes mellitus
- renal or hepatic dysfunction
- atherosclerosis and cardiovascular risk
factors including hyperlipidaemia
• pelvic/perineal/penile trauma and surgery
• medications/recreational drug use
• pelvic radiotherapy
• neurological disease
• endocrine disease
• psychiatric illness
• current psychological state (Table 2): with spe-
cial attention to symptoms of depression (Table
3), altered self-esteem and coping skills, past and
present partner relationships (given the interperso-
nal context of sexual problems), past and present
sexual practices, history of sexual trauma/abuse,
history of somatization, hypochondriasis, history
of obsession related to sexual function, job and
social position satisfaction, economic position,
educational attainment.
 DIAGNOSTIC AID :
SAMPLE QUESTIONS
Table 1: Sample Sexual History Questions:
• "Many men of your age start to experience sexual
difficulties, if you have such a problem, I would be
happy to discuss this further"
• " Could you describe your sexual problem?"
• "When did your erection problems begin?" "Please
describe the circumstances".
• "Tell me about your sexual life and satisfaction in
the past"
• "How are your erections that you achieve with mas-
turbation or those that occur with sleep or upon
awakening early in the morning ?" (The discussion
of masturbation is a sensitive issue that is often
influenced by cultural and religious perspectives.)
• "How strong is your desire for sex, now and in the
past?"
• "Do you have difficulties with ejaculating too fast
or too slow, either now or in the past?"
• "Do you know whether your partner was satisfied
with your sexual life together? Would it be helpful
for me to talk with your partner about your sexual
life and situation?"
• "What has been your partner’s reaction to your
sexual problem and does your partner want to
resume sexual intercourse now?"
• "What has been the effect of your sexual diffi-
culties on your overall lifestyle?"
715
Table 2: Sample Psychosocial Assessment Questions:
• "Do you suffer from depression or other mood
problems?"
• "Have you seen a psychiatrist or other mental
health professional in recent years? If yes, please
describe the circumstances and outcome"
• "How are your relationships with family members
and other important people in your life?"
• "Do you have any difficulties in your work situa-
tion, if applicable?"
• "How is your current relationship with your
partner? How was it in the past?"
• "Were you ever the victim of sexual abuse (e.g.
forced to have sex)? If yes, what effect did this
have on you then or now?"
• "Is your economic situation contributing to signi-
ficant stress in your life?"
Table 3: A 2-question scale for depression
• During the past month have you often been bothe-
red by feeling down, depressed or hopeless?
• During the past month have you often been bothe-
red by little interest or pleasure doing things?
Source : Whooley M.A., Avins A.L., Miranda J.,
Browner W.S. Case-finding instruments for depres-
sion. Two questions are as good as many. J. Gen.
Intern. Med. 1997; 12: 439-445
b) Erectile dysfunction intensity and
impact scales
Symptom intensity and impact scales are used for
several purposes:
• to aid clinicians in recognizing, diagnosing
and evaluating the disorder,
• to permit patients to acknowledge the problem
in routine office settings, and
• to assist researchers in the collection of epide-
miological and clinical trial data.
Brief symptom scales also assist clinicians in
classifying the severity of the disorder and its
impact on the patient.
The use of a brief, self-administered question-
naire is particularly recommended for assessment
of ED symptom intensity and impact.
The following scales are proposed for this purpose:
˚ 5-item Intensity Scale (Table 4)
The 5-item ED Intensity item is based on exten-
sive research and clinical experience, including
publication in recent years of several well-valida-
ted questionnaire measures of sexual function.
The 5 items in this scale characterize the ability to
achieve and maintain erection. These items have
high test-retest reliability and have been validated
linguistically in more than 30 languages. The
items have been selected from the International
Index of Erectile Function (Rosen et al., Urology,
1997-49:822-830), a 15-item questionnaire mea-
sure of male sexual function developed for use in
clinical trials of ED.
An aggregate score of the 5-item scale can be cal-
culated, and used to classify the severity of the
disorder
˚ Single item ED Impact scale (Table 4)
The single-item impact scale is adapted from a simi-
lar scale widely used in Benign Prostate Hyperpla-
sia, and which has been shown to be a sensitive and
reliable index of subjective distress. It has also been
included in a well-validated quality of life scale for
ED*. The single-item impact scale provides a quan-
titative index of subjective distress or bother asso-
ciated with the disorder (ED impact scale). This
score should be recorded separately from the aggre-
gate symptom score of the first 5 items (ED inten-
sity scale).
716
Brief symptom scales and quality of life mea-
sures* can assist the practitioner or clinical resear-
cher in obtaining clinically-relevant data in a
standardized and cost-efficient manner. These ins-
truments can also be used in patient follow-up to
document some aspects of clinical outcome. Des-
pite these advantages, symptom scales should not
be used as a substitute for physical examination
or medical history of the patient. These latter pro-
cedures are the sine qua non for clinical care of
the patient with ED. The substitution of a ques-
tionnaire may not address the specific religious,
cultural, educational and economic factors of the
individual patient.
Particular attention should be paid to:
• Patient expectations
A critical aspect of assessment is the identification
of patient needs, expectations, priorities and
treatment preferences which may be significantly
influenced by such factors as cultural, social, eth-
nic and religious perspectives. Patient education
is also important in fostering a therapeutic rela-
tionship, facilitating patient-physician communi-
cation and enhancing patient compliance.
• Partner involvement
Although not always possible on the first visit,
efforts should be made to involve the patient’s
partner early in the process. The partner’s presen-
ce may be influenced by cultural and social prefe-
rences as well as individual patient needs and pre-
ferences.
2. FOCUSED PHYSICAL EXAMINATION
A focused physical examination should be perfor-
med on every patient with ED. This examination
should include:
• assessment of body habitus (secondary sexual
characteristics)
• assessment of the cardiovascular, neurological
and genito-urinary system focusing on penile,
testicular and rectal exam. Blood pressure and
heart rate should be measured if not assessed in
the previous 3-6 months. The physical examina-
tion may corroborate aspects of the medical his-
tory and may occasionally reveal unsuspected
physical findings (e.g. penile plaques, atrophic
testes, suspicion of prostate cancer).
*There exists a validated quality of life scale for ED by
Fugl-Meyer et al., Int J Impot Res., 1997-9:141-148.
 Table 4: ED Intensity and Impact Scales
ERECTILE DYSFUNCTION INTENSITY SCALE
Each question has several responses. Put in the empty box the number of the response that best describes your own
situation. Please be sure that you select one and only one response for each question.
PATIENT NAME : DOB : ID : DATE OF ASSESSMENT :
Almost never A few times Sometimes Most times Almost always
or never (much less than (about half (much more than or always
half the time) the time) half the time)
1. HOW OFTEN WERE
YOU ABLE TO GET AN
ERECTION DURING 1 2 3 4 5
SEXUAL ACTIVITY?

