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European Journal of Endocrinology -18-1000 activity oftheirurineandinferred doses of testosteroneto men increased the estrogenic and Kundemonstratedthatadministrationoflarge 1920s ( Estrogens weredemonstratedintheurineofmen Introduction ADT orassolemodeofcouldbeausefulstrategyformenwithprostatecancer. insufficiently understoodtissue-specificestrogeniceffects).Finally,E2treatment,eitherasadd-backtoconventional testosterone andlowerE2),selectiveandrogenreceptormodulatorsestrogen (with use oftestosteroneasthetreatmentchoiceinmalehypogonadism,ratherthanaromataseinhibitors(whichraise clinical relevanceofE2actionsrequiresfurtherresearch.Fromaperspective,thecurrentevidencesupports the composition andglucosemetabolismvasomotorstability.Inothertissues,particularlybrain,elucidationofthe growth hormoneinsulin-likefactor-1axisregulation,boneandmaintenanceofskeletalhealth,body that, inmen,E2isanimportanthormoneforhypothalamic–pituitary–testicularaxisregulation,reproductivefunction, deprivation therapy(ADT)andfromobservationalstudiesincommunity-dwellingmen.Thecollectiveevidencesuggests steroid milieuinhealthymen,menwithorganichypogonadismorprostatecancertreatedandrogen reports ofmenlackingaromataseorafunctionalestrogenreceptoralpha,short-termexperimentsmanipulating sex reproductive andsomatictissues.HumanstudiescontributingevidencefortheroleofE2inmencompriserarecase at concentrationsexceedingthoseofpostmenopausalwomen,andestrogenreceptorsareexpressedinmanymale acting viatheandrogenreceptormayinfactbedependentonitsaromatizationtoestradiol(E2).Inmen,E2circulates Evidence hasbeenaccumulatingthat,inmen,someofthebiologicalactionstraditionallyattributedtotestosterone Abstract Endocrinology, AustinHealth,Heidelberg,Victoria,Australia 1 Nicholas Russell Estradiol asamalehormone MECHANISMS INENDOCRINOLOGY Department ofMedicineAustinHealth,UniversityMelbourne,Heidelberg,Victoria, Australiaand https://doi.org/ https://eje.bioscientifica.com Review and themolecularlevels. musculoskeletal andcardiometabolic healthbyandrogensandestrogens,both at theclinical health atAustinHospital, Melbourne,Australia.Hisresearch focusesontheregulationof (Austin Health),University ofMelbourneandconsultantendocrinologist head ofmen’s and in clinicalendocrinology. Heisaprofessorofmedicineatthe Department ofMedicine Mathis Grossmann Invited Author’s profile 1 ) and in the testis in 1952 ( 10.1530/EJE 1 , 2 -18-1000 and Mathis Grossmann , MD,PhD,FRACP, isaphysician-scientisttrainedinbothbasic biology 1 © 2019EuropeanSociety ofEndocrinology M Grossmann N Russelland 2 ). In 1937 Steinach in vivo Printed inGreatBritain 1 conversion , 2 responsible for aromatization of testosterone to 17 P450 enzyme,productofthe characterizationofthearomatase cytochrome regulatory included theidentification,isolation,sequencingand of testosterone to estrogens ( E2 inmen Published byBioscientifica Ltd. 2 Department of Downloaded fromBioscientifica.com at09/26/202106:51:16AM CYP19A1 3 ). Subsequent advances (2019) Endocrinology European Journalof [email protected] Email to M Grossmann should be addressed Correspondence 181 181 gene,theenzyme :1 , R23–R43

R23 –R43 via freeaccess β

European Journal of Endocrinology dehydrogenase ( to E1bythewidelydistributed17 potent endogenousestrogen,isreversibleoxidation The predominantmetabolicpathwayforE2,themost Metabolism ofestrogens assay methodologies( performed indifferentpopulationsandusing acrossstudies although theseconcentrationsvary substantially higher, rangingfromabout10to30 healthy malecirculating testosteroneconcentrationsare compared to 400 healthy youngmenand90 Median serum E2 concentrations are around 150 particularly inadiposetissue,muscle,boneandbrain( resulting fromperipheralaromatizationoftestosterone, originate from direct testicular secretion, with the rest One quartertoonehalfofcirculating E2isestimatedto Circulating E2inmen Physiology andmetabolismofestrogens human studies. of conclusions drawn from these provides a summary https://eje.bioscientifica.com estriol (E3),retainminorestrogenic activity( active forms( 