Cryptorchidism

One of the most common male

developmental abnormalities
27,000 orchidopexies annually in USA
89% of untreated males with bilateral
cryptorchidism develop azospermia
Lifetime risk of neoplasia 2-3%
4 fold higher than average risk

Issues
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
Azospermia
Increased risk for neoplasia
Treatment
Medical/hormonal
Surgical

Definitions
Cryptorchid: testis neither resides nor can be
manipulated into the scrotum
Ectopic: aberrant course
Retractile: can be manipulated into scrotum where
it remains without tension
Gliding: can be manipulated into upper scrotum
but retracts when released
Ascended: previously descended, then ascends
spontaneously
Epidemiology
Frequency 3.4 % in term boys
By 1 yo, incidence 0.8%
Is the incidence of
cryptorchidism increasing?
Literature controversial
Cryptorchidism, hypospadias, micropenis
Decreasing semen quality
Increasing testicular cancer
Increasing demand for assisted reproduction
Impact of environmental xenoestrogens
Herbicides, pesticides, PCBs, polystyrenes
Environmental antiandrogens
Linuron, vinclozolin, ppDDE, polyaromatic
hydrocarbons
Risk Factors
Hjerkvist 1989
IUGR, prematurity
Incidence in premies 30%
First-or second-born
Perinatal asphyxia
C-section
Toxemia of pregnancy
Congenital subluxation of hip
Seasonal (especially winter)

Issues
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
Azospermia
Increased risk for neoplasia
Treatment
Medical/hormonal
Surgical

Testicular development
6 wk primordial germ cells migrate to
genital ridge
7 wk testicular differentiation
8 wk testis hormonally active
Sertolis secrete MIF
10-11 wk Leydig cells secrete T
10-15 wk external genital differentiation
Testicular descent
5-8 wk processus vaginalis
Gubernaculum attaches to lower epididymis
12 wk transabdominal descent to internal
inguinal ring
26-28 wk gubernaculum swells to form
inguinal canal, testis descends into scrotum
Insulin-3 (INSL3) effects gubernacular
growth

INSL3
Member of the insulin/relaxin superfamily
Highly expressed in Leydig cells
In mice, targeted INSL3 deletion associated
with bilateral cryptorchidism, abnl
gubernaculum development

INSL3
Tomboc 2001
DNA analysis of 145 cryptorchid males, 36 controls
Found 2 mutations (2/145, 1.4%), several
polymorphisms
Baker 2002
DNA from 118 cryptorchid boys, 48 controls
Several polymorphisms
No specific mutations
Important in descent but mutations an uncommon
cause of cryptorchidism


Germ cell maturation
8 wk: gonocytes (fetal stem cells)
15 wk: spermatogonia
3 mo of age: adult dark spermatogonia
(adult stem cells) appear and remain
Neonatal surge in LH, FSH, T
4 yo: primary spermatocytes
Puberty: spermatogenesis
Issues
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
Azospermia
Increased risk for neoplasia
Treatment
Medical/hormonal
Surgical

Hypothalamus
Pituitary
Sertoli
Androgen resistance
Dysgenesis/anorchia
Testosterone biosynthetic problems
Hypopituitarism
Low/absent GnRH
Kallmanns
Prader Willi
Testosterone
dihydrotestosterone
Androgen receptor
Post-receptor effects
Leydig Germ cells
GnRH
MIF
FSH LH
5 reductase
5 reductase deficiency
MIF deficiency/persistent Mullerian ducts
Abnormal gonadotropins in
cryptorchid infants and boys
Insufficient T response to hCG in 36.5%
(Forest 1979)
Blunting of LH and FSH surge at 3 mo
(Gendrel 1980)
Leydig cell hypoplasia in some
undescended testes (Hadziselimovic 1986)
Defective onset of meiosis at
4-5 yo?
Normally see increase in urinary LH and
increased prominence of Leydig cells,
Appearance of primary spermatocytes
In cryptorchid males,
Low urinary LH & FSH
Impaired T response to hCG
May indicate deficiency of HP-gonadal axis as
a cause of defective meiosis
Issues
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
Azospermia
Increased risk for neoplasia
Treatment
Medical/hormonal
Surgical