2. WHEN YOU HAD

ERECTIONS WITH
SEXUAL STIMULATION,
HOW OFTEN WERE 1 2 3 4 5
YOUR ERECTIONS HARD
ENOUGH FOR PENETRA-
TION (ENTERING YOUR
PARTNER )?

3. WHEN YOU ATTEMPTED

INTERCOURSE, HOW OFTEN
WERE YOU ABLE TO PENE- 1 2 3 4 5
TRATE (ENTER) YOUR
PARTNER?

4. DURING SEXUAL INTER-

COURSE, HOW OFTEN WERE
YOU ABLE TO MAINTAIN 1 2 3 4 5
YOUR ERECTION AFTER
YOU HAD PENETRATED
(ENTERED) YOUR PARTNER?
Extremely Very Difficult Slightly Not
difficult difficult difficult difficult
5. DURING SEXUAL INTER-
COURSE, HOW DIFFICULT
WAS IT TO MAINTAIN YOUR 1 2 3 4 5
ERECTION TO COMPLETION
OF INTERCOURSE?

ED Intensity Score :
• Instructions for Scoring: Add the scores for each item 1-5 (total possible score =25).
ED Severity Classification: Total score 5-10 (severe); 11-15 (moderate); 16-20 (mild); 21-25 (normal).
Note: The above questions should only be completed by individuals who have been sexually active and have attempted sexual
intercourse in the past 3 months. For sexually inactive individuals, the questionnaire may be answered for the last period of time
(3 months or longer) during which the individual was sexually active.

ERECTILE DYSFUNCTION IMPACT SCALE

VERY RATHER MIXED, ABOUT RATHER VERY
DISSATISFIED DISSATISFIED EQUALLY SATISFIED SATISFIED SATISFIED
AND DISSATISFIED
IF YOU WERE TO SPEND
THE REST OF YOUR LIFE
WITH YOUR ERECTILE
CONDITION THE WAY 1 2 3 4 5
IT IS NOW, HOW WOULD
YOU FEEL ABOUT THAT?