4-hydroxylated metabolites undergomethylationtoless affinity, mayberelatively anti-estrogenic( less potentandtherefore,because theyretainER-binding the parentestrogens, while the2-hydroxy-estrogens are ( CYP1A2 andCYP3A4,locatedintheliverothertissues positions bycytochromeP450enzymes,particularly irreversible hydroxylationatthe2-,4-or16-carbon reaction ( oxidation ofE2toE1ismorerapidthanthereductive will predominantlydiscusshumanstudies. elucidating relevant biological mechanisms, this review Although pre-clinical models have beeninstrumental in articles were used to identify further relevant papers. November 1,2018.Referencelistsfromrelevantretrieved the MeSHterms‘estradiol’and‘men’,frominceptionto diverse structureshaveminorestrogenicactivity( and environmentalpharmaceuticalcompoundswith aromatized endogenoussteroids,estrogenmetabolites the majorendogenousestrogens( estradiol (E2)andandrostenedionetoestrone(E1), 14 Review ). The4-hydroxy-estrogensaresimilarinpotencyto For thisreviewthePubMeddatabasewassearched using 13 ). E2andE1,theparentestrogens,undergo 16 ). The16 pmol/L in premenopausal women, while pmol/L in premenopausal women, while 12 ). Forinfusionsoflabeledsteroid, 10 , 11 α hydroxyestrogens,including pmol/L in healthy older men, pmol/L inhealthyoldermen, ). M Grossmann N Russelland 4 ). Manyothernon- β hydroxysteroid 15 ). The2-and 17 ). pmol/L in pmol/L in al 1 Table nmol/L, nmol/L, 5 7 , , 6 8 ). , 9 ). ).

elsewhere ( for autocrineandparacrine actions.Asreviewed sex steroidsintargettissues themselves,withpotential complex ( from SHBGoralbumin perhapsasanSHBG-bound take intoaccountcellularuptake,eitherafterdissociation target tissuestoexerttheireffects.Thesestudiesdonot concept thatgonadal-producedsexsteroidscirculate to E2 concentrations,basedontheclassicalendocrine Most clinicalstudiesinferbiologicalactionsfromserum Intracrinology ofestrogens recently, thetransmembraneG-protein-coupledestrogen ( spectrometry to changewithincreasingclinicalavailability of mass are notcommonlymeasured,althoughthisislikely estrogens. Despitetheirabundance,estrogenmetabolites tissues wheredeconjugation may occurtoreleaseactive or bilebutalsomaycirculate inbloodandreachtarget Estrogen conjugates can not only beexcreted in urine by widelydistributedconjugationenzymes( conjugation withsulfate,glucuronideorglutathione, and their metabolites, are reversibly inactivated through ER ligandbindinginducesrapidphysiologicaleffects( factors. Therearealsonon-genomicpathwaysbywhich involved insignaltransductionbyreceptorsofgrowth ligand-independent fashion,bysecondmessengerkinases can alsobeactivatedtomodulategenetranscriptionina with genepromotersthatdonotcontainERE.TheER additional transcriptionfactors,allowinginteraction involve interactionoftheERwithcoregulatorsand bind to the same ERE. Other ligand-dependent pathways leading totheregulationoftranscription.ER to estrogenresponseelements(EREs)ingenepromoters ligand-activated ER dimerization with direct DNA binding ( tissue, pancreaticisletsandskeletalmuscle( in male brain, cardiovascular system, liver, bone, adipose throughout thehumanmalereproductivetract,andalso receptor 1(GPER)wasidentified( exist, createdbydifferentialsplicingofexons( superfamily. Multiple isoforms of eachreceptor type respectively, aremembersofthenuclearreceptor ER Estrogen receptorsinmen E2 inmen 22 α ). Theclassicligand-dependentpathwayinvolves andER In a parallel metabolic pathway, the parent estrogens, ER signalingoccursviaanumberofdistinctpathways 24 25 ), norlocalproductionand metabolismof β , encodedbythe ), someextragonadaltissues possessthe 16 ). Downloaded fromBioscientifica.com at09/26/202106:51:16AM ESR1 20 181 ). ERsareexpressed and :1 21 ESR2 ). α 19 andER 16 ). More genes , R24 23 18 via freeaccess ). ). β

