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10/04/2017 ErectileDysfunction:PracticeEssentials,Background,Anatomy

ErectileDysfunction
Updated:Oct11,2016
Author:EdwardDavidKim,MD,FACSChiefEditor:EdwardDavidKim,MD,FACSmore...

OVERVIEW

PracticeEssentials
TheNationalInstitutesofHealth(NIH)ConsensusDevelopmentConferenceonImpotence
(December79,1992)definedimpotenceas"maleerectiledysfunction,thatis,theinabilityto
achieveormaintainanerectionsufficientforsatisfactorysexualperformance."

Signsandsymptoms
ThefirststepinthemanagementofEDisathoroughhistorythatincludesthefollowing:

Sexualhistory
Medicalhistory
Psychosocialhistory

Aphysicalexaminationisnecessaryforeverypatient,emphasizingthegenitourinary,vascular,and
neurologicsystems.Afocusedexaminationentailsevaluationofthefollowing:

Bloodpressure
Peripheralpulses
Sensation
Statusofthegenitaliaandprostate
Sizeandtextureofthetestes
Presenceoftheepididymisandvasdeferens
Abnormalitiesofthepenis(eg,hypospadias,Peyronieplaques)

ThereisastrongcorrelationbetweenhypertensionandED.Thereisalsoacorrelationbetween
benignprostatichyperplasiaandED,thoughthecausalityisunclear.

SeePresentationformoredetail.

Diagnosis

LaboratorytestingforEDdependsoninformationgatheredduringtheinterviewitisnecessaryfor
mostpatients,althoughnotforall.Suchtestingmayincludethefollowing:

Evaluationofhormonalstatus(testosterone,serumhormonebindingglobulin,luteinizing
hormone[LH],prolactin,thyroidstimulatinghormone[TSH])NotethattheAmerican
CollegeofPhysicians(ACP)doesnotrecommendfororagainstroutineuseofhormonal
bloodtestsorhormonaltreatmentinEDpatients
Screeningbloodstudies(hemoglobinA 1c,serumchemistrypanel,lipidprofile)
Prostatespecificantigenlevels,ifthepatientisacandidateforprostatecancerscreening
(controversial)
Urinalysis

Functionalteststhatmaybehelpfulincludethefollowing:
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DirectinjectionofprostaglandinE1(PGE1alprostadil)intothecorporacavernosa(seethe
imagebelow)

AvasodilatorsuchasprostaglandinE1canbeinjectedintooneofthecorporacavernosa.Iftheblood
vesselsarecapableofdilating,astrongerectionshoulddevelopwithin5minutes.
ViewMediaGallery
BiothesiometryInfrequentlyindicated
NocturnalpeniletumescencetestingOncefrequentlyperformed,thisisrarelyusedin
currentpractice,thoughitcanbehelpfulwhenthediagnosisisindoubt
FormalneurologictestingNotneededinthevastmajorityofEDpatients,thoughitmay
offersomebenefittopatientswithahistoryofcentralnervoussystemproblems,peripheral
neuropathy,diabetes,orpenilesensorydeficit

Imagingstudiesarenotcommonlywarranted,exceptinsituationswherepelvictraumahasbeen
sustainedorsurgeryperformed.Modalitiesthatmaybeconsideredincludethefollowing:

Ultrasonographyofthepenis(toassessvascularfunctionwithinthepenis)
Ultrasonographyofthetestes(tohelpdiscloseabnormalitiesinthetestesandepididymides
rarelyindicated)
Transrectalultrasonography(todiscloseabnormalitiesintheprostateandpelvisthatmay
interferewitherectilefunction)
Angiography(inpatientswhoarepotentialcandidatesforvascularsurgery)

SeeWorkupformoredetail.

Management
TreatmentoptionsforEDincludethefollowing:

Sexualcounseling,ifnoorganiccausescanbefoundforthedysfunction
Oralmedications
Injected,implanted,ortopicallyappliedmedications
Externalvacuumandconstrictiondevices
Surgery

ManypatientswithEDalsohavecardiovasculardiseasethus,treatmentofEDinthesepatients
musttakecardiovascularrisksintoaccount.

AccordingtoAmericanUrologicalAssociation(AUA)guidelines,oralphosphodiesterasetype5
(PDE5)inhibitorsarefirstlinetherapyunlesscontraindicated.[1]Agentsincludethefollowing:

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Sildenafil
Vardenafil
Tadalafil
Avanafil

InpatientswithEDrefractorytooralPDE5inhibitors,oneoftheseagentscanbecombinedwithan
injectionofPGE1.[2]

Inaprospective,multicenter,singlearmedstudyofEDpatientswhoexhibitedasuboptimal
responsetoPDE5inhibitors,theinvestigatorsfoundthatpercutaneousimplantationofzotarolimus
elutingstentsinfocalatheroscleroticlesionswasbothsafeandfeasibleandwasassociatedwith
clinicallymeaningfulimprovementonsubjectiveandobjectivemeasuresoferectilefunction.[3]

Hormonereplacementmaybenefitmenwithseverehypogonadismandmaypossiblybeusefulas
adjunctivetherapywhenothertreatmentsareunsuccessful.Replacementandrogensareavailable
inoral(rarelyused),injectable,gel,andtransdermalpreparations.

Intracavernosalinjectiontherapymaybeconsideredandisalmostalwayseffectiveifthe
vasculaturewithinthecorporacavernosaishealthy.Agentsusedincludethefollowing:

Alprostadil(mostcommon)
Phentolamine
Papaverine

TheMedicatedUrethralSystemforErections(MUSE)involvestheformulationofalprostadil
(PGE1)intoasmallintraurethralsuppositorythatcanbeinsertedintotheurethra.Thismaybe
usefulformenwhodonotwanttouseselfinjectionsorthoseinwhomoralmedicationshave
failed.