717
 II. RECOMMENDED DIAGNOSTIC TESTS
The physician must tailor the laboratory work-up
based on patient complaints and risk factors outli-
ned by the history and take into consideration the
cost and availability of testing resources.
These tests include the following focused labora-
tory tests:
FASTING GLUCOSE OR GLYCOSYLATED
1. HAEMOGLOBIN (HBA1C) AND LIPID
PROFILE,
if not available within the previous 12 months, are
of clinical utility to rule out diabetes mellitus and
hyperlipidemia.
III. OPTIONAL DIAGNOSTIC TESTS
PSYCHOLOGICAL AND/OR PSYCHIA-
1. TRIC CONSULTATION
(if available) for thorough sexual and psychoso-
cial history
IV. SPECIALIZED EVALUATION AND DIAGNOSTIC TESTS
While the majority of patients with ED can be
managed within the primary care setting by a
physician educated in male sexual dysfunction,
specific circumstances may dictate the need for
referral for specialized testing and/or treatment
(Table 5).
Before considering specialized evaluation and
Table 5: Specific Indications for Referral and/or Treatment
1. Patient requests referral for specfic testing or treat-
ment.
2. Patient requiring vascular, neurological or cardiolo-
gic evaluation
3. Young patient with pelvic, perineal or penile surgery
or trauma who may be a candidate for reconstructi-
ve vascular surgery.
4. Patient with La Peyronie’s disease and/or a signifi-
cant penile bend or deformity that might require
surgical correction.
718
EVALUATION OF THE HYPOTHALAMIC-
2. PITUITARY-GONADAL AXIS WITH A TES-
TOSTERONE ASSAY
Although controversy exists as to the relative
value of the various testosterone assays (total, free
or bioavailable), strong consensus exists that at
least one of these assays should be performed par-
ticularly in case of low sexual desire and of testes
of diminished size.
Although it might be argued that testosterone tes-
ting is associated with a low positive yield, in the
group of men with ED secondary to hypogona-
dism, it might represent a potentially reversible
form of ED.
2. LABORATORY INVESTIGATIONS:
• Serum prolactin, LH
• Thyroid stimulating hormone (TSH)
• Complete blood count (CBC) if not available
during the last 6 months
• Urinalysis (dip-stick or microscopic)
diagnostic testing, the physician should consider
whether the patient’s case profile meets the indi-
cations for specialist referral.
The physician must also consider the ability of his
clinic facility to provide and support specific hor-
monal, vascular, neurologic and psychological tes-
ting.
5. Patient with refractory depression, bipolar disorder,
psychosis or history of sexual abuse or trauma and
those patients with complicated psychiatric or psy-
chosexual disorder as well as those with complex
relationship issues.
6. Patient with a complicated endocrinopathy inclu-
ding complicated diabetes mellitus
7. Patient with treatment failures who may be a candi-
date for intracavernosal injection therapy or penile
implant surgery.
 IN DEPTH PSYCHOSEXUAL AND S PECIALIZED ENDOCRINOLOGICAL
1. RELATIONSHIP EVALUATION 5. TESTING

2. PSYCHIATRIC EVALUATION - Thyroid function studies

- Hypothalamic-pituitary-gonadal function studies
NOCTURNAL PENILE TUMESCENCE
3. AND RIGIDITY (NPTR) ASSESSMENT
- MRI sella turcica

4. VASCULAR DIAGNOSTICS 6. NEURO-PHYSIOLOGICAL TESTING

- Vibrometry
- In office penile injection pharmacotesting
- Bulbocavernosus reflex latency
- Penile Doppler ultrasound
- Cavernosal EMG
- Dynamic infusion pharmacocavernosometry
- Somatosensory evoked potential testing
and pharmacocavernosography
- Pudendal and sphincter EMG
- Penile arteriography
- CT and MR imaging (to evaluate trauma and
infection)
- Nuclear imaging

V. CONCLUSION
The first step in the management of the patient The identification and recognition of medical and
with ED is to facilitate the patient’s and partner’s psychological factors associated with ED in the
(if available) understanding of the condition and individual patient, must be emphasized.
the results of the diagnostic assessment and to
identify the patient’s and partner’s needs, expecta-
tions, priorities and preferences.

