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Goodman&Gilman's:ThePharmacologicalBasisofTherapeutics,12e>

Chapter41:Androgens
PeterJ.Snyder

TESTOSTERONEANDOTHERANDROGENS
Inmen,testosteroneistheprincipalsecretedandrogen.TheLeydigcellssynthesizethemajorityof
testosteronebythepathwaysshowninFigure411.Inwomen,testosteronealsoisprobablytheprincipal
androgenandissynthesizedbothinthecorpusluteumandtheadrenalcortexbysimilarpathways.The
testosteroneprecursorsandrostenedioneanddehydroepiandrosteroneareweakandrogensthatcanbe
convertedperipherallytotestosterone.

Figure411.

PathwayofsynthesisoftestosteroneintheLeydigcellsofthetestes.InLeydigcells,the11and21
hydroxylases(presentinadrenalcortex)areabsentbutCYP17(17hydroxylase)ispresent.Thus
androgensandestrogensaresynthesizedcorticosteroneandcortisolarenotformed.Boldarrowsindicate
favoredpathways.

SecretionandTransportofTestosterone.Themagnitudeoftestosteronesecretionisgreaterinmenthan
inwomenatalmostallstagesoflife,adifferencethatexplainsmanyoftheotherdifferencesbetweenmen
andwomen.Inthefirsttrimesterinutero,thefetaltestesbegintosecretetestosterone,whichistheprincipal
factorinmalesexualdifferentiation,probablystimulatedbyhumanchorionicgonadotropin(hCG)fromthe
placenta.Bythebeginningofthesecondtrimester,theserumtestosteroneconcentrationisclosetothatof
midpuberty,250ng/dL(Figure412)(DawoodandSaxena,1977Forest,1975).Testosteroneproduction
thenfallsbytheendofthesecondtrimester,butbybirththevalueisagain250ng/dL,possiblydueto
stimulationofthefetalLeydigcellsbyluteinizinghormone(LH)fromthefetalpituitarygland.The
testosteronevaluefallsagaininthefirstfewdaysafterbirth,butitrisesandpeaksagainat250ng/dLat2
3monthsafterbirthandfallsto<50ng/dLby6months,whereitremainsuntilpuberty(Forest,1975).

Figure412.

Schematicrepresentationoftheserumtestosteroneconcentrationfromearlygestationtooldage.

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Duringpuberty,from12to17yearsofage,theserumtestosteroneconcentrationinmalesincreasestoa
muchgreaterdegreethaninfemales,sothatbyearlyadulthoodtheserumtestosteroneconcentrationis500
ng/dLto700ng/dLinmen,comparedto30ng/dLto50ng/dLinwomen.Themagnitudeofthetestosterone
concentrationinthemaleisresponsibleforthepubertalchangesthatfurtherdifferentiatemenfromwomen.
Asmenage,theirserumtestosteroneconcentrationsgraduallydecrease,whichmaycontributetoother
effectsofaginginmen.

LH,secretedbythepituitarygonadotropes(Chapter38),istheprincipalstimulusoftestosteronesecretionin
men,perhapspotentiatedbyfolliclestimulatinghormone(FSH),alsosecretedbygonadotropes.The
secretionofLHbygonadotropesispositivelyregulatedbyhypothalamicgonadotropinreleasinghormone
(GnRH),andtestosteronedirectlyinhibitsLHsecretioninanegativefeedbackloop.LHissecretedinpulses,
whichoccurapproximatelyevery2hoursandaregreaterinmagnitudeinthemorning.Thepulsatility
appearstoresultfrompulsatilesecretionofGnRHfromthehypothalamus.PulsatileadministrationofGnRH
tomenwhoarehypogonadalduetohypothalamicdiseaseresultsinnormalLHpulsesandtestosterone
secretion,butcontinuousadministrationdoesnot(Crowleyetal.,1985).Testosteronesecretionislikewise
pulsatileanddiurnal,thehighestplasmaconcentrationsoccurringat8a.m.andthelowestat8p.m.The
morningpeaksdiminishasmenage(Bremneretal.,1983).

Inwomen,LHstimulatesthecorpusluteum(formedfromthefollicleafterreleaseoftheovum)tosecrete
testosterone.Undernormalcircumstances,however,estradiolandprogesterone,nottestosterone,arethe
principalinhibitorsofLHsecretioninwomen.Sexhormonebindingglobulin(SHBG)binds40%of
circulatingtestosteronewithhighaffinity,renderingtheboundhormoneunavailableforbiologicaleffects.
Albuminbindsalmost60%ofcirculatingtestosteronewithlowaffinity,leaving2%unboundorfree.Insome
testosteroneassays,thelattertwocomponentsareconsideredas"bioavailable"testosterone.

MetabolismofTestosteronetoActiveandInactiveCompounds.Testosteronehasmanydifferenteffects
inmanytissues.Onemechanismbywhichthevariedeffectsaremediatedisthemetabolismoftestosterone
totwootheractivesteroids,dihydrotestosteroneandestradiol(Figure413).Someeffectsoftestosterone
appeartobemediatedbytestosteroneitself,somebydihydrotestosterone,andsomebyestradiol.

Figure413.

Metabolismoftestosteronetoitsmajoractiveandinactivemetabolites.

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Theenzyme5reductasecatalyzestheconversionoftestosteronetodihydrotestosterone.Althoughboth
testosteroneanddihydrotestosteroneactviatheandrogenreceptor,dihydrotestosteronebindswithhigher
affinity(Wilbertetal.,1983)andactivatesgeneexpressionmoreefficiently(Deslypereetal.,1992).Asa
result,actingviadihydrotestosteroneandintissuesexpressing5reductase,testosteroneisabletoaffect
tissuesthatwouldotherwisenotbeaffectedbycirculatinglevelsoftestosterone.Twoformsof5reductase
havebeenidentified:typeI,whichisfoundpredominantlyinnongenitalskin,liverandbone,andtypeII,
whichisfoundpredominantlyinurogenitaltissueinmenandgenitalskininmenandwomen.Theeffectsof
dihydrotestosteroneinthesetissuesaredescribedlater.