European Journal of Endocrinology phenotypes reportedinmany clinicalstudies. associations ofcirculating E2concentrationswithbiologic immunoassays, maycontribute totherelativelymodest known but,incombination withtheuseofinaccurate estrogenic compoundsinindividualtargettissuesarenot tissues. Thenetbiologiceffectsofsuchlocallyacting steroidogenic enzymes not reportedto be active in gonadal produced dehydroepiandrosterone sulfate, andexpress metabolism ofcirculating precursors,suchasadrenal capacity for growth factor-1;KNDy,kisspeptin,neurokininBanddynorphin;T,testosterone. BPH, benignprostatehypertrophy;E2,estradiol;ER,estrogenreceptor; GH, growthhormone;HPT,hypothalamic–pituitary–testicular;IGF-1,insulin-like Temperature Brain Metabolism Body composition Bone GH-IGF-1 axis Reproduction HPT axis System Table 1 Review regulation Biological rolesofestradiolinmen. de novo Vasomotor stability Cognition Masculinization ofbrain Lipid metabolism Glucose metabolism Fat mass Muscle massandstrength Attainment andmaintenance Growth Hepatic IGF-1secretion Pituitary GHsecretion Prostate development, Maintenance oflibidoand Testicular descentand Negative feedback Process anatomy andphysiology of bonemass carcinogenesis hypertrophy, erectile function spermatogenesis sexsteroidsynthesisand/orfor M Grossmann N Russelland • • • • • • • • • • Comment • • • • • • • • • E2 stimulatesthepubertalgrowthspurtinboys E2 inhibitshepaticIGF-1responsetoGH pituitary level secretion witheffectsatbothhypothalamicand E2 appearstobetheprincipaldeterminantofGH reduce circulatingTtocastrateconcentrations. estrogens ifusedatsupraphysiologicaldosesto is consistentwithanetantineoplasticeffectof In menwithprostatecancer,clinicalevidence of E2inBPHorcarcinogenesis. There isnodefinitivehumandatatodefineanyrole signaling in In vitro role E2 appearstohaveabeneficialbutnon-essential descent andspermatogenesis ER signalingappearstoplayaroleintesticular sensitivity toGnRH. amplitude byreducingpituitarygonadotrope E2 producesnegativefeedbackonLHpulse frequency, probablyindirectlyviaKNDyneurons. E2 producesnegativefeedbackonGnRHpulse prevention ofhotflushes E2 isthepredominantsexsteroidresponsiblefor of Thavenotdemonstratedanycognitivebenefit small trialsofE2add-backinmenwithcastratelevels No roleforE2incognitionhasbeenprovenand cisgender identity ER been defined.Wherereported,menwithcongenital No roleforE2inbraindevelopmentmenhas metabolism E2 maynothaveanydirecteffectonlipid mixed onwhetherthisishepatic,peripheralorboth E2 appearstoimproveinsulinsensitivity.Dataare mixed onwhetherthisisadepotspecificeffect E2 appearstopreventgainoffatmass.Dataare Minimal roleifany normal bonemineraldensityandmicrostructure sex steroidforattainmentandmaintenanceof E2, actingviaER E2 directlycauseslatepubertalgrowthplateclosure likely viaGH–IGF-1axisstimulation α deficiencyandaromatasehavehad andanimalmodelssuggestaroleforER gonadotropin production( indirectly ( nucleus ofthehypothalamus toregulateGnRHneurons expressing (so-called KNDy) neurons in theinfundibular acts onER neurons express ER Human gonadotropin-releasinghormone(GnRH) axis regulation Hypothalamic–pituitary–testicular in utero E2 inmen α appearstobethepredominant prostateglanddevelopment. α 27 inkisspeptin,neurokininB,anddynorphin- ). E2 also has direct effects on pituitary ). E2alsohasdirecteffects onpituitary β but not ER Downloaded fromBioscientifica.com at09/26/202106:51:16AM 28 , 29 https://eje.bioscientifica.com α ). ( 26 181 ). It is likely that E2 26 102 32 :1 Clinical reference , 121 47 27 , 53 , 82 35 152 103 , , 54 , 82 68 64 50 28 35 , , 104 , 129 89 71 36 68 54 , , , , , , , , , 121 153 47 104 89 69 65 53 29 , , , , 96 157 38 133 , , 54 30 R25 , , 105 97 , 31 via freeaccess , European Journal of Endocrinology https://eje.bioscientifica.com of thepotentialforpharmacological AR-mediated of pure androgen agonists, while providing evidence concentrations ( suppressed testosterone,E2, LHandFSHtocastrate effects on prostate growth in healthy older men, DHT dihydrotestosterone (DHT) designed to assess androgen pharmacological dosesofthenon-aromatizableandrogen men. In a 2-year randomized controlled trial (RCT) of feedbackalsomay occurin hypothalamic-pituitary to GnRH. toreduce sensitivity also directlyactsonthepituitary suggestingthat circulatingarea underthecurve, E2 peaksand follicle-stimulating hormone(FSH)secretory gonadotropin secretion,E2add-backreducedLHand action. When