SUMMARY
DIAGNOSIS AND EVALUATION OF ERECTILE DYSFUNCTION
I. HIGHLY RECOMMENDED III. OPTIONAL DIAGNOSTIC
EVALUATION AND TESTS TESTS
1. COMPREHENSIVE SEXUAL, MEDICAL AND 1. PSYCHOLOGIC AND/OR PSYCHIATRIC
PSYCHO-SOCIAL HISTORY CONSULTATION
a) Medical and Sexual History 2. LABORATORY INVESTIGATIONS
b) Erectile Dysfunction Intensity and Impact Scales (Serum prolactin, LH, TSH, CBC, Urinalysis)
2. FOCUSED PHYSICAL EXAMINATION
IV. SPECIALIZED EVALUATION
AND DIAGNOSTIC TESTS
II. RECOMMENDED
1. IN DEPTH PSYCHOSEXUAL AND RELATIONSHIP
EVALUATION
1. FASTING GLUCOSE OR GLYCOSYLATED
HEMOGLOBIN (HBA1C) AND LIPID PROFILE
2. PSYCHIATRIC EVALUATION
3. NOCTURNAL PENILE TUMESCENCE AND RIGIDITY
2. EVALUATION OF THE HYPOTHALAMIC- (NPTR) ASSESSMENT
PITUITARY-GONADAL AXIS WITH A TESTO-
4. VASCULAR DIAGNOSTICS
STERONE ASSAY.
5. SPECIALIZED ENDOCRINOLOGIC TESTING
6. NEURO-PHYSIOLOGIC TESTING