Theenzymecomplexaromatase,whichispresentinmanytissues,especiallytheliverandadiposetissue,
catalyzestheconversionoftestosteronetoestradiol.Thisconversionaccountsfor85%ofcirculating
estradiolinmentheremainderissecreteddirectlybythetestes,probablytheLeydigcells(MacDonaldet
al.,1979).Theeffectsoftestosteronethoughttobemediatedviaestradiolaredescribedbelow.

Testosteroneismetabolizedinthelivertoandrosteroneandetiocholanolone(Figure413),whichare
biologicallyinactive.Dihydrotestosteroneismetabolizedtoandrosterone,androstanedione,and
androstanediol.

PhysiologicalandPharmacologicalEffectsofAndrogens

Thebiologicaleffectsoftestosteronearemediatedbythereceptoritactivatesandbythetissuesinwhich
thereceptorandresponsesoccuratvariousstagesoflife.Testosteronecanactasanandrogeneither
directly,bybindingtotheandrogenreceptor,orindirectlybyconversiontodihydrotestosterone,whichalso
bindstotheandrogenreceptor.Testosteronealsocanactasanestrogenbyconversiontoestradiol,which
bindstotheestrogenreceptor(Figure414).

Figure414.

Directeffectsoftestosteroneandeffectsmediatedindirectlyviadihydrotestosteroneorestradiol.

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EffectsThatOccurviatheAndrogenReceptor.Testosteroneanddihydrotestosteroneactasandrogens
viaasingleandrogenreceptor(Figure415).TheandrogenreceptorofficiallydesignatedNR3Aisa
memberofthenuclearreceptorsuperfamily,whichincludessteroidhormonereceptors,thyroidhormone
receptors,andorphanreceptorsthatlackaknownligand(Chapter3).

Figure415.

Structureoftheandrogenreceptor.

Theandrogenreceptorhasanaminoterminaldomainthatcontainsapolyglutaminerepeatofvariable
length,aDNAbindingdomainconsistingoftwoZnfingermotifs,andacarboxyterminalligandbinding
domain.Thepolyglutaminerepeatofvariablelengthisuniquetotheandrogenreceptorashorterlength
appearstoincreaseitsactivity.Intheabsenceofaligand,theandrogenreceptorislocatedinthecytoplasm
associatedwithaheatshockproteincomplex.Whentestosteroneordihydrotestosteronebindstotheligand
bindingdomain,theandrogenreceptordissociatesfromtheheatshockproteincomplex,dimerizes,and
translocatestothenucleus.ThedimerthenbindsviatheDNAbindingdomainstoandrogenresponse
elementsoncertainresponsivegenes.Theligandreceptorcomplexrecruitscoactivatorsandactsasa
transcriptionfactorcomplex,stimulatingorrepressingexpressionofthosegenes(AgoulnikandWeigel,
2008BrinkmannandTrapman,2000).

Themechanismsbywhichandrogenshavedifferentactionsindiversetissueshavebecomeclearerin
recentyears.Onemechanismisthehigheraffinitywithwhichdihydrotestosteronebindstoandactivatesthe
androgenreceptorcomparedtotestosterone(Deslypereetal.,1992).Anothermechanisminvolves
transcriptioncofactors,bothcoactivatorsandcorepressors,whicharetissuespecific.Atthistime,theroles
ofcofactorsarebetterdescribedforothernuclearreceptorsthanfortheandrogenreceptor(Smithand
O'Malley,2004).

Theimportanceoftheandrogenreceptorisillustratedbytheconsequencesofitsmutations.Predictably,
mutationsthateitheraltertheprimarysequenceoftheproteinorcauseasingleaminoacidsubstitutionin
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thehormoneorDNAbindingdomainsresultinresistancetotheactionoftestosterone,beginninginutero
(McPhaulandGriffin,1999).Malesexualdifferentiationthereforeisincomplete,asispubertaldevelopment.

Anotherkindofmutationoccursinpatientswhohavespinalandbulbarmuscularatrophy,knownas
Kennedy'sdisease.ThesepatientshaveanexpansionoftheCAGrepeat,whichcodesforglutamine,atthe
aminoterminusofthemolecule(WalcottandMerry,2002).Theresultisverymildandrogenresistance,
manifestprincipallybygynecomastia(Dejager,2002),andprogressivelyseveremotorneuronatrophy.The
mechanismbywhichtheneuronalatrophyoccursisunknownbutpharmacologicalinductionofautophagyin
amodelcellsystemdegradesthemutantARandrescuesthecellsfromdamage(Montieetal,2009).Other
trinucleotiderepeatsarealsoassociatedwithneurologicaldisorders(Mollaetal.,2009).

Otherkindsofandrogenreceptormutationsmayexplainwhyprostatecancerthatistreatedbyandrogen
deprivationeventuallybecomesandrogenindependent.Atthetimeofitsclinicalpresentation,prostate
cancerisusuallyandrogensensitive,andthissensitivityformsthebasisfortheinitialtreatmentofmetastatic
prostatecancerbyandrogendeprivation.Metastaticprostatecanceroftenregressesinitiallyinresponseto
thistreatmentbutthenbecomesunresponsivetocontinueddeprivation.Theandrogenreceptornotonly
continuestobeexpressedinandrogenindependentprostatecancer,butitssignalingremainsactive,as
indicatedbyexpressionoftheandrogenreceptordependentprostatespecificantigen(PSA).Ithasbeen
postulatedthattheseobservationscanbeexplainedbymutationsintheandrogenreceptorgeneorchanges
inandrogenreceptorcoregulatoryproteins.Insomepatientsresistanttostandardandrogendeprivation
therapy,thetumorrespondstofurtherdepletionofandrogensbyinhibitorsofadrenalandrogensynthesis,
suchasabiraterone,adruginlatestagesofclinicaldevelopment(Chapter63)(HeinleinandChang,2004).

EffectsThatOccurviatheEstrogenReceptor.Theeffectsoftestosteroneonatleastonetissueare
mediatedbyitsconversiontoestradiol,catalyzedbythearomataseenzymecomplex.Intherarecasesin
whichamaledoesnotexpressaromataseortheestrogenreceptor(Smith,1994),theepiphysesdonotfuse
andlongbonegrowthcontinuesindefinitelymoreover,suchpatientsareosteoporotic.Administrationof
estradiolcorrectstheboneabnormalitiesinpatientswitharomatasedeficiencybutnotinthosewithan
estrogenreceptordefect.Becausemenhavelargerbonesthanwomen,andboneexpressestheandrogen
receptor(Colvardetal.,1989),testosteronealsomayhaveaneffectonboneviatheandrogenreceptor.The
effectoftestosteroneonmalelibidoalsomaybemediatedbyconversiontoestradiol:administrationof
estradioltoamanwitharomatasedeficiencyincreasedhislibido(RochiraandCarani,2009).