these men were given GnRH tostimulate role for circulating E2 in reducing hypothalamic GnRH E2 add-backreducedLHpulsefrequency, suggestinga have normaltohighserumtestosterone.Inthesemen, with congenital aromatase deficiency ( pre andpostphysiologicalE2add-backintwomen hypothalamus ( feedback, itspredominantnegativeeffectoccursatthe E2 orplaceboadd-backconcludedthat,whilehasdual aromatase byhigh-doseketoconazole,andtestosterone, experimental castrationandsimultaneousinhibitionof subsequent study subjecting healthy and IHH men to of E2action,likelytoreduceGnRHpulsefrequency. A differential suggestedanadditionalhypothalamicsite in IHHmenundergoingthehypothalamic clamp. This healthy menwereapproximatelytwicethoserecorded thereby reducingLHpulseamplitude.incrementsin physiology, sensitivitytoGnRH, E2reducespituitary been pituitary, andtheauthorsinferredthat,innormal the hypothalamicclamp,siteofthisE2effectmusthave negative feedbackonLHsecretion.Formenundergoing that aromatizationoftestosteronetoE2isrequiredfor testosterone rise, LH increased in both groups, suggesting testosterone intothesupraphysiologicalrange.Despite AI treatment suppressed serum E2 and elevated serum of E2withdrawalcouldbedistinguished.Inbothgroups, andhypothalamic-dependenteffects pituitary-dependent responses in those undergoing the hypothalamic clamp, ( (AI) onluteinizinghormone(LH)secretion was examined hypothalamic clamp),theeffectofanaromataseinhibitor IHH) receivingfixedGnRHtreatment(generatinga men (withidiopathichypogonadotropichypogonadism; 30 Review ). BycomparingLHresponsesinhealthymento Direct androgenreceptor(AR)-mediatednegative Rochira In parallel experiments in healthy and GnRH-deficient t al. et 31 32 ). ). However, supraphysiologicaldoses examined gonadotropin secretion M Grossmann N Russelland 29 ). Suchmen de facto

these caseobservations. AR-dependent effectsinadulthoodisnotresolvedby programmingoractivational hypothalamic–pituitary hypogonadism, butnosemen analysiswasreported( cryptorchid righttestis,hypoplastic left testisandprimary viability ( normal spermcountwith a minorreductioninsperm years,haddescendedtestesofnormalvolume and 28 ESR1 in two men with homozygous missense mutations in the epididymis( disruption offluidreabsorptionintheefferentductules of been lessdramaticandconclusive. estrogen signalinginmalefertility, studies inmenhave studies inmicehavedemonstratedimportantrolesfor efferent ductulesofthetestisandepididymis( is foundinhumanimmaturegermcells,spermatozoa, there areconflictingdataincertaincelltypes.Aromatase reproductive tract,includingingermcells,although ER this manuscriptandrecentreviewsexist( function and spermatogenesis is beyond the scope of A comprehensivediscussion of theroleE2intesticular Spermatogenesis Reproduction AR-mediated effectsalsoplayarole. E2 isimportantforthisnegativefeedback,itlikelythat actions.Moreover,both hypothalamicandpituitary while negative feedbackongonadotropinactivationinvolves these inferredeffectsareorganizational during are alsorequiredtoreduceLHproduction( a normalLHconcentration,butthatAR-mediatedeffects and LH.ThissuggeststhatE2isnotsufficienttomaintain external phenotype,highconcentrationsoftestosterone have, despitecirculating E2sufficienttocauseafemale (CAIS) duetoinactivatingARmutations.Thesewomen women withcompleteandrogeninsensitivitysyndrome feedback notrequiringitsaromatizationtoE2. testosterone exerts a direct negative hypothalamic and testosterone add-back have also concluded that to above ( physiology. Experimentalparalleldesignstudiesreferred effects, donotprovethattheseeffectsareimportantin E2 inmen α andER Overall, human studies suggest that E2-mediated Additional indirectevidencecomesfrom46,XY Male ER causingnon-functional ER 35 31 β .Tescn a,a g 8 years,hada ). Thesecondman,atage 18 ) using medical castration with ketoconazole areexpressedthroughoutthehumanmale α -knockout miceareinfertiledueto 34 ). Testicular functionhasbeenreported Downloaded fromBioscientifica.com at09/26/202106:51:16AM α . Thefirstman,atage 181 :1 33 21 ). Whether 21 ). Briefly, ). While in utero R26 36 via freeaccess ).