719
 C. The Key to the Treatment of
Erectile Dysfunction (Algorithm B)
The selection of therapy is strongly influenced by
personal, cultural, ethnic, religious and econo-
mic (affordability) factors.
The presentation and stratification of therapies
I. ALTER MODIFIABLE RISK FACTORS OR CAUSES
Prior to direct intervention, good medical practice
recognizes the value of altering modifiable risk
factors. Although frequently insufficient to reverse
ED completely, this step may be of great value in
selected patients.
Although the quantitative benefits of altering modi-
fiable risk factors or causes, particularly when asso-
ciated with the need to modify behavior, are not
documented, good clinical practice mandates
attention to these issues either prior to, or along
with, direct therapies as a key to treating ED.
These potentially modifiable risk factors and causes
include the following:
LIFESTYLE AND PSYCHOSOCIAL FAC-
1. TORS
Lifestyle factors such as cigarette smoking, alcoho-
lism, substance abuse, may require priority mana-
gement specific to the particular issue.
Psychosocial factors include relationship issues
e.g. partner conflict, sexual misinformation, limited
sexual practices and also depression
2. SEXUAL TECHNIQUE AND INFORMATION
This includes lack of awareness of psychological
impact on sexual function, information about nor-
mal age-related changes, need for partner foreplay
and lubrication.
PRESCRIPTION OR NON-PRESCRIP-
3. TION DRUG USE
Most commonly used antihypertensives, psychotro-
pic drugs including antidepressants and anti-psy-
chotics, as well as anti-arrhythmics and antiandro-
gens and steroids.
Alterations in drug dosages or classes may be of
significant benefit in selected patients, but this
should be coordinated with the primary physician
managing, for example, the patient’s hypertension
or depression.
720
may therefore vary among individuals, among per-
sons from different cultural or religious back-
grounds, or among persons with varying socio-
economic backgrounds.
4. HORMONE REPLACEMENT THERAPY
for hormonal abnormalities (e.g. hypogonadism,
hyperprolactinemia)
Hormone replacement therapy is appropriate in the
presence of a documented deficiency (e.g. andro-
gen deficiency and hypogonadism). However, ade-
quate replacement may not necessarily improve
ED and thus one may need to consider direct inter-
vention therapy even in this patient population.
The issue of androgen replacement therapy is com-
plicated. There is a statistical decline of testoste-
rone levels, particularly free testosterone, in ageing
men. While this fall is only moderate, ageing men
show clinical signs of hypogonadism (loss of
muscle mass/strength, reduction in bone mass and
an increase in visceral fat). Testosterone replace-
ment or supplement therapy may improve bone
mass, muscle mass, strength and frequently noc-
turnal erections as well in this age group. However,
the effects on sexual function, mood and cognition
are less clear, but may be meaningful in certain
men. The identification of that segment of the
ageing male population that might possibly benefit
from androgen supplementation remains unclear.
Questions still remain regarding the magnitude and
longevity of these potential beneficial effects.
More importantly, the long-term risks of androgen
therapy in this age group are not really known,
especially in the areas of cardiovascular and pros-
tate diseases. It has been known that testosterone in
general should be employed as replacement thera-
py. Despite increasing evidence that patients with
subnormal or borderline normal levels of testoste-
rone could be considered as candidates for testoste-
rone treatment, until more information is available
testosterone and androgens in general should not
be recommended as supplement therapy.
 II. DIRECT TREATMENT INTERVENTIONS FOR ERECTILE DYSFUNCTION
The patient and his partner (if available) should be
informed about all of the available and accep-
table treatment options applicable to his clinical
condition and the related benefits, risks, and costs
of each modality.
The development of ED can significantly affect
the quality of life, but it is not a life-threatening
disease. Consequently, it is reasonable to discuss
the benefits, risks, and costs of the available treat-
ment strategies with the patient and have the
patient actively participate in the choice of
therapy (shared decision-making).
There is a documented correlation between car-
diovascular disease and ED. In a significant num-
ber of patients ED is a sign of vascular desease
An important issue prior to the institution of any the-
rapy and the subsequent resumption of sexual acti-
vity is the patient’s overall cardiovascular condi-
tion. Is this patient able to resume the exercise of
sexual activity? If not, priority cardiovascular
assessment and intervention may be appropriate.
The partner’s sexual function if possible should
be considered prior to initiating therapy.
The vast majority of patients will need to consider
direct treatment options for ED. Only those phar-
macological treatments that have been thorough-
ly tested in randomized clinical trials, with subse-
quent publication of results in peer-reviewed lite-
rature, should be considered for general use.
Long-term follow-up of all treatment options must
be performed to demonstrate durability and conti-
nued efficacy and safety, as well as patient and
partner acceptability. Additionally, new treatment
options that enter the arena will need to meet not
only the above efficacy and safety criteria but
should also be compared to available therapies for
cost-effectiveness.
The treatment selected by a patient will be
influenced not only by issues such as efficacy and
safety, but also by the patient’s cultural, religious
and economic background.
Additionally, such factors as:
1. the mechanism of action: peripheral vs central,
inducer vs enhancer and
2. ease of administration
3. invasiveness
4. reversibility
5. cost
6. legal regulatory approval and availability
721
may all critically influence the individual
patient’s selection of therapy. As previously men-