EffectsofAndrogensatDifferentStagesofLife

InUtero.Whenthefetaltestes,stimulatedbyhCG,begintosecretetestosteroneatabouttheeighthweek
ofgestation,thehighlocalconcentrationoftestosteronearoundthetestesstimulatesthenearbyWolffian
ductstodifferentiateintothemaleinternalgenitalia:theepididymis,vasdeferens,andseminalvesicles.
Furtheraway,intheanlageoftheexternalgenitalia,testosteroneisconvertedtodihydrotestosterone,which
causesthedevelopmentofthemaleexternalgenitalia:thepenis,scrotum,andprostate.Theincreasein
testosteroneattheendofgestationmayresultinfurtherphallicgrowth.

Infancy.Theconsequencesoftheincreaseintestosteronesecretionbythetestesduringthefirstfew
monthsoflifearenotyetknown.

Puberty.Pubertyinthemalebeginsatameanageof12yearswithanincreaseinthesecretionofFSHand
LHfromthegonadotropes,stimulatedbyincreasedsecretionofGnRHfromthehypothalamus.The
increasedsecretionofFSHandLHstimulatesthetestesnotsurprisingly,thefirstsignofpubertyisan
increaseintesticularsize.TheincreaseintestosteroneproductionbyLeydigcellsandtheeffectofFSHon
theSertolicellsstimulatethedevelopmentoftheseminiferoustubules,whicheventuallyproducemature
sperm.Increasedsecretionoftestosteroneintothesystemiccirculationaffectsmanytissuesvirtually
simultaneously,andthechangesinmostofthemoccurgraduallyduringthecourseofseveralyears.The
phallusenlargesinlengthandwidth,thescrotumbecomesrugated,andtheprostatebeginssecretingthe
fluiditcontributestothesemen.Theskinbecomescoarserandoilierduetoincreasedsebumproduction,
whichcontributestothedevelopmentofacne.Sexualhairbeginstogrow,initiallypubicandaxillaryhair,
thenhaironthelowerlegs,andfinallyotherbodyhairandfacialhair.Fulldevelopmentofthelattertwomay
notoccuruntil10yearsafterthestartofpubertyandmarksthecompletionofpuberty.Musclemassand
strength,especiallyoftheshouldergirdle,increase,andsubcutaneousfatdecreases.Epiphysealbone
growthaccelerates,resultinginthepubertalgrowthspurt,butepiphysealmaturationleadseventuallytoa
slowingandthencessationofgrowth.Bonealsobecomesthicker.Theincreaseinmusclemassandbone
resultinapronouncedincreaseinweight.Erythropoiesisincreases,resultinginhigherhematocritand
hemoglobinconcentrationsinmenthanboysorwomen.Thelarynxthickens,resultinginalowervoice.
Libidodevelops.

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Otherchangesalsomayresultfromtheincreaseintestosteroneduringpuberty.Mentendtohaveabetter
senseofspatialrelationsthandowomenandtoexhibitbehaviorthatdiffersinsomewaysfromthatof
women,includingbeingmoreaggressive.

Adulthood.Theserumtestosteroneconcentrationandthecharacteristicsoftheadultmanaremaintained
largelyduringearlyadulthoodandmidlife.Onechangeduringthistimeisthegradualdevelopmentofmale
patternbaldness,beginningwithrecessionofhairatthetemplesand/oratthevertex.

Twochangesthatcanoccurintheprostateglandduringadulthoodareofmuchgreatermedicalsignificance.
Oneisthegradualdevelopmentofbenignprostatichyperplasia,whichoccurstoavariabledegreeinalmost
allmen,sometimesobstructingurineoutflowbycompressingtheurethraasitpassesthroughtheprostate.
Thisdevelopmentismediatedbytheconversionoftestosteronetodihydrotestosteroneby5reductaseII
withinprostaticcells(Wilson,1980).

Theotherchangethatcanoccurintheprostateduringadulthoodisthedevelopmentofcancer.Althoughno
directevidencesuggeststhattestosteronecausesthedisease,prostatecancerdependsonandrogen
stimulation.Thisdependencyisthebasisoftreatingmetastaticprostatecancerbyloweringtheserum
testosteroneconcentrationorbyblockingitsactionatthereceptor.

Senescence.Asmenage,theserumtestosteroneconcentrationgraduallydeclines(Figure412),andthe
SHBGconcentrationgraduallyincreases,sothatbyage80,thetotaltestosteroneconcentrationis80%
andthefreetestosteroneis40%ofthoseatage20(Harmanetal.,2001).Thisfallinserumtestosterone
couldcontributetoseveralotherchangesthatoccurwithincreasingageinmen,includingdecreasesin
energy,libido,musclemass(Forbes,1976)andstrength(Murrayetal.,1980),andbonemineraldensity.
Androgendeprivationalsoleadstoinsulinresistance,truncalobesity,andabnormalserumlipids,as
observedinpatientswithmetastaticprostatecancerreceivingthistreatment(seealsoChapter63).Acausal
roleissuggestedbytheoccurrenceofsimilarchangeswhenmendevelophypogonadismatayoungerage
causedbyknowndiseases,asdiscussedlaterinthischapter.

ConsequencesofAndrogenDeficiency

Theconsequencesofandrogendeficiencydependonthestageoflifeduringwhichthedeficiencyfirst
occursandonthedegreeofthedeficiency.