Impact on Fertility
At bx, # spermatogonia/tubule prognostic for
subsequent fertility potential
Bx without germ cells 33-100% risk of infertility
Possible causes of subfertility
Reduction in total # germ cells (already present in 1
st

year of life)
Defect in one or more steps in germ cell maturation
Defective transformation of gonocytes into Ad spermatogonia
(Hadziselimovic 1986)
Delayed disappearance of gonocytes
Incidence of Azospermia
Azospermia in normal population 0.4-0.5%
Unilateral Bilateral
Untreated 13.6%
(10/73)
88.6%
(31/35)
Medically
treated
13.3%
(28/210)
32.0%
(46/142)
Surgically
treated
13.3%
(126/942)
46.4%
(224/484)
Hadziselimovic 2001
Chronological development of germ cells (#/cross
section)
0
1
2
3
4
5
n=15 n=15 n=12 n=15 n=13 n=10
age (mo)
g
e
r
m

c
e
l
l
s
/
t
x
s
UDT
CDT
Hadziselimovic 2001
3-7 8-12 13-18 19-25 29-60 <120
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0.3 0.9 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5
Year
A
d
/
T
UDT
CDT
Number Ad spermatogonia/tubular cross-section from 0-9 yo
Hadziselimovic 2001
0
1
2
3
4
5
6
Age
< 6 mo
6-24 mo
0
20
40
60
80
100
120
140
160
180
Age
< 6 mo
6-24 mo
# germ cells/tubular cross-section

Normal in 1
st
6 mo, greatly decreased
Between 6-24 mo

Hadziselimovic 2001
Sperm/ejaculate (1x10
6
)

If Ad spermatogonia present at orchidopexy,
Tended to have normal sperm count as adults

Ad
spermatogonia
No Ad
spermatogonia
Abnormal germ cell deveopment
Huff 2001
767 boys with unilateral cryptorchidism
Bilateral bx and orchidopexy between 0-9
yo
238 < 1 yo at orchidopexy
Transformation of gonocytes into Ad
spermatogonia
529 2-9 yo at orchidopexy
Onset of meiosis

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
germ
cells/tubule
1 3 5 7 9 11
month
UDT
CDT
Total germ cell counts significantly higher in undescended testes, p=0.024
Huff 2001
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
gonocytes/
tubule
13579
1
1
month
UDT
CDT
Total gonocyte counts significantly higher in undescended testes, p<00005
Huff 2001
0
0.05
0.1
0.15
0.2
0.25
1 3 5 7 9 11
month
UDT
CDT
Total adult dark spermatogonia counts significantly lower in undescended testes,
p<00005, Huff 2001
Adult dark spermatogonia
Boys < 1 yo
Gonocytes failed to disappear
Adult dark spermatogonia failed to appear
Indicates defect in germ cell maturation and
failure to establish an adequate adult stem
cell pool
Boys 2-9 yo
In undescended testes
Primary spermatocyte counts lower (p<0.0005)
failed to appear in undescended testes
Appeared in only 19% of contralat descended testes
Total germ cell counts lower (p<0.0005)
Adult dark spermatogonia lower (p<0.0005)
Indicates defect in onset of meiosis
Which normally occurs at 4-5 yo
Similar, less severe changes in contralateral
descended testes
Abnormal Epididymal Growth
de Miguel 2001
Decrease in differentiation of each segment
Decreased size of efferent and epididymal ducts
Decreased epithelial height, muscular wall height,
& lumen of epididymis
Cryptorchid epididymis grows more slowly during
transition to puberty, smaller in adult males
Suggests a primary congenital defect of testis
Implies surgical descent would not completely
reverse these changes