Externaldevicesthatmaybeusedincludethefollowing:

Vacuumdevicestodrawbloodintothepenis
Constrictiondevicesplacedatthebaseofthepenistomaintainerection

SelectedpatientswithEDarecandidatesforsurgicaltreatment.Procedurestobeconsidered
includethefollowing:

Revascularization(rarelyindicated)
Surgicaleliminationofvenousoutflow(rarelyindicated)
Placementofpenileimplant(semirigidormalleablerodimplant,fullyinflatableimplant,or
selfcontainedinflatableunitaryimplant)Oncetheonlyeffectivetherapyformenwith
organicED,thisisthelastoptionconsideredincurrentpractice

SuggestedmeasuresforpreventingEDincludethefollowing:

Optimalmanagementofdiabetes,heartdisease,andhypertension
Lifestylemodificationstoimprovevascularfunction(eg,notsmoking,maintainingidealbody
weight,andengaginginregularexercise)

SeeTreatmentandMedicationformoredetail.

Background
Erectiledysfunction(ED)affects50%ofmenolderthan40years,[4]exertingsubstantialeffectson
qualityoflife.[5]Thiscommonproblemiscomplexandinvolvesmultiplepathways.Penile
erectionsareproducedbyanintegrationofphysiologicprocessesinvolvingthecentralnervous,
peripheralnervous,hormonal,andvascularsystems.Anyabnormalityinthesesystems,whether

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frommedicationordisease,hasasignificantimpactontheabilitytodevelopandsustainan
erection,ejaculate,andexperienceorgasm.

AcommonandimportantcauseofEDisvasculogenic.ManymenwithEDhavecomorbid
conditionssuchashyperlipidemia,hypercholesterolemia,tobaccoabuse,diabetesmellitus,or
coronaryarterydisease(CAD).[6]ThePrincetonIIIConsensusrecommendsscreeningmenwho
presentwithEDforcardiovascularriskfactorsEDmaybetheearliestpresentationof
atherosclerosisandvasculardisease.[7]

Additionally,thephysiologicprocessesinvolvingerectionsbeginatthegeneticlevel.Certaingenes
becomeactivatedatcriticaltimestoproduceproteinsvitaltosustainingthispathway.Some
researchershavefocusedonidentifyingparticulargenesthatplacemenatriskforED.Atpresent,
thesestudiesarelimitedtoanimalmodels,andlittlesuccesshasbeenreportedtodate.[4]
Nevertheless,thisresearchhasgivenrisetomanynewtreatmenttargetsandabetter
understandingoftheentireprocess.

ThefirststepintreatingthepatientwithEDistotakeathoroughsexual,medical,and
psychosocialhistory.Questionnairesareavailabletoassistcliniciansinobtainingimportantpatient
data.(SeePresentation.)Successfultreatmentofsexualdysfunctionhasbeendemonstratedto
improvesexualintimacyandsatisfaction,improvesexualaspectsofqualityoflife,improveoverall
qualityoflife,andrelievesymptomsofdepression.(SeeTreatment.)

Theavailabilityofphosphodiesterase5(PDE5)inhibitorssildenafil,vardenafil,tadalafil,and
avanafilhasfundamentallyalteredthemedicalmanagementofED.Inaddition,directto
consumermarketingoftheseagentsoverthelast15yearshasincreasedthegeneralpublics
awarenessofEDasamedicalconditionwithunderlyingcausesandeffectivetreatments.

Unfortunately,somepatientsmayhaveanoverlysimplifiedunderstandingoftheroleofPDE5
inhibitorsinEDmanagement.Suchpatientsmaynotexpectorbewillingtoundergoalong
evaluationandtestingprocesstoobtainabetterunderstandingoftheirsexualproblem,andthey
maybelesslikelytoinvolvetheirpartnerindiscussingtheirsexualrelationshipwiththephysician.
Theymayexpecttoobtainmedicationsthroughaphonecalltotheirdoctororevenoverthe
Internet,withminimalornophysiciancontactatall.

Insuchcases,thephysiciansrolemayhavetoincludeeffortstoeducatepatientsaboutrealistic
sexualexpectations(seePatientEducation).Theseeffortscanhelppreventthemisuseoroveruse
oftheseremarkablemedications.

AlthoughthisarticlefocusesprimarilyonthemalewithED,itisessentialtorememberthatthe
sexualpartnerplaysanintegralroleintreatment.Ifsuccessfulandeffectivemanagementistobe
achieved,evaluationanddiscussionofanyinterventionmustincludebothpartners.

Diagnosticcriteria(DSM5)forerectiledisorder
TheDiagnosticandStatisticalManualofMentalDisorders,FifthEdition(DSM5),classifieserectile
disorderasbelongingtoagroupofsexualdysfunctiondisorderstypicallycharacterizedbya
clinicallysignificantinabilitytorespondsexuallyortoexperiencesexualpleasure.[8]

Sexualfunctioninginvolvesacomplexinteractionamongbiologic,sociocultural,andpsychological
factors,andthecomplexityofthisinteractionmakesitdifficulttoascertaintheclinicaletiologyof
sexualdysfunction.Beforeanydiagnosisofsexualdysfunctionismade,problemsthatare
explainedbyanonsexualmentaldisorderorotherstressorsmustfirstbeaddressed.Thus,in
additiontothecriteriaforerectiledisorder,thefollowingmustbeconsidered:

Partnerfactors(eg,partnersexualproblemsorhealthissues)
Relationshipfactors(eg,communicationproblems,differinglevelsofdesireforsexual
activity,orpartnerviolence)

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Individualvulnerabilityfactors(eg,historyofsexualoremotionalabuse,existingpsychiatric
conditionssuchasdepression,orstressorssuchasjobloss)
Culturalorreligiousfactors(eg,inhibitionsorconflictedattitudesregardingsexuality)
Medicalfactors(eg,anexistingmedicalconditionortheeffectsofdrugsormedications)

ThespecificDSM5criteriaforerectiledisorderareasfollows[8]:

Inalmostallorall(75100%)sexualactivity,theexperienceofatleastoneofthefollowing
three3symptoms:(1)markeddifficultyinobtaininganerectionduringsexualactivity,(2)
markeddifficultyinmaintaininganerectionuntilthecompletionofsexualactivity,or(3)
markeddecreaseinerectilerigidity
Thesymptomsabovehavepersistedforapproximately6months
Thesymptomsabovecausesignificantdistresstotheindividual
Thedysfunctioncannotbebetterexplainedbynonsexualmentaldisorder,amedical
condition,theeffectsofadrugormedication,orsevererelationshipdistressorother
significantstressors

Theseverityofdelayedejaculationisclassifiedasmild,moderateorsevereonthebasisofthe
levelofdistressthepatientexhibitsoverthesymptoms.Thedurationofthedysfunctionisspecified
asfollows:

Lifelong(presentsincefirstsexualexperience)
Acquired(developingafteraperiodofrelativenormalsexualfunctioning)

Inaddition,thecontextinwhichthedysfunctionoccursisspecifiedasfollows:

Generalized(notlimitedtocertaintypesofstimulation,situations,orpartners)
Situational(limitedtospecifictypesofstimulation,situations,orpartners)

Lifelongerectiledisorderisassociatedwithpsychologicalfactors,whereasacquirederectile
disorderismoreoftenrelatedtobiologicfactors.Distressassociatedwitherectiledisorderislower
amongoldermenthanamongyoungermen.

Anatomy
AnunderstandingofpenileanatomyisfundamentaltomanagementofED.[2]Thecommonpenile
artery,whichderivesfromtheinternalpudendalartery,branchesintothedorsal,bulbourethral,and
cavernousarteries(seetheimagebelow).

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Vascularanatomyofthepenis.
ViewMediaGallery

Thedorsalarteryprovidesforengorgementoftheglansduringerection,whereasthebulbourethral
arterysuppliesthebulbandthecorpusspongiosum.Thecavernousarteryeffectstumescenceof
thecorpuscavernosumandthusisprincipallyresponsibleforerection.Thecavernousarterygives
offmanyhelicinearteries,whichsupplythetrabecularerectiletissueandthesinusoids.These
helicinearteriesarecontractedandtortuousintheflaccidstateandbecomedilatedandstraight
duringerection.[9]

Venousdrainageofthecorporaoriginatesintinyvenulesthatleadfromtheperipheralsinusoids
immediatelybeneaththetunicaalbuginea.Thesevenulestravelinthetrabeculaebetweenthe
tunicaandtheperipheralsinusoidstoformthesubtunicalvenousplexusbeforeexitingasthe
emissaryveins(seetheimagebelow).[9]

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Theseimagesdepictpenileanatomy.Notethesinusoidalmakeupofthecorporaandthickfascia(ie,Buck
fascia)thatcoversthecorporacavernosa.Themajorbloodvesselstothecorporacavernosaenterthrough
tributariesfromthemainvesselsrunningalongthedorsumofthepenis.
ViewMediaGallery

Sexualbehaviorinvolvestheparticipationofautonomicandsomaticnervesandtheintegrationof
numerousspinalandsupraspinalsitesinthecentralnervoussystem(CNS).Thepenileportionof
theprocessthatleadstoerectionsrepresentsonlyasinglecomponent.

Thehypothalamicandlimbicpathwaysplayanimportantroleintheintegrationandcontrolof
reproductiveandsexualfunctions.Themedialpreopticcenter,paraventricularnucleus,and
anteriorhypothalamicregionsmodulateerectionsandcoordinateautonomiceventsassociated
withsexualresponses.

Afferentinformationisassessedintheforebrainandrelayedtothehypothalamus.Theefferent
pathwaysfromthehypothalamusenterthemedialforebrainbundleandprojectcaudallynearthe
lateralpartofthesubstantianigraintothemidbraintegmentalregion.

Severalpathwayshavebeendescribedtoexplainhowinformationtravelsfromthehypothalamus
tothesacralautonomiccenters.Onepathwaytravelsfromthedorsomedialhypothalamusthrough
thedorsalandcentralgraymatter,descendstothelocusceruleus,andprojectsventrallyinthe
mesencephalicreticularformation.Inputfromthebrainisconveyedthroughthedorsalspinal
columnstothethoracolumbarandsacralautonomicnuclei.

Theprimarynervefiberstothepenisarefromthedorsalnerveofthepenis,abranchofthe
pudendalnerve.Thecavernosalnervesareapartoftheautonomicnervoussystemand
incorporatebothsympatheticandparasympatheticfibers.Theytravelposterolaterallyalongthe
prostateandenterthecorporacavernosaandcorpusspongiosumtoregulatebloodflowduring
erectionanddetumescence.Thedorsalsomaticnervesarealsobranchesofthepudendalnerves.
Theyareprimarilyresponsibleforpenilesensation.[10]

Pathophysiology
Factorsmediatingcontractionandrelaxation
Thedegreeofcontractionofcavernosalsmoothmuscledeterminesthefunctionalstateofthe
penis.[11]Thebalancebetweencontractionandrelaxationiscontrolledbycentralandperipheral
factorsthatinvolvemanytransmittersandtransmittersystems.