tioned, affordability is a prime factor worldwide in
influencing patient acceptance and utilization of a
specific therapy for ED.
˚ The use of the internet to prescribe therapies
for ED is to be condemned since it fails to meet
the need for direct physician-patient contact in
the assessment of all patients presenting with this
complaint.
1. SEXUAL COUNSELLING AND EDUCATION
Sexual counselling and education (sex therapy,
psychosexual therapy or marital therapy) for indi-
viduals or couples address specific psychological
or interpersonal factors such as relationship dis-
tress, sexual performance concerns, dysfunctional
communication patterns and comorbid sexual
conditions that are likely to impact sexual functio-
ning. Modified sex therapy may serve as an adjunct
to the other direct therapies for ED to address psy-
chological reactions to these medical or surgical
therapies which may be perceived as temporary,
unnatural or unacceptable by the patient and/or
partner. The advantages of psychosexual therapy
include its noninvasive nature and broad applicabi-
lity. The disadvantages of psychosexual therapy
include its variable efficacy in the treatment of ED,
cost acceptability by the patient or the couple and
availability of qualified providers.
2. ORAL AGENTS
When indicated, oral therapies will probably
become the first-line treatment for the majority
of patients because of potential benefits and lack of
invasiveness.
Historically, oral medications such as yohimbine
have been utilized empirically without the support
of rigorous clinical trial data on efficacy and safety.
Oral therapies may act:
• centrally as dopaminergic agonists
• both centrally and peripherally as alpha adre-
nergic blockers or
• peripherally as phosphodiesterase 5 (PDE 5)
inhibitors or nitric oxide (NO) precursors
• as an inducer or as an enhancer
a) Sildenafil
Sildenafil, a selective inhibitor of phosphodiestera-
se type 5 (PDE 5), has been approved in many
countries for the treatment of ED. PDE-5 is the
enzyme responsible for the breakdown of the intra-
cellular second messenger of NO i.e. cyclic guano-
sine monophosphate (cGMP). PDE 5 is the predo-
minant isoform of phosphodiesterases found in the
corporal smooth muscle. Sexual stimulation is
necessary to initate NO release within the corpora,
accordingly sildenafil is ineffective in the abscence
of sexual stimulation.
In clinical trials, sildenafil has shown broad spec-
trum efficacy in a majority of patients regardless of
the underlying aetiology of ED, the baseline seve-
rity of ED or the age of the patient. Recent studies
in patients with specific disorders such as diabetes
mellitus, hypertension, spinal cord injury, multiple
sclerosis and depression have also shown sildenafil
to be effective.
It is important to stress that the co-administration of
nitrates and sildenafil is strictly contraindicated.
Severe hypotension may ensue following this com-
bination.
Side-effects include transient headache, flushing,
dyspepsia, nasal stuffiness and transient altered
colour-vision (due to PDE 6 inhibition).
Although there was no difference in CV mortality
compared to placebo in the controlled trials presen-
ted for registration, a number of deaths have been
reported in association with sildenafil usage in post
marketing reporting but the specific relationship to
the drug is uncertain. In several of these cases,
nitrates and sildenafil were administered conco-
mitantly against the prescribing information.
In general, sildenafil when prescribed appropriate-
ly has demonstrated broad efficacy and an accep-
table safety profile.
b) Apomorphine
Apomorphine is a dopaminergic agonist acting on
the central nervous system. It was initially admi-
nistered subcutaneously, however intolerable
adverse events prompted the development of a
sublingual pill. Apomorphine has shown efficacy
in placebo-controlled fixed and dose escalation
studies. In responders erectile activity is usually
experienced within 20 minutes. Its principal
722
adverse effect is nausea, which has been reported
as usually mild at lower dosages (2 mg and 4 mg).
Other adverse effects are dizziness, sweating,
somnolence, yawning and rarely syncopy. It is
under review at the time of writing.
c) Phentolamine
Phentolamine is an alpha-adrenergic blocking
agent with both central and peripheral activity. In
placebo controlled studies, phentolamine mesylate
has been found to have modest efficacy in patients
with mild-to-moderate ED. Adverse events
includes dizziness, nasal stuffiness and tachycardia
which is generally well tolerated at the 40 mg dose.
It is under review at the time of writing.
d) Other drugs
Other drugs under investigation include:
• IC 351 is a more pharmacologically selective
and longer acting PDE-5 inhibitor, the clinical
significance of which remains under investigation
in clinical trials
• melanotan II an alpha-MSH analogue and
• the combination of L-arginine and yohimbine.
In the future, combination oral therapy may be
employed and potentially demonstrate additive or
synergistic actions (e.g. theoretically sildenafil
and apomorphine). Because of the possible additi-
ve effects of combination therapy (e.g. hypoten-
sion), clinical trials must be first performed to
evaluate not only efficacy but also safety.
The advantages of oral drug therapies include
broad patient acceptance, ease of administration
and relative efficacy. The disadvantages include
specific contraindications such as the concomitant
use of nitrates with respect to sildenafil, the relati-
vely high cost and lack of long-term use follow-up
data.
3. LOCAL THERAPIES
Local therapies include intracavernosal injection
therapy, intraurethral therapy and vacuum devi-
ce therapy. Patients who fail oral drug therapy,
who have contraindications to specific oral drugs
or who experience adverse events with oral drugs
might consider these local therapies. Additionally,
individual preferences may direct a patient to
consider local therapies prior to, or as an alter-
native to, an oral drug therapy.
a) Intracavernosal injection therapy
Intracavernosal injection therapy is a well establi-