European Journal of Endocrinology non-AI cohort,andalsoby linear regressionmodelingof each outcome in theAI cohort with the outcome in the were inferredindirectly, bycomparingmeanchangefor of meninwhomE2was clamped.E2-relatedeffects assessed directly by comparing changes between groups E2-dependent effects.Testosterone-related effects were design allowed for discrimination of testosterone from each testosteronedoseincrement(non-AIcohort).This or withtheexpectedcorrespondingE2incrementsfor lowconcentrations (AIcohort) with E2clampedtovery ranging fromcastratetomildlysupraphysiologic,either doses thatproducedserumtestosteroneconcentrations to add-backwithoneoffivetransdermaltestosterone gel weeks( for 16 GnRH analogwithorwithoutAIto400healthyyoungmen surgical castration( using estrogensmaybettermaintainsexualfunctionthan cancer suggeststhatandrogendeprivationtherapy(ADT) ( during E2 treatment, either alone ( deficiency hadincrementsinlibidoandsexualactivity role. Innon-blindedstudies,twomenwitharomatase but various lines of evidence support some physiological essential formalelibidoanderectilefunction( ER The evidence from menwithcongenital non-functional Libido anderectilefunction the reproductivetract( be expectedtoretainligand-independentER explanation isthatmenwitharomatasedeficiencywould there isnodirectevidenceforthisinhumans.Analternative phytoestrogenintake( to berelateddietary function despitecongenitallackofE2hasbeenpostulated The fact that some men appear to have normal testicular a roleforE2intesticulardescentandspermatogenesis. germ cellarrest( degrees of impaired spermatogenesis including varying deficiency haveundergonetesticularbiopsy, showing altered spermmotility( were normal( reported ( ( 43 In mostcases,testicularsizewasnormal( been reportedinmenwithcongenitalaromatasedeficiency. spermatogenesis withaging( 46 47 Review , α , ). Non-definitive evidencefrom menwithprostate 44 oraromatasedeficiencysuggeststhatE2isnot In aphysiologicalexperiment,Finkelstein Aromatase-knockout miceexhibitprogressivelyimpaired 47 , , 45 48 ), although a few men had low testicular volume ), althoughafewmenhadlowtesticularvolume 43 , 49 , 42 45 54 ), and cryptorchidism has been commonly ), andcryptorchidism hasbeencommonly , , ). Participantswerefurtherrandomized 46 44 47 52 , ) orreduced( , 48 ) andGnRHanalogs( 48 50 44 , ). Where reported, sperm counts ). Wherereported,spermcounts ). , 49 46 ). These observations suggest suggest ). Theseobservations ). A few men with aromatase ). Afewmenwitharomatase 37 ), and abnormalities have ), andabnormalitieshave M Grossmann N Russelland 39 51 , ) or with testosterone 46 ), commonly with ), commonlywith 38 , 53 39 α 37 signaling in signalingin ). , et al. ), although ), although 40 39 , gavea 41 , , 46 42 ), , ( cells whileER ER stroma ( Estrogens aresynthesizedbyaromataseintheprostate Prostate might havecontributedtoreductionsinlibido. disturbance), inadditiontotheirE2-loweringactions, adverse effectsofAI(e.g.hotflushesandassociatedsleep not reported,itcannotbeexcludedthatpotential serum E2isnotcompletelyexcluded.Moreover, although between cohorts that were not due todifferences in no placebo, so the possibility of systematic differences to theAIcohortwasnotrandomizedandthere erectile function,independentoftestosterone.Assignment E2 clearlyexertedapositiveeffectonsexualinterestand the cohort–testosteronedoseinteraction.Inthisanalysis, ER that DHTwouldactually inhibit prostategrowthvia because thestudywasdesigned totestthehypothesis arms. However, theseresultsaredifficult tointerpret no differenceinprostategrowth betweenDHTandplacebo maintenance ofAR-signaling( older men;gonadotropins,E2andTweresuppressed,with to thishypothesis,ina2-yeartrialofDHTtreatment of the prostatearearomatizationdependent.Addingsupport authors toinferthatthetropiceffectsoftestosteroneon treated and testosterone/AI-treated men, leading the increase inprostatevolumecomparedwithplacebo- receiving testosteronealonehadasmallsignificant months. Men was change in prostate volume after 12 outcome transdermal testosteroneplusAI.Theprimary randomized toplacebo,transdermaltestosteroneor age-associated mildlylowtestosterone( on BPHinmenreceivingtestosteronereplacementfor from non-aromatization-dependenteffectsoftestosterone trial ( of benignprostatichypertrophy(BPH)( 5 are clearlyAR-mediatedeffectsillustratedbythefactthat in testosterone-stimulatedprostategrowth,althoughthere prostate cancerriskinanimalmodels( during prostateglanddevelopmentinfluenceslater unphysiologically timedordosedestrogenexposure of highsystemicestrogenexposure( role duringnormalprostatedevelopment epithelial progenitorcells( E2 inmen 56 α -reductase inhibitors are effective in treating symptoms -reductase inhibitorsareeffectiveintreatingsymptoms β α ). GPERhasbeendemonstratedinstromalcellsand -mediated effectsofitsmetabolite, 3 appearstobeprimarilylocatedinprostatestromal Aromatization to E2 is hypothesized to be important Aromatization toE2ishypothesizedbeimportant n