Thenervesandendotheliumofsinusoidsandvesselsinthepenisproduceandrelease
transmittersandmodulatorsthatcontrolthecontractilestateofcorporalsmoothmuscles.Although
themembranereceptorsplayanimportantrole,downstreamsignalingpathwaysarealso
important.TheRhoARhokinasepathwayisinvolvedintheregulationofcavernosalsmooth
musclecontraction.[12]

Factorsthatmediatecontractioninthepenisincludenoradrenaline,endothelin1,neuropeptideY,
prostanoids,angiotensinII,andothersnotyetidentified.Factorsthatmediaterelaxationinclude
acetylcholine,nitricoxide(NO),vasoactiveintestinalpolypeptide,pituitaryadenylylcyclase
activatingpeptide,calcitoningenerelatedpeptide,adrenomedullin,adenosinetriphosphate,and
adenosineprostanoids.

Nitricoxidepathway

TheNOpathwayisofcriticalimportanceinthephysiologicinductionoferections.Thedrugs
currentlyusedtotreatEDweredevelopedasaresultofexperimentalandclinicalworkshowing

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thatNOreleasedfromnerveendingsrelaxesthevascularandcorporalsmoothmusclecellsofthe
penilearteriesandtrabeculae,resultinginanerection.

NOisproducedbytheenzymeNOsynthase(NOS).[13]NOSplaysmanyroles,rangingfrom
homeostasistoimmunesystemregulation.Todate,3subtypeshavebeenidentified:nNOS,iNOS,
andeNOS,whichareproducedbythegenesNOS1,NOS2,andNOS3,respectively.This
nomenclatureisderivedfromthesourcesoftheoriginalisolates:neuronaltissue(nNOS),
immunoactivatedmacrophagecelllines(iNOS),andvascularendothelium(eNOS).Thesubtypes
arenot,however,limitedtothetissuesfromwhichtheywerefirstisolated.

AllNOSsubtypesproduceNO,buteachmayplayadifferentbiologicroleinvarioustissues.nNOS
andeNOSareconsideredconstitutiveformsbecausetheysharebiochemicalfeatures:Theyare
calciumdependent,theyrequirecalmodulinandreducednicotinamideadeninedinucleotide
phosphateforcatalyticactivity,andtheyarecompetitivelyinhibitedbyargininederivatives.nNOS
isinvolvedintheregulationofneurotransmission,andeNOSisinvolvedintheregulationofblood
flow.

iNOSisconsideredaninducibleformbecauseitiscalciumindependent.iNOSisinducedbythe
inflammatoryprocess,inwhichitparticipatesintheproductionofnitrogenousamines.This
subtypehasbeenshowntobeinvolvedincarcinogenesis,leadingtotransitionalcellcarcinoma.

Insidethecell,NOScatalyzestheoxidationofLargininetoNOandLcitrulline.Endogenous
blockersofthispathwayhavebeenidentified.ThegaseousNOthatisproducedactsasa
neurotransmitterorparacrinemessenger.Itsbiologichalflifeisonly5seconds.NOmayactwithin
thecellordiffuseandinteractwithnearbytargetcells.Inthecorporacavernosa,NOactivates
guanylatecyclase,whichinturnincreasescyclicguanosinemonophosphate(cGMP).Relaxation
ofvascularsmoothmusclesbycGMPleadstovasodilationandincreasedbloodflow.

AlterationofNOlevelsisthefocusofseveralapproachestothetreatmentofED.Inhibitorsof
phosphodiesterase,whichprimarilyhydrolyzecGMPtype5,providedthebasisforthe
developmentofthePDE5inhibitors.ChenetaladministeredoralLarginineandreported
subjectiveimprovementin50menwithED.[14]Thesesupplementsarereadilyavailable
commercially.Reportedadverseeffectsincludenausea,diarrhea,headache,flushing,numbness,
andhypotension.

IncreasingevidenceindicatesthatNOactscentrallytomodulatesexualbehaviorandtoexertits
effectsonthepenis.NOisthoughttoactinthemedialpreopticareaandtheparaventricular
nucleus.InjectionofNOSinhibitorspreventstheerectileresponseinratsthathavebeengiven
erectogenicagents.

Normalerectileprocess
Erectionsoccurinresponsetotactile,olfactory,andvisualstimuli.Theabilitytoachieveand
maintainafullerectiondependsnotonlyonthepenileportionoftheprocessbutalsoonthestatus
oftheperipheralnerves,theintegrityofthevascularsupply,andbiochemicaleventswithinthe
corpora.Theautonomicnervoussystemisinvolvedinerection,orgasm,andtumescence.The
parasympatheticnervoussystemisprimarilyinvolvedinsustainingandmaintaininganerection,
whichisderivedfromS2S4nerveroots.

Sexualstimulationcausesthereleaseofneurotransmittersfromcavernosalnerveendingsand
relaxationfactorsfromendothelialcellsliningthesinusoids.NOSproducesNOfromLarginine,
andthis,inturn,producesothermusclerelaxingchemicals,suchascGMPandcyclicadenosine
monophosphate(cAMP),whichworkviacalciumchannelandproteinkinasemechanisms(seethe
imagebelow).Thisresultsintherelaxationofsmoothmuscleinthearteriesandarteriolesthat
supplytheerectiletissue,producingadramaticincreaseinpenilebloodflow.