shed medical therapy for ED. The delivery, by
penile injection, of agents that directly relax cor-
poral smooth muscle such as papaverine, phento-
lamine or more recently alprostadil (prostaglan-
din E1) is associated with broad efficacy and rela-
tive safety.
• Alprostadil is widely approved worldwide as
alprostadil sterile powder or alfadex.
• Combinations of agents have established effica-
cy and safety based upon common usage.
Injection therapy with alprostadil or a combina-
tion of drugs is effective in a large majority of
patients, although discontinuation rates are
usually high.
The side-effects associated with injection therapy
are primarily local and include pain, priapism and
scar tissue formation over time. This therapy is
contraindicated in patients with sickle cell
anaemia and with other conditions that predispose
to priapism.
The advantages of penile injection therapy inclu-
de broad efficacy, relative safety and rapid onset of
action. The disadvantages include invasive local
administration and relatively high cost.
b) Intraurethral therapy
The intraurethral application of alprostadil is an
alternative to injection therapy. Intraurethral thera-
py is associated with significanlty less efficacy
than direct injection of alprostadil. The efficacy
may be increased by using an elastic band placed
at the base of the penis. The associated side-effects
include pain as well as systemic hypotension.
The advantages of intraurethral therapy include
its less invasive nature. The disadvantages include
local as well as systemic side-effects, relatively
high cost and partner-related vaginal irritation.
Transdermal penile delivery of vasoactive drugs
is currently under investigation at the time of wri-
ting.
c) Vacuum constriction devices
Vacuum constriction devices (VCDs) are widely
available including over-the-counter (without
prescription) in some countries. They are of appeal
to a group of men not interested in pharmacolo-
723
gical therapies or who have specific contra-indi-
cations to these therapies.
VCDs apply a negative pressure to the pendulous
penis, thus drawing blood into the penis, which is
then retained by application of an elastic band at
the base of the penis.
The side-effects associated with VCD therapy
include penile pain, penile numbness, bruising and
retarded ejaculation.
The advantages of VCD therapy include its non-
pharmacological nature, on-demand use, lack of
contraindications and cost.
The disadvantages of VCD therapy include their
cumbersome utilization and minor local side-
effects.
4. SURGICAL THERAPY
a) Vascular surgery
Microvascular arterial bypass and venous liga-
tion surgery may achieve the goal of increasing
arterial inflow and decreasing venous outflow.
Certain young patients with vascular insufficiency
may be candidates for surgical cure or improve-
ment of ED. These patients must be evaluated by
specialized testing and should be treated by an
experienced surgeon.
b) Penile implants
The final treatment option for ED is the surgical
implantation of a malleable or inflatable penile
prosthesis. This option is highly invasive and irre-
versible and should therefore be reserved for
select cases failing other treatment modalities.
However, under unique and uncommon circum-
stances, a penile implant could be selected as a
primary option. When properly selected, penile
prostheses may be associated with high rates of
patient satisfaction. Penile implant surgery is
uncommonly associated with prosthesis infection,
but such cases usually require explantation and
may result in severe scarring and penile deformity.
The advantages of penile prosthesis implantation
include relative efficacy and a «long-term solu-
tion». The disadvantages of penile prostheses
include irreversibility, invasiveness, surgical
complications and mechanical failure.
724
725
 III. REASSESSMENT AND FOLLOW-UP
Reassessment and follow-up should be conducted
at regular intervals for every patient receiving
treatment for ED. The goals of follow-up include:
1. The need for dose titration or substitution of
another treatment intervention should be
considered at each treatment follow-up visit.
Patients may change treatment preferences,
seek new information, or wish to re-evaluate
their current treatment choices.
2. Patient communication. Patients may have
concerns regarding treatment administration,
other sexual dysfunctions (e.g. premature eja-
culation), partner issues (e.g. anorgasmia) or
lifestyle factors (e.g. emotional stress).
GENERAL CONCLUSION
The field of sexual health medicine is rapidly
evolving. The consensus opinions expressed in
this 1st International Consultation will require
updating with the rapid developement in:
- basic and clinical sciences
- culture/race/ ethnic specific epidemiology
- new drugs in all classes
- gene therapy
- prevention strategies.
These International recommendations for the
key to resolving ED (algorithms A and B) have
been based on a thorough review of the litera-
ture and the opinions of recognized worldwide
726
3. Patients may change medication regimens,
either for ED or a concomitant medical disor-
der. The possibility of adverse drug reactions
or drug interaction effects with oral medica-
tion for ED should be carefully monitored.
4. General medical and psychosocial reassess-
ment should be performed at regular intervals,
depending upon the patient’s health, physical
and psychosocial needs. Follow-up also pro-
vides an additional opportunity for patient edu-
cation.
experts in the field. They are rational and step-
wise with respect to diagnostic and treatment
interventions. These recommendations recogni-
ze and respect the influence of cultural, ethnic,
religious and individual patient and partner
perspectives and, in general, attempt to ensure
broad global applicability and appeal.
The diagnosis and treatment of ED by Inter-
net or any other electronic or otherwise
distant interaction between patient and phy-
sician which prevents direct one-on-one
assessment and examination is strongly dis-
couraged.
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731