= 31) was conducted to differentiate aromatization 31) wasconductedtodifferentiatearomatization 55 ) andhaveautocrineparacrineactions. β isfoundprimarilyintheepithelium Downloaded fromBioscientifica.com at09/26/202106:51:16AM 57 ). Estrogensappeartohavea 32 https://eje.bioscientifica.com ). In this trial, there was ). Inthistrial,therewas 181 58 56 63 β :1 Adiol. ). , ). A recent small ). Arecentsmall 59 in utero 57 ). Men were ). Menwere ). However, , atime R27 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com is insufficientiflocalE2 production remainsimpaired because restorationofnormal circulating E2concentration GH–IGF-1 axis in the setting of congenital E2 deficiency or possibly becauseofabnormal developmentofthe these menwasnotableto normalize GHsecretion( insulin-like growthfactor-1(IGF-1)( stimulated growthhormone(GH)secretionandlow Men withcongenitalaromatasedeficiencyhaveimpaired factor-1 axis Growth hormoneinsulin-likegrowth disease arepoorlyunderstood. gland, buttheconsequencesforprostatehealthand ER signalingalsohascomplexeffectsontheprostate testicular descent,spermatogenesisandsexualfunction. in variousaspectsofmalereproductivehealth,including is consistentwiththefactthatERsignalingplaysarole experimental studiesinhealthyyoungerandoldermen studies (including ER and aromatase-deficient men) and carcinogenic testosterone signalingisabolished. effects ofestrogenicsignalingappearoutweighedifpro- trials suggest that potential prostate cancer-promoting increased cardiovascular risks ( transdermal E2asasolemodeofADThavenotreported effect ( toxicity duetotheprothrombotichepaticfirst-pass using oralestrogens were negated by cardiovascular any clinical benefit ( in addition to surgical or medical castration did not show trials ofestrogensignalingablationthroughtheuseAI Conversely, inmenwithcastrateresistantprostatecancer, to castrate concentrations in men with prostate cancer. supraphysiologic dosestoreducecirculating testosterone antineoplastic effectofestrogen-basedtreatmentifusedat metabolites ininducingprostatecarcinogenesis ( important rolesforgenotoxicityofhydroxylatedestrogen and diseasedprostate.Evidencefromratmodelssuggests predict, andbiologiceffectsmaydifferbetweenhealthy prostate or prostate cancer cells has been difficult to result, theneteffectofestrogenicsignalinginnormal be antiproliferativeandanticarcinogenic ( prostate, but ER ER suggesting thepotentialforautocrinesignalingvia in human prostate adenocarcinoma epithelial cells Review α ( In summary, thecollectiveevidencefromrarecase The clinicalevidenceislargelyconsistentwithanet Aberrant aromataseexpressionhasbeendemonstrated 55 64 ). ER ), morerecentsmallerstudiesusinghigh-dose α activation has proliferative effects in the β - and GPER-mediated effects appear to 63 ). While benefits in early studies 65 M Grossmann N Russelland ). Overall, these clinical 66 ). Exogenous E2 in ). ExogenousE2in 60 , 61 62 ). Asa ). 66 ),

the hypothalamus. However, Er the possibility that theE2effect may beatthe level of no differenceinGHsecretionbetweengroups,raising stimulationtests,therewas secretion inmen.Inpituitary concluded that E2 isthe principal determinant of GH positively correlatedwithE2concentration.Theauthors (91 301 the transdermalplaceboarm.MeanE2concentration was 50% higher in the E2 arm than the intervention, endpoint,overnightGHsecretiononday22of primary et al. AI plustransdermalE2orplacebocontrols),Roelfsema analog plusintramuscular(IM)testosteroneadd-back and indirectmechanisms( is importantinregulation of GHsecretionbybothdirect women, andindirectevidencefrommen,suggestthatE2 ( reducing bone resorption and increasing bone formation. effect ofwhichistomaintain remodelingbalanceby increase bonesizeinmen. role, particularlyinpromoting periostealappositionto skeleton ( steroid inthedevelopmentandmaintenanceofmale points toE2,actingviaER cells contain ER and AR ( Osteoblasts, osteocytes,osteoclastsandmarrowstromal Bone main sexsteroidregulatoroftheGH-IGF-1axisinmen. signal forIGF-1( downstream oftheGHreceptor, andthus,thetranscription which inhibitstheJanuskinase2(JAK)2phosphorylation stimulating suppressorofcytokinesignaling(SOCS)-2, ( and liver relative exposure of hypothalamus/pituitary to GHsothattheneteffectofE2onIGF-1depends stimulating GHrelease,E2inhibitshepaticIGF-1response produce anincreaseinIGF-1concentration( upregulates somatotrophGHsynthesisandrelease( factor 1,apotentGHtranscriptionfactor, whichinturn ER although theGHpromoterlacksERE,E2actsviaER somatotrophs,and in pituitary E2 inmen 67 70 β ). Additionallinesofevidencefrompreclinicalmodels, , ± to stimulate pituitary-specific positivetranscription tostimulatepituitary-specific ± Using aT/E2clampinhealthyoldermen(GnRH E2 hasmultipledirectand indirect actions,thenet In summary, E2ratherthantestosteroneappearsthe E2-stimulated GHinRoelfsema’s studydidnot 71 isolatedtheeffect of E2onGHsecretion (

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66 pmol/L). PulsatileGHsecretionwasstrongly ). E2inhibitsthehepaticIGF-1responsetoGHby pmol/L was triple the basal E2 concentration 74 ). Androgens have a smaller but important 70 ). Downloaded fromBioscientifica.com at09/26/202106:51:16AM 72 67 , , α 73 68 , asthepredominantsex ). The weight of evidence α ). in vitro and ER 181 datashowthat, :1 β are expressed 68 ). Despite 68 ). The 69 α R28 and ). via freeaccess European Journal of Endocrinology and cessationofgrowth( growth plateinbothsexes causesgrowthplateclosure has beenrecentlyreviewedelsewhere ( via E2-mediatedstimulation oftheGH–IGF-1axis.This studies suggestthatthisislikelytobeanindirectaction of E2 on increasing linear growth in men. Pre-clinical do notresolvethemechanismofearlypubertaleffect ( linear growthwithin12 months resulted inrapidepiphysealclosureandtermination of congenital aromatasedeficiency, E2treatment initiation ( the 50th centile at age 17 to the 90th centile at age 20 of E2 treatment, with an increase in relative heightfrom undetectable. Inthisman,growthcontinuedafterinitiation testosterone concentrationsweresupranormalandE2was Tanner stage V,before treatment, bone age was12 years, years, with congenitalaromatasedeficiency. Atage17 pre andpostinitiationofE2treatmentinayoungman growth inboyswasdemonstratedbythecharts of appendiculargrowth( growth spurt,withaccelerationoftruncalanddeceleration and tissue E2 concentrations stimulate the pubertal growth, leadingtolongerleglength( predominantly becauseofalongerperiodprepubertal not ariseuntilpuberty( by theGH–IGF-1axis( skeletal growth,moreappendicularthanaxial,ismediated Pre-puberty, serum andtissueE2 is extremelylow, and E2 hasconcentration-dependenteffectsonskeletalgrowth. achievement ofpeakbonemass E2, linearbonegrowth,cessationofgrowthand acting uponthem( bones isregulatedaccordingtothepowerofmuscles mechanism bywhichbonestrengthofload-bearing important formechanotransduction,thehomeostatic effects ofER cells ( kappa Bligandtoosteoprotegerinbyosteoblastlineage production, andthesecretionratioofnuclearfactor in particularbyreducingT-cell tumornecrosisfactor- and immune cells in ways that limit bone resorption, osteoblasts. E2 alters cytokine production from bone and promotedifferentiationinhibitapoptosisof differentiation andpromoteapoptosisofosteoclasts in women,thepredominantactionsofE2aretoinhibit Based largelyonpreclinicalevidence,andsomestudies 40 Review ). Incontrast,inanolder(age In early puberty, in boys and girls, increased serum In latehumanpuberty, higherE2availabilityatthe 73 ). Inpreclinicalstudies,ligand-independent α andER 75 76 ). β ). Skeletal sexual dimorphism does ). Skeletalsexualdimorphismdoes 77 inosteoblastlineagecellsare 79 ). Men are taller than women, ). Menaretallerthanwomen, 79 , ). Thisisadirecteffectof 80 M Grossmann N Russelland , 82 81 = ). These observations ). Theseobservations 78 27 years) man with years) manwith 27 ). The E2 effect on ). TheE2effecton 83 ). ). α