Relaxationofthesinusoidalsmoothmuscleincreasesitscompliance,facilitatingrapidfillingand
expansion.Thevenulesbeneaththerigidtunicaalbugineaarecompressed,resultinginneartotal
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occlusionofvenousoutflow.Theseeventsproduceanerectionwithanintracavernosalpressureof
100mmHg.

Additionalsexualstimulationinitiatesthebulbocavernousreflex.Theischiocavernousmuscles
forcefullycompressthebaseofthebloodfilledcorporacavernosa,andthepenisreachesfull
erectionandhardnesswhenintracavernosalpressurereaches200mmHgormore.Atthis
pressure,bothinflowandoutflowofbloodtemporarilycease.

Detumescenceresultsfromcessationofneurotransmitterrelease,breakdownofsecond
messengersbyphosphodiesterase,andsympatheticnerveexcitationduringejaculation.
Contractionofthetrabecularsmoothmusclereopensthevenouschannels,allowingthebloodto
beexpelledandtherebyresultinginflaccidity.

Roleoftestosterone
BothEDandlowtestosterone(hypogonadism)increasewithage.Theincidenceofthelatteris
40%inmenaged45yearsandolder.[15]Testosteroneisknowntobeimportantinmood,
cognition,vitality,bonehealth,andmuscleandfatcomposition.Italsoplaysakeyroleinsexual
dysfunction(eg,lowlibido,poorerectionquality,ejaculatoryororgasmicdysfunction,reduced
spontaneouserections,orreducedsexualactivity).[16]

TheassociationbetweenlowtestosteroneandEDisnotentirelyclear.Althoughthese2processes
certainlyoverlapinsomeinstances,theyaredistinctentities.Some221%ofmenhaveboth
hypogonadismandEDhowever,itisuncleartowhatdegreetreatingtheformerwillimprove
erectilefunction.[17]About3540%ofmenwithlowtestosteroneseeanimprovementintheir
erectionswithtestosteronereplacementhowever,almost65%ofthesemenseenoimprovement.
[15]

OnestudyexaminedtheroleoftestosteronesupplementationinhypogonadalmenwithED.These
menwereconsiderednonresponderstosildenafil,andtheirerectionsweremonitoredbyassessing
nocturnalpeniletumescence(NPT).Afterthesemenweregiventestosteronetransdermallyfor6
months,thenumberofNPTsincreased,asdidthemaximumrigiditywithsildenafil.[18]Thisstudy
suggeststhatacertainleveloftestosteronemaybenecessaryforPDE5inhibitorstofunction
properly.

Inarandomizeddoubleblind,parallel,placebocontrolledtrial,sildenafilplustestosteronewasnot
superiortosildenafilplusplaceboinimprovingerectilefunctioninmenwithEDandlow
testosteronelevels.[19]Theobjectiveofthestudywastodeterminewhethertheadditionof
testosteronetosildenafiltherapyimproveserectileresponseinmenwithEDandlowtestosterone
levels.

However,incontrast,arecentsystematicreviewofpublishedstudies,theauthorsconcludedthat
overall,theadditionoftestosteronetoPDE5inhibitorsmightbenefitpatientswithEDassociated
withtestosteronelevelsoflessthan300ng/dL(10.4nmol/L)whofailedmonotherapy.[20]A
limitationofexistingstudiesaretheirheterogeneousnatureandmethodologicaldrawbacks.

Themechanismsbywhichtestosteroneplaysaroleinerectilefunctionarenotcompletely
understood.Astudyevaluatingtheeffectoftestosteroneonerectionsinsurgicallycastrated
rabbitsandcontrolanimals,inwhichtherabbitsintracavernosalpressureswerecomparedafter
cavernosalnervestimulation,determinedthatcastratedrabbitshadmuchlowerpressuresafter
stimulationthancontrolrabbitsdid.[21]Notably,thepressuresincreasedwhencastratedrabbits
receivedexogenoustestosteronereplacement.

Anotherstudycomparedtheresponseofsurgicallyandmedicallycastratedrabbitstovardenafil
withthatofcontrolrabbits.[22]Castratedrabbitsdidnotrespondtovardenafil,whereas

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noncastratedrabbitsdidrespondappropriately.Thisresultsuggeststhataminimumamountof
testosteroneisnecessaryforPDE5inhibitorstoproduceanerection.

Anotherstudyfoundthatcastratedratshaderectionsifgiventestosteronealoneor
dihydrotestosterone(DHT)and5alphareductaseinhibitorsbutnotifgiventestosteroneand5
alphareductaseinhibitors.[23]ThisfindingsuggeststhatDHTistheactivecomponentandis
necessaryatacertainlevelforratstohaveanerection.

ThisstudyalsomeasuredintracavernosalpressuretomonitorerectionsandNOSactivityinthe
penilecytosol.[23]NOlevelscorrelatedwithintracavernosalpressure,whichsuggeststhat
testosteroneandDHTactthroughNOS.TestosteroneandDHTmayactatthegenomiclevelto
stimulateproductionofNOS.

ItappearsthattestosteronehasNOSindependentpathwaysaswell.Inonestudy,castratedrats
wereimplantedwithtestosteronepelletsandthendividedintoagroupthatreceivedanNOS
inhibitor(LnitroLargininemethylester[LNAME])andacontrolgroupthatreceivednoenzyme.
[24] ThecastratedratsthatweregiventestosteronepelletsandLNAMEstillhadpartialerections,a
resultsuggestingthepresenceofapathwayindependentofNOSactivity.