DuringFetalDevelopment.Testosteronedeficiencyinamalefetusduringthefirsttrimesterinuterocauses
incompletesexualdifferentiation.Testosteronedeficiencyinthefirsttrimesterresultsonlyfromtesticular
disease,suchasdeficiencyof17hydroxylase(CYP17)deficiencyofLHsecretionbecauseofpituitaryor
hypothalamicdiseasedoesnotresultintestosteronedeficiencyduringthefirsttrimester,presumably
becauseLeydigcellsecretionoftestosteroneatthattimeisregulatedbyplacentalhCG.Complete
deficiencyoftestosteronesecretionresultsinentirelyfemaleexternalgenitalialessseveretestosterone
deficiencyresultsinincompletevirilizationoftheexternalgenitaliaproportionatetothedegreeofdeficiency.
Testosteronedeficiencyatthisstageofdevelopmentalsoleadstofailureofthewolffianductstodifferentiate
intothemaleinternalgenitalia,suchasthevasdeferensandseminalvesicles,butthemllerianductsdo
notdifferentiateintothefemaleinternalgenitaliaaslongastestesarepresentandsecretemllerian
inhibitorysubstance.Similarchangesoccuriftestosteroneissecretednormally,butitsactionisdiminished
becauseofanabnormalityoftheandrogenreceptororofthe5reductaseenzyme.Abnormalitiesofthe
androgenreceptorcanhavequitevariedeffects.Themostsevereformresultsincompleteabsenceof
androgenactionandafemalephenotypemoderatelysevereformsresultinpartialvirilizationoftheexternal
genitaliaandthemildestformspermitnormalvirilizationinuteroandresultonlyinimpaired
spermatogenesisinadulthood(McPhaulandGriffin,1999).Abnormal5reductaseresultsinincomplete
virilizationoftheexternalgenitaliainuterobutnormaldevelopmentofthemaleinternalgenitalia,which
requiresonlytestosterone(Wilsonetal.,1993).

Testosteronedeficiencyduringthethirdtrimester,causedeitherbyatesticulardiseaseoradeficiencyof
fetalLHsecretion,hastwoknownconsequences.First,thephallusfailstogrowasmuchasitwould
normally.Theresult,calledmicrophallus,isacommonoccurrenceinboyslaterdiscoveredtobeunableto
secreteLHduetoabnormalitiesofGnRHsynthesis.Second,thetestesfailtodescendintothescrotumthis
condition,calledcryptorchidism,occurscommonlyinboyswhoseLHsecretionissubnormal(Chapter38).

BeforeCompletionofPuberty.Whenaboycansecretetestosteronenormallyinuterobutlosestheability
todosobeforetheanticipatedageofpuberty,theresultisfailuretocompletepuberty.Allofthepubertal
changespreviouslydescribed,includingthoseoftheexternalgenitalia,sexualhair,musclemass,voice,and
behavior,areimpairedtoadegreeproportionatetotheabnormalityoftestosteronesecretion.Inaddition,if

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growthhormonesecretionisnormalwhentestosteronesecretionissubnormalduringtheyearsofexpected
puberty,thelongbonescontinuetolengthenbecausetheepiphysesdonotclose.Theresultislongerarms
andlegsrelativetothetrunktheseproportionsarereferredtoaseunuchoid.Anotherconsequenceof
subnormaltestosteronesecretionduringtheageofexpectedpubertyisenlargementofglandularbreast
tissue,calledgynecomastia.

AfterCompletionofPuberty.Whentestosteronesecretionbecomesimpairedafterpuberty(e.g.,castration
orantiandrogentreatment),regressionofthepubertaleffectsoftestosteronedependsonboththedegree
andthedurationoftestosteronedeficiency.Whenthedegreeoftestosteronedeficiencyissubstantial,libido
andenergydecreasewithinaweekortwo,butothertestosteronedependentcharacteristicsdeclinemore
slowly.Decreasesinmusclemassandstrengthprobablycanbedetectedbytestinggroupsofmenwithina
fewmonths,butaclinicallydetectabledecreaseinmusclemassinanindividualdoesnotoccurforseveral
years.Apronounceddecreaseinhematocritandhemoglobinwilloccurwithinseveralmonths.Adecreasein
bonemineraldensityprobablycanbedetectedbydualenergyabsorptiometrywithin2years,butan
increaseinfractureincidencewouldnotbelikelytooccurformanyyearsAlossofsexualhairtakesmany
years.

InWomen.Lossofandrogensecretioninwomenresultsinadecreaseinsexualhair,butnotformany
years.Androgensmayhaveotherimportanteffectsinwomen,andthelossofandrogens(especiallywiththe
severelossofovarianandadrenalandrogensthatoccursinpanhypopituitarism)mayresultinthelossof
theseeffects.Testosteronepreparationsthatcanyieldserumtestosteroneconcentrationsinthe
physiologicalrangeinwomencurrentlyarebeingdeveloped.Theavailabilityofsuchpreparationswillallow
clinicaltrialstodetermineiftestosteronereplacementinandrogendeficientwomenimprovestheirlibido,
energy,musclemassandstrength,andbonemineraldensity.

TherapeuticAndrogenPreparations

Theneedforacreativeapproachtopharmacotherapywithandrogensarisesfromthefactthatingestionof
testosteroneisnotaneffectivemeansofreplacingtestosteronedeficiency.Eventhoughingested
testosteroneisreadilyabsorbedintothehepaticcirculation,therapidhepaticcatabolismensuresthat
hypogonadalmengenerallycannotingestitinsufficientamountsandwithsufficientfrequencytomaintaina
normalserumtestosteroneconcentration.Mostpharmaceuticalpreparationsofandrogens,therefore,are
designedtobypasshepaticcatabolismoftestosterone.

TestosteroneEsters.Esterifyingafattyacidtothe17hydroxylgroupoftestosteronecreatesacompound
thatisevenmorelipophilicthantestosteroneitself.Whenanester,suchastestosteroneenanthate
(heptanoate)orcypionate(cyclopentylpropionate)(Figure416)isdissolvedinoilandadministered
intramuscularlyevery24weekstohypogonadalmen,theesterhydrolyzesinvivoandresultsinserum
testosteroneconcentrationsthatrangefromhigherthannormalinthefirstfewdaysaftertheinjectiontolow
normaljustbeforethenextinjection(Figure417).Attemptstodecreasethefrequencyofinjectionsby
increasingtheamountofeachinjectionresultinwiderfluctuationsandpoorertherapeuticoutcomes.The
undecanoateesteroftestosterone(Figure416),whendissolvedinoilandingestedorally,isabsorbedinto
thelymphaticcirculation,thusbypassinginitialhepaticcatabolism.Testosteroneundecanoateinoilalsocan
beinjectedandproducesstableserumtestosteroneconcentrationsfor2months(Schubertetal.,2004).The
undecanoateesteroftestosteroneisnotcurrentlymarketedintheU.S.