Increased risk of neoplasia
Cortes 2001: 1638 testicular samples from
1335 patients (23% bilateral, 77%
unilateral)
Mean age @ surgery 11.7 yo (0.1-18.9 yr)
1 invasive germ cell tumor
6 carcinoma in situ
1 Sertoli cell tumor

Neoplasia & cryptorchidism
3 neoplasms in intra-abdominal testes
4 neoplasms in boys with abnormal external
genitalia
2 neoplasms in boys with known abnormal
karyotype
Risk of neoplasia 5% with intraabdominal
testes, abnormal external genitalia or
abnormal karyotype (Cortes 2001)
Issues
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
Azospermia
Increased risk for neoplasia
Treatments
Medical/hormonal
Surgical

Treatments
Hormonal
hCG
GnRH
hMG
Combined (hCG & GnRH)
Surgical
Hormonal Therapy
hCG since 1930
GnRH since 1974 (IM) and 1975
(intranasal) (Europe)
Variable rates of success
hCG 0-55%
GnRH 9-78%


Confounding Variables in Data
Inclusion/exclusion of retractile testes
Variable ages of treatment
Randomized or not
Different dose regimens and durations
Original testicular position not documented
in all studies
Small patient numbers
hCG vs GnRH: multicenter trial
330 boys (?ages)
Randomized to
hCG 100 IU/kg IM twice weekly x 3 wk
GnRH 200 ug intranasal TID x 28 d
Placebo intranasal TID x 28 d
Success if both testes located at bottom of
scrotum after treatment
Placebo GnRH hCG
Not palp 12
6 1
8
2
8
2 1
Inguinal 86
5 69 1 1
70
4 46 8 2
70
2 31
Suprascrotal 6
14 1 3
21
2 5 4 6
11
6
High scrotal 12
1 3
15
1 5 4 6
7
1 15 5 2
Scrotal
1 2 3 5

1 12 4 7

3 17 6 5
Changes in position in boys with bilateral cryptorchidism after
treatment. Christiansen 1992
0
5
10
15
20
25
%
Placebo GnRH hCG
Bilateral
Unilateral
Rates of descent of the undescented testes following treatment.
Christiansen 1992.
Bilateral: p=0.0016
Unilateral: p=0.013
A review & meta-analysis of
hormonal treatment of
cryptorchidism (Pyorala 1995)
Reports from 1958-1990, in English
Primary treatment with GnRH or hCG
Excluded articles not documenting final
testicular position
Durations of treatment
GnRH 1 day 4 wk
hCG 1 wk 12 mo

Review & meta-analysis
33 studies including 3282 boys, 4524 undescended
testes
RCTs (n=11) included 872 boys, 1174
undescended testes
Meta-analysis only on RCTs that compared GnRH
vs placebo (n=9 trials)
Risk ratio for descent after GnRH 3.21 (1.83-5.64)
(p<0.001)
4 trials excluded retractile testes, risk ratio 2.57 (1.39-
4.74) (p<0.01)
0
5
10
15
20
25
%
Placebo
hCG
GnRH
Mean success rate (%) for treatment in combined RCTs comparing
hGC and GnRH with placebo. Pyorala 1995
# Trials 9 2 11

Testes 472 148 554
0
2
4
6
8
10
12
14
16
18
20
%
Placebo
hCG
GnRH
Mean success rate (%) for treatment in RCTs exluding retractile testes, comparing
hGC and GnRH with placebo. Pyorala 1995
# Trials 4 2 5

Testes 308 148 335
0
10
20
30
40
50
60
%
Abdominal
Inguinal
Prescrotal
High srotal
Mean success rates (%) by original location, includes both RCTs and
nonRCTs after GnRH and hCG. Pyorala 1995
# trials 17 21 14 4