Etiology
EDusuallyhasamultifactorialetiology.Organic,physiologic,endocrine,andpsychogenicfactors
areinvolvedintheabilitytoobtainandmaintainerections.Ingeneral,EDisdividedinto2broad
categories,organicandpsychogenic.AlthoughmostEDwasonceattributedtopsychological
factors,purepsychogenicEDisinfactuncommonhowever,manymenwithorganicetiologies
mayalsohaveanassociatedpsychogeniccomponent.

ConditionsthatmaybeassociatedwithEDincludediabetes,[25,26,27]hypertension,[28],and
CAD,aswellasneurologicdisorders,endocrinopathies,benignprostatichyperplasia,[29],sleep
apnea[30],COPD[31],anddepression(seeTable1below).[32,33,34,35]Infact,almostany
diseasemayaffecterectilefunctionbyalteringthenervous,vascular,orhormonalsystems.
Variousdiseasesmayproducechangesinthesmoothmuscletissueofthecorporacavernosaor
influencethepatientspsychologicalmoodandbehavior.

Table1.DiseasesandConditionsAssociatedWithErectileDysfunction(OpenTableinanew
window)

Vascularcauses Atherosclerosis

Peripheralvasculardisease

Myocardialinfarction

Arterialhypertension

Vascularinjuryfromradiationtherapy

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Vascularinjuryfromprostatecancertreatment

Bloodvesselandnervetrauma(eg,fromlongdistancebicycleriding)

Medicationsfortreatmentofvasculardisease

Diabetesmellitus

Scleroderma

Renalfailure

Livercirrhosis

Systemicdiseases
Idiopathichemochromatosis

Cancerandcancertreatment

Dyslipidemia

Hypertension

Neurologiccauses Epilepsy

Stroke

Multiplesclerosis

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GuillainBarrsyndrome

Alzheimerdisease

Trauma

Chronicobstructivepulmonarydisease

Respiratorydisease
Sleepapnea

Hyperthyroidism

Hypothyroidism

Endocrineconditions
Hypogonadism

Diabetes

Peyroniedisease

Epispadias
Penileconditions

Priapism

Psychiatricconditions Depression

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Widowersyndrome

Performanceanxiety

Posttraumaticstressdisorder

Malnutrition

Nutritionalstates
Zincdeficiency

Sicklecellanemia

Hematologic
diseases Leukemias

Surgicalprocedures Brainandspinalcordprocedures

Retroperitonealorpelviclymphnodedissection

Aortoiliacoraortofemoralbypass

Abdominalperinealresection

Proctocolectomy

Transurethralresectionoftheprostate

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Radicalprostatectomy

Cryosurgeryoftheprostate

Cystectomy

Antihypertensives

Antidepressants

Antipsychotics

Medications
Antiulceragents(eg,cimetidine)

5Alphareductaseinhibitors(eg,finasterideanddutasteride)

Cholesterolloweringagents

Conditionsassociatedwithreducednerveandendotheliumfunction(eg,aging,hypertension,
smoking,hypercholesterolemia,anddiabetes)alterthebalancebetweencontractionand
relaxationfactors(seePathophysiology).Theseconditionscausecirculatoryandstructural
changesinpeniletissues,resultinginarterialinsufficiencyanddefectivesmoothmusclerelaxation.
Insomepatients,sexualdysfunctionmaybethepresentingsymptomofthesedisorders.

Giventhemultiplicityofpossibleetiologicfactors,itmaybedifficulttodeterminehowmuchany
givenfactoriscontributingtotheproblem.Athoroughevaluationisnecessaryforcorrect
identificationofthespecificcauseorcausesinanygivenindividual.

Vasculardiseases
Vasculardiseasesaccountfornearly50%ofallcasesofEDinmenolderthan50years.These
diseasesincludeatherosclerosis,peripheralvasculardisease,myocardialinfarction(MI),and
arterialhypertension.

Vasculardamagemayresultfromradiationtherapytothepelvisandprostateinthetreatmentof
prostatecancer.[36]Boththebloodvesselsandthenervestothepenismaybeaffected.Radiation
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damagetothecruraofthepenis,whicharehighlysusceptibletoradiationdamage,caninduce
ED.Dataindicatethat50%ofmenundergoingradiationtherapyloseerectilefunctionwithin5
yearsaftercompletingtherapyfortunately,somerespondtooneofthePDE5inhibitors.

Trauma
TraumatothepelvicbloodvesselsornervescanalsoleadresultinED.Bicycleridingforlong
periodshasbeenimplicatedasanetiologicfactordirectcompressionoftheperineumbythe
bicycleseatmaycausevascularandnerveinjury.[37]Ontheotherhand,bicyclingforlessthan3
hoursperweekmaybesomewhatprotectiveagainstED.[37]Someofthenewerbicycleseats
havebeendesignedtodiminishpressureontheperineum.[37,38]

Diabetesmellitus

DiabetesisawellrecognizedriskfactorforED,withapproximately50%ofdiabeticmen
experiencingthiscondition.TheetiologyofEDindiabeticmenprobablyinvolvesbothvascularand
neurogenicmechanisms.Evidenceindicatesthatestablishinggoodglycemiccontrolcanminimize
thisrisk.

Abnormalcholesterollevels
TheMassachusettsMaleAgingStudy(MMAS)documentedaninversecorrelationbetweenED
riskandhighdensitylipoprotein(HDL)cholesterollevelsbutdidnotidentifyanyeffectfrom
elevatedtotalcholesterollevels.[15]Anotherstudyinvolvingmalesubjectsaged4554yearsfound
acorrelationwithabnormalHDLcholesterollevelsbutalsofoundacorrelationwithelevatedtotal
cholesterollevels.TheMMASincludedapreponderanceofoldermen.