Figure416.

Structuresofandrogensavailablefortherapeuticuse.

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AlkylatedAndrogens.Severaldecadesago,chemistsfoundthataddinganalkylgrouptothe17position
oftestosterone(Figure416)retardeditshepaticcatabolism.Consequently,17alkylatedandrogensare
androgenicwhenadministeredorallyhowever,theyarelessandrogenicthantestosteroneitself,andthey
causehepatotoxicity(Cabasso,1994),whereasnativetestosteronedoesnot.

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TransdermalDeliverySystems.Recentattemptstoavoidthe"firstpass"inactivationoftestosteronebythe
liverhaveemployednoveldeliverysystemschemicalscalledexcipientsareusedtofacilitatetheabsorption
ofnativetestosteroneacrosstheskininacontrolledfashion.Thesetransdermalpreparationsprovidemore
stableserumtestosteroneconcentrationsthandoinjectionsoftestosteroneesters.Thefirstsuch
preparationswerepatches,oneofwhich(androderm)isstillavailable.Newerpreparationsincludegels
(androgel,testim)andabuccaltablet(striant).Thesepreparationsproducemeanserumtestosterone
concentrationswithinnormalrangeinhypogonadalmen(Figure417).

Figure417.

Pharmacokineticprofilesofthreetestosteronepreparationsduringtheirchronicadministrationto
hypogonadalmen.Dosesofeachweregivenattime0.Shadedareasindicaterangeofnormallevels.[Data
adaptedfromA.SnyderandLawrence(1980)B.Dobsetal.(1999)C.Swerdloffetal.(2000)]

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AttemptstoDesignSelectiveAndrogens

AlkylatedAndrogens.Decadesago,investigatorsattemptedtosynthesizeanalogsoftestosteronethat
possessedgreateranaboliceffectsthanandrogeniceffectscomparedtonativetestosterone.Several
compoundsappearedtohavesuchdifferentialeffects,basedonagreatereffectonthelevatoranimuscle
comparedtotheventralprostateoftherat.Thesecompoundswerecalledanabolicsteroids,andmostare
17alkylatedandrogens.Noneofthesecompounds,however,hasbeenconvincinglydemonstratedtohave
suchadifferentialeffectinhumanbeings.Nonetheless,theyhaveenjoyedpopularityamongathleteswho
seektoenhancetheirperformance.Anotheralkylatedandrogen,7methyl19nortestosterone,ispoorly
convertedtodihydrotestosterone.

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SelectiveAndrogenReceptorModulators.Stimulatedbythedevelopmentofselectiveestrogenreceptor
modulators,whichhaveestrogeniceffectsinsometissuesbutnotothers(Chapter40),investigatorsare
attemptingtodevelopselectiveandrogenreceptormodulators.Anotherstimulusisthedesirableeffectsof
testosteroneinsometissues,suchasmuscleandbone,andtheundesirableeffectsinothertissues,suchas
theprostate.Nonsteroidalmoleculeshavebeendevelopedthatbindtotheandrogenreceptorandhave
greatereffectonmuscleandbonethanontheprostate.Someofthesecompoundshavebeguntrialsin
humans(Narayananetal.,2008).

TherapeuticUsesofAndrogens

MaleHypogonadism.Thebestestablishedindicationforadministrationofandrogensistestosterone
deficiencyinmen(i.e.,treatmentofmalehypogonadism).Anyofthetestosteronepreparationsor
testosteroneestersjustdescribedcanbeusedtotreattestosteronedeficiency.Monitoringtreatmentfor
beneficialanddeleteriouseffectsdifferssomewhatinadolescentsandtheelderlyfromthatinothermen.

MonitoringforEfficacy.Thegoalofadministeringtestosteronetoahypogonadalmanistomimicas
closelyaspossiblethenormalserumconcentration.Therefore,measuringtheserumtestosterone
concentrationduringtreatmentisthemostimportantaspectofmonitoringtestosteronetreatmentforefficacy.
Whentheserumtestosteroneconcentrationismeasureddependsonthetestosteronepreparationused
(Figure417).Occasionalrandomfluctuationscanoccur,however,someasurementsshouldberepeated
foranydose.Whentheenanthateorcypionateestersoftestosteroneareadministeredonceevery2weeks,
theserumtestosteroneconcentrationmeasuredmidwaybetweendosesshouldbenormalifnot,thedosage
scheduleshouldbeadjustedaccordingly.Iftestosteronedeficiencyresultsfromtesticulardisease,as
indicatedbyanelevatedserumLHconcentration,adequacyoftestosteronetreatmentalsocanbejudged
indirectlybythenormalizationofLHwithin2monthsoftreatmentinitiation(Findlayetal.,1989Snyderand
Lawrence,1980).

Normalizationoftheserumtestosteroneconcentrationinducesnormalvirilizationinprepubertalboysand
restoresvirilizationinmenwhobecamehypogonadalasadults.Withinafewmonths,andoftensooner,
libido,energy,andhematocritreturntonormal.Within6months,musclemassincreasesandfatmass
decreases.Bonedensity,however,continuestoincreasefor2years(Snyderetal.,2000).