# testes 907 1430 295 67
0
5
10
15
20
25
%
<4yo >4yo
Placebo
Homone
Mean success rates (%) of hormonal treatment (GnRH or hCG) in combined
RCTs in boys under 4 yo vs boys > 4 yo. Pyorala 1995 p=NS
# trials 2 2 3 4

# testes 48 49 167 267
Long term outcomes
5/11 randomized GnRH trials
24% (13-35%) ascended/relapsed
Conclusions:
GnRH more effective than placebo
hCG seems effective, but not as much data
Combined GnRH and hCG
Giannopoulous 2001
2467 boys with 2962 cryptorchid or gliding
testes
GnRH nasal spray 1.2 ug QD x 4 wk
hCG 5 doses (by age) at 2 d intervals
59% in scrotum after combined rx

4 different regimes
Bertelloni 2001
155 boys 10-48 mo with unilateral inguinal
testis
1. hCG 500 IU/wk (<2yo), 1000 IU/wk
(>2yo)
2. hCG as in 1 + hMG 75 IU/wk x 6 wk
3. GnRH 1200 ug/d x 28 d
4. GnRH as in 3, + hCG 1500 IU/wk x 3 wk
Bertelloni 2001 cont.
Overall success rate 19.3% (30/155)
No significant differences between regimes
Relapse 23.3% (7/30)
No significant difference between regimes
When to treat?
Hamza 2001
As spontaneous testicular descent closely
related to postnatal LH and T surges,
In term boys, 4 mo
In premies, 6 mo

Impact of age on treatment
success
Job 1982: success with hCG twice as high
in 3-4 yo than in boys < 3 yo
Hagberg 1982: highest success with GnRH
in 2-5 yo
De Muinck Keizer-Schrama 1986: most
success with GnRH in 5-12 yo
Pyorala 1995: no significant differences < 4
yo vs > 4 yo
When to operate?

Lee 2002
Inverse correlation between age at surgery
and T
Inverse correlation between body wt and T
Direct correlation between T and sperm
density, motility, morphology
Indicates direct relationship between
spermiogenesis and T in cryptorchid men
No differences in mean free T, T, LH between pts
and controls
No differences in time to conception in fertile
cryptorchid men vs controls
Suggests that orchidopexy later in childhood assoc
with subclinically depressed Leydig cell function
May result in subotpimal hormonal milieu for
adult reproduction
Is further treatment after surgery
indicated?
Subfertility correlates with reduced total
germ cell counts
Defects in germ cell maturation associated
with blunting of normal surges LH/FSH
Prepubertal treatment with GnRH could
theoretically trigger normal germ cell
maturation & proliferation
Hormonal treatment for
subfertility of cryptorchidism
Huff 2001
12 boys (7 mo 12 yo) with cryptorchidism
& poor prognosis for fertility (<0.21 germ
cells/tubule)
Treated with Naferelin 200 ug biweekly x 6
mo after orchidopexy
Biopsy 5 mo after Naferelin completed (2-
14 yo)
Improvement if 2
nd
bx > 1 category
Hormonal treatment for
subfertility of cryptorchidism
Huff 2001
8/12 (67%) showed improvement in total germ
cell counts in one or both testes
No significant change if patients
Had no germ cells initially
Were older at treatment
8/18 (44%) undescended testes improved
5/6 (83%) contralateral descended testes improved
Naferelin induced improvement in 75% of patients
Erythropoietin and germ cells
Cortes 2001
2 boys (6 mo, 21 mo) with renal function
impairment
Epo 100 IU/kg SQ weekly x 3 mo before
orchidopexy for inguinal cryptorchidism
# spermatogonia unusually high (& normal)
compared to 698 controls
Possible mechanisms
Stimulation of T production
?direct on Leydig cells
Direct effect on germ cell proliferation and
antiapoptotic signalling by blocking p53-
gene mediated apoptosis (as seen in
erythropoiesis)
Clinical trial ongoing
Issues
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
Azospermia
Increased risk for neoplasia
Treatment
Medical/hormonal
Surgical