Respiratorydiseases

MenwithsleepdisorderscommonlyexperienceED.[39]Herutietalrecommendedthatinadult
malepatients,EDshouldbeconsideredwhenasleepdisorderespeciallysleepapneasyndrome
issuspected,andviceversa.[40]

Endocrinedisorders

Hypogonadismthatresultsinlowtestosteronelevelsadverselyaffectslibidoanderectilefunction.
HypothyroidismisaveryrarecauseofED.

Penileconditions

Peyroniediseasemayresultinfibrosisandcurvatureofthepenis.MenwithseverePeyronie
diseasemayhaveenoughscartissueinthecorporatoimpedebloodflow.

Mentalhealthdisorders

Mentalhealthdisorders,particularlydepression,arelikelytoaffectsexualperformance.The
MMASdataindicateanoddsratioof1.82formenwithdepression.Otherassociatedfactors,both
cognitiveandbehavioral,maycontribute.Inaddition,EDalonecaninducedepression.

Cosgroveetalreportedahigherrateofsexualdysfunctioninveteranswithposttraumaticstress
disorder(PTSD)thaninveteranswhodidnotdevelopthisproblem.[41]Thedomainsonthe
InternationalIndexofErectileFunction(IIEF)questionnairethatdemonstratedthemostchange
includedoverallsexualsatisfactionanderectilefunction.[42,43]MenwithPTSDshouldbe
evaluatedandtreatediftheyhavesexualdysfunction.
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Prostatesurgery

ProstatesurgeryforbenignprostatichyperplasiahasbeendocumentedtobeassociatedwithED
in1020%ofmen.Thisassociationisthoughttoberelatedtonervedamagefromcauterization.
Newerprocedures(eg,microwave,laser,orradiofrequencyablation)haverarelybeenassociated
withED.

RadicalprostatectomyforthetreatmentofprostatecancerposesasignificantriskofED.Anumber
offactorsareassociatedwiththechanceofpreservingerectilefunction.Ifbothnervesthatcourse
onthelateraledgesoftheprostatecanbesaved,thechanceofmaintainingerectilefunctionis
reasonable.Theoddsdependontheageofthepatient.Menyoungerthan60yearshavea75
80%chanceofpreservingpotency,butmenolderthan70yearshaveonlya1015%chance.

TheCanceroftheProstateStrategicUrologicResearchEndeavor(CaPSURE)study,designedto
determinewhetheranindividualmanssexualoutcomesaftermostcommontreatmentsforearly
stageprostatecancercouldbeaccuratelypredictedonthebasisofbaselinecharacteristicsand
treatmentplans,foundthat2yearsaftertreatment,177(35%)of511menwhounderwent
prostatectomyreportedtheabilitytoattainfunctionalerectionssuitableforintercourse.[44]

Incomparison,37%ofmenwhohadreceivedexternalradiotherapyastheirprimarytherapy
reportedtheabilitytoattainfunctionalerectionssuitableforintercourse,alongwith43%ofmen
whohadreceivedbrachytherapyasprimarytreatment.Pretreatmentsexualhealthrelatedquality
oflifescore,age,serumprostatespecificantigen(PSA)level,raceorethnicity,bodymassindex,
andintendedtreatmentdetailswereassociatedwithfunctionalerections2yearsaftertreatment.
[44]

Aftersurgery,oneoftheoralPDE5inhibitors(sildenafil,vardenafil,ortadalafil)isfrequentlyused
toassistintherecoveryoferectilefunction.Thebenefitofpenilerehabilitationtherapyisunder
investigation,butresultshavebeenmixed.[45,46]

Medications

EDisanadverseeffectofmanycommonlyprescribedmedications.Forexample,some
psychotropicdrugsandantihypertensiveagentsareassociatedwithED.Persistentposttreatment
EDisalistedadverseeffectofthe5alphareductaseinhibitorsfinasterideanddutasterideandof
alphablockers.

However,areviewofaUnitedKingdommedicalrecorddatabasefoundnoevidencethattheuseof
5alphareductaseinhibitorsindependentlyincreasetheriskforED.In71,849menwithbenign
prostatichyperplasia(BPH),theriskofEDwasnotincreasedwiththeuseoffinasterideor
dutasterideonly(oddsratio[OR]0.94),ora5alphareductaseinhibitorplusanalphablocker(OR
0.92)comparedwithanalphablockeronly.Inaddition,theriskofEDwasnotincreasein12346
menprescribedfinasteride1mgforalopecia,comparedwithunexposedmenwithalopecia(OR
0.95).TheriskofEDdidincreasewithlongerdurationofBPH,regardlessofdrugexposure.[47]

Inactivity

Exerciseandlifestylemodificationsmayimproveerectilefunction.Weightlossmayhelpby
decreasinginflammation,increasingtestosterone,andimprovingselfesteem.Patientsshouldbe
educatedtoincreaseactivity,reduceweight,andstopsmoking,astheseeffortscanimproveor
restoreerectilefunctioninmenwithoutcomorbidities.Preciseglycemiccontrolindiabeticpatients
andpharmacologictreatmentofhypertensionmaybeimportantinpreventingorreducingsexual
dysfunction.[48]

Smoking

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Cigarettesmokinghasbeenshowntobeanindependentriskfactor.Instudiesevaluatingmore
than6000men,theriskofdevelopingEDincreasedbyafactorof1.5.