MonitoringforDeleteriousEffects.Whentestosteroneitselfisadministered,asinoneofthetransdermal
preparationsorasanesterthatishydrolyzedtotestosterone,ithasno"sideeffects"(i.e.,noeffectsthat
endogenouslysecretedtestosteronedoesnothave),aslongasthedoseisnotexcessive.Modified
testosteronecompounds,suchasthe17alkylatedandrogens,dohaveundesirableeffectsevenwhen
dosagesaretargetedatphysiologicalreplacement.Someoftheseundesirableeffectsoccurshortlyafter
testosteroneadministrationisinitiated,whereasothersusuallydonotoccuruntiladministrationhasbeen
continuedformanyyears.Raisingtheserumtestosteroneconcentrationfromprepubertalormidpubertal
levelstothatofanadultmaleatanyagecanresultinundesirableeffectssimilartothosethatoccurduring
puberty,includingacne,gynecomastia,andmoreaggressivesexualbehavior.Physiologicalamountsof
testosteronedonotappeartoaffectserumlipidsorapolipoproteins.Replacementofphysiologicallevelsof
testosteroneoccasionallymayhaveundesirableeffectsinthepresenceofconcomitantillnesses.For
example,stimulationoferythropoiesiswouldincreasethehematocritfromsubnormaltonormalinahealthy
manbutwouldraisethehematocritabovenormalinamanwithapredispositiontoerythrocytosis,suchasin
chronicpulmonarydisease.Similarly,themilddegreeofsodiumandwaterretentionwithtestosterone
replacementwouldhavenoclinicaleffectinahealthymanbutwouldexacerbatepreexistingcongestive
heartfailure.Ifthetestosteronedoseisexcessive,erythrocytosisand,uncommonly,saltandwaterretention
andperipheraledemaoccureveninmenwhohavenopredispositiontotheseconditions.Whenaman's
serumtestosteroneconcentrationhasbeeninthenormaladultmalerangeformanyyears,whetherfrom
endogenoussecretionorexogenousadministration,andheis>40yearsofage,heissubjecttocertain
testosteronedependentdiseases,includingbenignprostatichyperplasiaandprostatecancer.

Theprincipaladverseeffectsofthe17alkylatedandrogensarehepatic,includingcholestasisand,
uncommonly,peliosishepatis,bloodfilledhepaticcysts.Hepatocellularcancerhasbeenreportedrarely.
Casereportsofcancerregressionafterandrogencessationsuggestapossiblecausalrole,butanetiologic
linkisunproven.The17alkylatedandrogens,especiallyinlargeamounts,maylowerserumhighdensity
lipoproteincholesterol.

MonitoringattheAnticipatedTimeofPuberty.Administrationoftestosteronetotestosteronedeficient
boysattheanticipatedtimeofpubertyshouldbeguidedbytheconsiderationsjustdescribedbutalsobythe
factthattestosteroneacceleratesepiphysealmaturation,leadinginitiallytoagrowthspurtbutthento
epiphysealclosureandpermanentcessationoflineargrowth.Consequently,theheightandgrowthhormone

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statusoftheboymustbeconsidered.Boyswhoareshortbecauseofgrowthhormonedeficiencyshouldbe
treatedwithgrowthhormonebeforetheirhypogonadismistreatedwithtestosterone.

MaleSenescence.Preliminaryevidencesuggeststhatincreasingtheserumtestosteroneconcentrationof
menwhoseserumlevelsaresubnormalfornoreasonotherthantheiragewillincreasetheirbonemineral
densityandleanmassanddecreasetheirfatmass(Amoryetal.,2004Kennyetal.,2001Snyderetal.,
1999a,1999b).Itisentirelyuncertainatthistime,however,ifsuchtreatmentwillworsenbenignprostatic
hyperplasiaorincreasetheincidenceofclinicallydetectableprostatecancer.

FemaleHypogonadism.Littledataexistregardingwhetherincreasingtheserumtestosterone
concentrationsofwomenwhoseserumtestosteroneconcentrationsarebelownormalwillimprovetheir
libido,energy,musclemassandstrength,orbonemineraldensity.Inastudyofwomenwithlowserum
testosteroneconcentrationsduetopanhypopituitarism,increasingthetestosteroneconcentrationtonormal
wasassociatedwithsmallincreasesinbonemineraldensity,fatfreemass,andsexualfunctioncomparedto
placebo(Milleretal.,2006).

EnhancementofAthleticPerformance.Someathletestakedrugs,includingandrogens,toattemptto
improvetheirperformance.Becauseandrogensforthispurposeusuallyaretakensurreptitiously,information
abouttheirpossibleeffectsisnotascompleteasthatforandrogenstakenfortreatmentofmale
hypogonadism.Citingpotentiallyserioushealthrisks,theFDAhasrecommendedagainsttheuseofbody
buildingproductsthataremarketedascontainingsteroidsorsteroidlikesubstances(FDA,2009).

KindsofAndrogensUsed.Virtuallyallandrogensproducedforhumanorveterinarypurposeshavebeen
takenbyathletes.Whenusebyathletesbeganmorethantwodecadesago,17alkylatedandrogensand
othercompoundsthatwerethoughttohavegreateranaboliceffectsthanandrogeneffectsrelativeto
testosterone(socalledanabolicsteroids)wereusedmostcommonly.Becausethesecompoundscanbe
detectedreadilybyorganizationsthatgovernathleticcompetitions,preparationsthatincreasetheserum
concentrationoftestosteroneitself,suchasthetestosteroneestersorhCG,haveincreasedinpopularity.
Testosteroneprecursors,suchasandrostenedioneanddehydroepiandrosterone(DHEA),alsohave
increasedinpopularityrecentlybecausetheyaretreatedasnutritionalsupplementsandthusarenot
regulatedbynationalgovernmentsorathleticorganizations.

Anewdevelopmentinuseofandrogensbyathletesisrepresentedbytetrahydrogestrinone(THG),apotent
androgenthatappearstohavebeendesignedandsynthesizedinordertoavoiddetectionbyantidoping
laboratoriesonthebasisofitsnovelstructure(Figure416)andrapidcatabolism.

Efficacy.Therehavebeenfewcontrolledstudiesoftheeffectsofpharmacologicaldosesofandrogenson
musclestrength.Inonecontrolledstudy,43normalyoungmenwererandomizedtooneoffourgroups:
strengthtraining600mgoftestosteroneenanthateonceaweek(morethansixtimesthereplacement
dose)ornoexercisetestosterone.Themenwhoreceivedtestosteroneexperiencedanincreaseinmuscle
strengthcomparedtothosewhoreceivedplacebo,andthemenwhoexercisedsimultaneouslyexperienced
evengreaterincreases(Bhasinetal.,1996).Inanotherstudy,normalyoungmenweretreatedwithaGnRH
analogtoreduceendogenoustestosteronesecretionseverelyandinarandomblindedfashion,weekly
dosesoftestosteroneenanthatefrom25mgto600mg.Therewasadosedependenteffectoftestosterone
onmusclestrength(Bhasinetal.,2001).