Epidemiology
UnitedStatesandinternationalstatistics
Sexualdysfunctionishighlyprevalentinmenandwomen.IntheMMAS,52%oftherespondents
reportedsomedegreeoferectiledifficulty.CompleteED,definedas(1)thetotalinabilitytoobtain
ormaintainanerectionduringsexualstimulationand(2)theabsenceofnocturnalerections,
occurredin10%oftherespondents.MildandmoderateEDoccurredin17%and25%of
responders,respectively.[15]

AlthoughtherateofmildEDintheMMASremainedconstant(17%)inmenaged4070years,the
numberofmenreportingmoderateEDdoubled(1734%)andthenumberofmenreporting
completeEDtripled(515%).IftheMMASdataareextrapolatedtotheUSpopulation,an
estimated1830millionmenareaffectedbyED.[49]

IntheNationalHealthandSocialLifeSurvey(NHSLS),anationallyrepresentativeprobability
sampleofmenandwomenaged1859years,10.4%ofmenreportedbeingunabletoachieveor
maintainanerectionduringthepastyear.[50]Thereisastrikingcorrelationwiththeproportionof
menintheMMASwhoreportedcompleteED.

StudiesconductedaroundtheworldreportsimilarriskfactorsandsimilarprevalenceratesforED.
[51,52]

Agerelateddemographics

Allstudiesdemonstrateastrongassociationwithage,evenwhendataareadjustedforthe
confoundingeffectsofotherriskfactors.Theindependentassociationwithagingsuggeststhat
vascularchangesinthearteriesandsinusoidsofthecorporacavernosa,similartothosefound
elsewhereinthebody,arecontributingfactors.Otherriskfactorsassociatedwithaginginclude
depression,sleepapnea,andlowHDLlevels.

Longtermpredictionsbasedonanagingpopulationandanincreaseinriskfactors(eg,
hypertension,diabetes,vasculardisease,pelvicandprostatesurgery,benignprostatic
hyperplasia,andlowerurinarytractsymptoms)suggestalargeincreaseinthenumberofmenwith
ED.Inaddition,theprevalenceofEDisunderestimatedbecausephysiciansfrequentlydonot
questiontheirpatientsaboutthisdisorder.

Prognosis
Inaprospectivepopulationbasedstudyof1709menaged4070years,AraujoetalfoundthatED
wassignificantlyassociatedwithincreasedallcausemortality.[53]Theincreaseprimarilyresulted
fromcardiovascularmortality.

InaprospectivestudyfromtheProstateCancerPreventionTrialdatabase,Thompsonetal
reportedthatmenpresentingwithEDhadasignificantlyhigherchanceofdevelopinga
cardiovasculareventovera7yearfollowupperiod.[54]Thehazardratiowas1.45,whichisinthe
rangeofriskassociatedwithcurrentsmokingorafamilyhistoryofMI.

Ananalysisof14studiesinvolvingmorethan90,000patientswithEDconfirmedtherelation
betweenEDandanincreasedriskofcardiovasculareventsandmortality.[55]Comparedwith
patientswithoutED,thosewithEDhada44%increasedriskofcardiovascularevents,a25%
increasedriskofallcausemortality,a62%increasedriskofMI,anda39%increasedriskof
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cerebrovascularevents.TreatmentofED,eitherthroughlifestyleinterventionsorbypharmacologic
means,mayimproveprognosisandreducerisk.

Associatedmorbiditymayincludevariousothermalesexualdysfunctions,suchaspremature
(early)ejaculationandmalehypoactivesexualdesiredisorder.TheNHSLSfoundthat28.5%of
menaged1859yearsreportedprematureejaculation,and15.8%lackedsexualinterestduring
thepastyear.Anadditional17%reportedanxietyaboutsexualperformance,and8.1%hadalack
ofpleasureinsex.[50]

MenwithEDmayalsoexperienceanxietyordepression[56].Erectiledisorderiscommoninmen
withlowerurinarytractsymptomsrelatedtoBPH.

PatientEducation
Thelaboratoryresultsshouldbediscussedwiththepatientand,ifpossible,withhissexualpartner.
Thiseducationalprocessallowsareviewofthebasicaspectsoftheanatomyandphysiologyof
thesexualresponseandanexplanationofthepossibleetiologyandassociatedriskfactors(eg,
smokingandtheuseofvariousmedications).Treatmentoptionsandtheirbenefitsandrisks
shouldbediscussed.Thistypeofdialogueallowsthepatientandphysiciantocooperatein
developinganoptimalmanagementstrategy.

PatientswithbothEDandcardiovasculardiseasewhoreceivetreatmentwithanoralPDE5
inhibitorrequireeducationregardingwhattodoifanginalepisodesdevelopwhilethedrugisin
theirsystem.Sucheducationincludesstressingtheimportanceofalertingemergencycare
providerstothepresenceofthedrugsothatnitratetreatmentisavoided.

Patientsreceivingpenileprosthesesshouldbeinstructedintheoperationoftheprosthesisbefore
surgeryandagaininthepostoperativeperiod.Theprosthesisusuallyisnotactivateduntil
approximately6weeksaftersurgery,soastoallowtheedemaandpaintosubside.Theprosthesis
ischeckedintheofficebeforethepatientbeginstouseit.

Forpatienteducationinformation,seethefollowing:

ErectileDysfunctionCenter
CancerandTumorsCenter
Impotence/ErectileDysfunction
ErectileDysfunctionFAQs
NonsurgicalTreatmentofErectileDysfunction
UnderstandingErectileDysfunctionMedications
CausesofErectileDysfunction
DiagnosingErectileDysfunction
SurgicalTreatmentofErectileDysfunction
BladderCancer

ClinicalPresentation

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