Inadoubleblindstudyofandrostenedione,menwhotook100mgthreetimesadayfor8weeksdidnot
experienceanincreaseinmusclestrengthcomparedtomenwhotookplacebo.Failureofthistreatmentto
increasemusclestrengthisnotsurprisingbecauseitalsodidnotincreasethemeanserumtestosterone
concentration(Kingetal.,1999).

SideEffects.Allandrogenssuppressgonadotropinsecretionwhentakeninhighdosesandthereby
suppressendogenoustesticularfunction.Thisdecreasesendogenoustestosteroneandspermproduction,
resultingindiminishedfertility.Ifadministrationcontinuesformanyyears,testicularsizemaydiminish.
Testosteroneandspermproductionusuallyreturntonormalwithinafewmonthsofdiscontinuationbutmay
takelonger.Highdosesofandrogensalsocauseerythrocytosis(Drinkaetal.,1995).

Whenadministeredinhighdoses,androgensthatcanbeconvertedtoestrogens,suchastestosterone
itself,causegynecomastia.AndrogenswhoseAringhasbeenmodifiedsothatitcannotbearomatized,
suchasdihydrotestosterone,donotcausegynecomastiaeveninhighdoses.

The17alkylatedandrogensaretheonlyandrogensthatcausehepatotoxicity.Theseandrogensalso
appeartobemuchmorelikelythanothers,whenadministeredinhighdoses,toaffectserumlipid
concentrations,specificallytodecreasehighdensitylipoprotein(HDL)cholesterolandincreaselowdensity

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lipoprotein(LDL)cholesterol.Othersideeffectshavebeensuggestedbymanyanecdotesbuthavenotbeen
confirmed,includingpsychologicaldisordersandsuddendeathduetocardiacdisease,possiblyrelatedto
changesinlipidsortocoagulationactivation.

Certainsideeffectsoccurspecificallyinwomenandchildren.Bothexperiencevirilization,includingfacial
andbodyhirsutism,temporalhairrecessioninamalepattern,andacne.Boysexperiencephallic
enlargement,andwomenexperienceclitoralenlargement.Boysandgirlswhoseepiphyseshavenotyet
closedexperienceprematureclosureandstuntingoflineargrowth.

Detection.Anandrogenotherthantestosteronecanbedetectedbygaschromatographyandmass
spectroscopyiftheathleteisstilltakingitwhenheistested.Exogenoustestosteroneitselfcanbedetected
byoneoftwomethods.OneistheT/Eratio,theratiooftestosteroneglucuronidetoitsendogenousepimer,
epitestosteroneglucuronide,inurine.Administrationofexogenoustestosteronesuppressessecretionof
bothtestosteroneandepitestosteroneandreplacesthemwithonlytestosterone,sotheT/Eratioishigher
thannormal.Thistechniqueislimited,however,byheterozygosityintheUDPglucuronosyltransferasethat
convertstestosteronetotestosteroneglucuronide.Anathletewhohasadeletionofoneorbothcopiesofthe
genecodingforthisenzymeandwhotakesexogenoustestosteronewillhaveamuchlowerT/Eratiothan
onewhohavebothcopies(Schulze,2008).

Asecondtechniquefordetectingadministrationofexogenoustestosteroneemploysgaschromatography
combustionisotoperatiomassspectrometrytodetectthepresenceof13Cand12Ccompounds.Urinary
steroidswithalow13C/12Cratioarelikelytohaveoriginatedfrompharmaceuticalsourcesasopposedto
endogenousphysiologicalsources(Aguileraetal.,2001).

MaleContraception.AndrogensinhibitLHsecretionbythepituitaryandtherebydecreaseendogenous
testosteroneproduction.Basedontheseobservations,scientistshavetriedformorethanadecadetouse
androgens,eitheraloneorincombinationwithotherdrugs,asamalecontraceptive.Becausethe
concentrationoftestosteronewithinthetestes,100timesthatintheperipheralcirculation,isnecessaryfor
spermatogenesis,suppressionofendogenoustestosteroneproductiongreatlydiminishesspermatogenesis.
Initialuseoftestosteronealone,however,requiredsupraphysiologicdoses,andadditionofGnRH
antagonistsrequireddailyinjections.Amorepromisingapproachisthecombinationofaprogestinwitha
physiologicaldoseoftestosteronetosuppressLHsecretionandspermatogenesisbutprovideanormal
serumtestosteroneconcentration(Bebbetal.,1996).Onetrialemployedinjectionsoftestosterone
undecanoatewithadepotprogestinevery2months(Guetal.,2004).Anotherandrogenbeingtestedaspart
ofamalecontraceptiveregimenis7methyl19nortestosterone,asyntheticandrogenthatcannotbe
metabolizedtodihydrotestosterone(Cummingsetal.,1998).

CatabolicandWastingStates.Testosterone,becauseofitsanaboliceffects,hasbeenusedinattemptsto
amelioratecatabolicandmusclewastingstates,butthishasnotbeengenerallyeffective.Oneexceptionis
inthetreatmentofmusclewastingassociatedwithacquiredimmunodeficiencysyndrome(AIDS),which
oftenisaccompaniedbyhypogonadism.TreatmentofmenwithAIDSrelatedmusclewastingandsubnormal
serumtestosteroneconcentrationsincreasestheirmusclemassandstrength(Bhasinetal.,2000).

Angioedema.Chronicandrogentreatmentofpatientswithangioedemaeffectivelypreventsattacks.The
diseaseiscausedbyhereditaryimpairmentofC1esteraseinhibitororacquireddevelopmentofantibodies
againstit(Cicardietal.,1998).The17alkylatedandrogens,suchasstanozololanddanazol,stimulatethe
hepaticsynthesisoftheesteraseinhibitor.Inwomen,virilizationisapotentialsideeffect.Inchildren,
virilizationandprematureepiphysealclosurepreventchronicuseofandrogensforprophylaxis,although
theyareusedoccasionallytotreatacuteepisodes.Asanalternativetoprophylacticandrogens,
concentratedC1esteraseinhibitorderivedfromhumanplasma(cinryze)maybeusedforprotectionin
patientswithhereditaryangioedema.

BloodDyscrasias.Androgensoncewereemployedtoattempttostimulateerythropoiesisinpatientswith
anemiasofvariousetiologies,buttheavailabilityoferythropoietinhassupplantedthatuse.Androgens,such
asdanazol,stillareusedoccasionallyasadjunctivetreatmentforhemolyticanemiaandidiopathic
thrombocytopenicpurpurathatarerefractorytofirstlineagents.

ANTIANDROGENS
Becausesomeeffectsofandrogensareundesirable,atleastundercertaincircumstances,agentshave
beendevelopedspecificallytoinhibitandrogensynthesisoreffects.Otherdrugs,originallydevelopedfor
differentpurposes,havebeenaccidentallyfoundtobeantiandrogensandnowareusedintentionallyforthis

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indication.SeeChapter63foramoredetaileddiscussionofandrogendeprivationtherapyforprostate
cancer.

InhibitorsofTestosteroneSecretion.AnalogsofGnRHeffectivelyinhibittestosteronesecretionby
inhibitingLHsecretion.GnRH"superactive"analogs,givenrepeatedly,downregulatetheGnRHreceptorand
areavailablefortreatmentofprostatecancer.AnextendedreleaseformoftheGnRHantagonist,abarelix
(plenaxisnolongeravailableintheU.S.)isusedfortreatingprostatecancer(Trachtenbergetal.,2002).
Becauseitdoesnottransientlyincreasesexsteroidproduction,thispreparationmaybeespeciallyusefulin
prostatecancerpatientsinwhomanystimulustotumorgrowthmighthaveseriousadverseconsequences,
suchaspatientswithmetastasesimpingingonthespinalcord,inwhomfurthertumorgrowthcouldcause
paralysis.

Someantifungaldrugsoftheimidazolefamily,suchasketoconazole(Chapter57),inhibitCYPsandthereby
blockthesynthesisofsteroidhormones,includingtestosteroneandcortisol.Becausetheymayinduce
adrenalinsufficiencyandareassociatedwithhepatotoxicity,thesedrugsgenerallyarenotusedtoinhibit
androgensynthesisbutsometimesareemployedincasesofglucocorticoidexcess(Chapter42).

InhibitorsofAndrogenAction

Thesedrugsinhibitthebindingofandrogenstotheandrogenreceptororinhibit5reductase.

AndrogenReceptorAntagonists

Flutamide,Bicalutamide,andNilutamide.Theserelativelypotentandrogenreceptorantagonistshave
limitedefficacywhenusedalonebecausetheincreasedLHsecretionstimulateshigherserumtestosterone
concentrations.TheyareusedprimarilyinconjunctionwithaGnRHanaloginthetreatmentofmetastatic
prostatecancer(Chapter63).Inthissituation,theyblocktheactionofadrenalandrogens,whicharenot
inhibitedbyGnRHanalogs.Flutamidealsohasbeenusedtotreathirsutisminwomen,anditappearstobe
aseffectiveasothertreatmentsforthispurpose(Venturolietal.,1999)however,itsassociationwith
hepatotoxicitywarrantscautionagainstitsuseforthiscosmeticpurpose.

Spironolactone.Spironolactone(aldactoneChapter25)isaninhibitorofaldosteronethatalsoisaweak
inhibitoroftheandrogenreceptorandaweakinhibitoroftestosteronesynthesis.Whentheagentisusedto
treatfluidretentionorhypertensioninmen,gynecomastiaisacommonsideeffect(CaminosTorresetal.,
1977).Inpartbecauseofthisadverseeffect,theselectivemineralocorticoidreceptorantagonisteplerenone
(inspra)wasdeveloped.Spironolactonecanbeusedinwomentotreathirsutismitismoderatelyeffective
(Cummingetal.,1982)butmaycauseirregularmenses.

CyproteroneAcetate.Cyproteroneacetateisaprogestinandaweakantiandrogenbyvirtueofbindingto
theandrogenreceptor.Itismoderatelyeffectiveinreducinghirsutismaloneorincombinationwithanoral
contraceptive(Venturolietal.,1999)butisnotapprovedforuseintheU.S.
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5ReductaseInhibitors.Finasteride(proscar)isanantagonistof5reductase,especiallythetypeII
dutasteride(avodart)isanantagonistofbothtypeIandtypeII.Bothagentsblocktheconversionof
testosteronetodihydrotestosterone,especiallyinthemaleexternalgenitalia.Thesedrugsweredeveloped
totreatbenignprostatichyperplasia,andtheyareapprovedintheU.S.andmanyothercountriesforthis
purpose.Whentheyareadministeredtomenwithmoderatelyseveresymptomsduetoobstructionofurinary
tractoutflow,serumandprostaticconcentrationsofdihydrotestosteronedecrease,prostaticvolume
decreases,andurineflowrateincreases(McConnelletal.,1998).Impotenceisawelldocumented,albeit
infrequent,sideeffectofthisuse,althoughthemechanismisnotunderstood.Gynecomastiaisanevenless
commonsideeffect(Thompson,2003).

Finasteridealsoisapprovedforuseinthetreatmentofmalepatternbaldnessunderthetradename
PROPECIA,eventhoughthateffectispresumablymediatedviathetypeIenzyme.Itappearstobeas
effectiveasflutamideandthecombinationofestrogenandcyproteroneinthetreatmentofhirsutism
(Venturolietal.,1999).

CLINICALSUMMARY
Testosteroneistheprincipalcirculatingandrogeninmen.Thevariedeffectsoftestosteroneareduetoits
abilitytoactbyatleastthreemechanisms:bybindingtotheandrogenreceptorbyconversionincertain
tissuestodihydrotestosterone,whichalsobindstotheandrogenreceptorandbyconversiontoestradiol,
whichbindstotheestrogenreceptor.Consequencesoftestosteronedeficiencydependonwhetherthe
deficiencyoccursinutero,beforepuberty,orinadulthood.

Testosteronedeliverysystemsaredesignedtoavoidtherapidhepaticcatabolismthatoccurswhennative
testosteroneisingestedorally.Availabledeliverysystemsincludeinjectableestersoftestosterone,implants,
andseveraltransdermalpreparations.Themajortherapeuticindicationfortestosteronetreatmentismale
hypogonadism.Treatmentshouldbemonitoredforefficacybymeasurementoftheserumtestosterone
concentrationandfordeleteriouseffectsbyevaluatingforobstructiontourineflowduetobenignprostatic
hyperplasia,forprostatecancer,andforerythrocytosis.

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