identified hundredsofotherlociacrossthegenome.In association studies(GWAS) onadultheighthave associated withadultheightbutlargegenomewide differentiation) ( containing gene, as sexchromosome-relatedshortstaturehomeobox- promoting genesontheadditionalXchromosome(such likely tobepartlydueanincreaseddoseofgrowth- in Klinefeltersyndromehasapre-pubertalonsetandis E2-mediated growthplateclosure.However, thetallstature greater legandlessertruncallength, because offailure tall staturewitheunuchoidproportions,characterizedby do not experience a pubertal growth spurt, but develop truncal length( period of intra-pubertal growth and greater adulthood earlier cessationofgrowthsothatboyshavealonger of chondrocytes( E2 ininhibiting proliferation and promoting apoptosis congenital aromatasedeficiency: lackofpubertalgrowth phenotype. However, the phenotype is similar in menwith be invoked to explain other features of the skeletal E2 resistance,whichresults inhighserumE2andcould over-activated inmenwith non-functionalER ( or roles for ER dependent role for ER hypogonadism ( in menwithcongenitalaromatasedeficiency( which isincontrasttothehighboneremodelingseen functional ER ( but bonemineraldensity(BMD)datawerenotreported left testis,lowserumtestosteroneanddelayedboneage, second manhadanundescendedrightandhypoplastic thickness andtrabecularvolumewerereduced.The bone mass,evenadjustedforlowage.Cortical growth intoadulthood.Thiswasaccompaniedbyreduced delayed epiphysealclosureresultingincontinuedlinear 89 testicular sizeandserumtestosteronewerenormal( had delayedbonematuration. In thefirstcase, inwhich cartilage development. many newlyassociatedgenesinvolvedinskeletaland related tochondrocytesandosteoblastsincluded these lociareparticularlyhighlyexpressedintissues 20% oftheheritabilityinheight( ancestry, 697variants,clusteredin423lociexplained a recentstudyofover250,000individualsEuropean E2 inmen 36 36 ), therewasabsenceofthepubertalgrowthspurtand , ). Interestinglythebestcharacterizedmanwithnon- ESR1 The tworeportedmenwithnon-functionalER 74 ). These non-ER ( 86 ) and α ( 78 90 β 85 89 or GPER in suppressing remodeling ). Menwithprepubertalhypogonadism SHOX 84 , ). ) hadalowboneremodelingstate, 91 ). HigherE2ingirlsstimulatesan α CYP19 -mediated effects of E2 are potentially -mediated effects of E2 are potentially ). Thismayindicateanon-ligand- α in promoting bone remodeling Downloaded fromBioscientifica.com at09/26/202106:51:16AM , which influences chondrocyte ( 87 https://eje.bioscientifica.com ) polymorphismsare 181 88 :1 ). Thegenesin α -induced 40 ) and R29 35 via freeaccess α ,

European Journal of Endocrinology https://eje.bioscientifica.com contrast, testosteroneconcentrations werenotassociated strong evidenceofacausal link betweenE2andBMD.In general caveats of Mendeliananalyses, this provides in thevariouscohortsranged from18to76 years. Within measured inadulthood( with a0.048standarddeviationincreaseinLSBMD 3.7 lumbar spine(LS)andfemoralnecktotheextentthat a positive relationship between serum E2 and BMD at the Genetic FactorsinOsteoporosisConsortiumreported a and BMDdatafromvariouscohortscontributingtothe resultsfromtheEuropean GWASusing summary ( in GWAS ( E2 concentrations in European and Chinese adult men cortical thickness( deficiency producedadramaticincreaseinbonesizeand withcongenitalaromatase old man(boneage12 years) aromatase dependent because E2 treatment of a 17 year- testosterone effectonperiostealexpansioninmenis measured directly( that freehormonefractionswerecalculatedratherthan immunoassay ratherthanmoreaccuratemethods,and free E2,notingthatsexsteroidsweremeasuredby serum-free testosteroneandnegativelyassociatedwith bone masswaspositively associated withcross-sectional reported thatperiostealcircumference atthetimeofpeak of alargehomogenouscohort18-to200year-oldmen Osteoporosis andObesityDeterminants(GOOD)study being estrogendeplete( 46,XY CAIS have deficits in spineBMDdespite never appears tobethecase in humans because womenwith direct AR-mediated effects in late puberty ( pattern ( secretory neonatal testosteronesurgeimprintstheadultmaleGH growth dependonanintactGH–IGF-1axis ( rodents suggeststhatsexdifferencesinradialbone width byendocorticalapposition( bone formationandpredominantlyincreasecortical bone massinadulthood.Women havelessperiosteal than females, resulting in greater cortical width and peak puberty, menhavegreaterperiostealboneexpansion function of bone mineral content and bone size. During important determinantoflifetimefracturerisk( ER Together, suggest that E2 signaling via these observations This phenotypeisremediablewithE2therapy( leading totallstature;genuvalgumandlowbonemass. spurt; continuedlineargrowthaftersexualmaturation, Review α pmol/L genetically increased serum E2 was associated iscriticalinnormalmalebonedevelopment. Peak bonemassatthecompletionofgrowthisan SNPs in 96 CYP19 , 97 ). Mendelianrandomizationanalysis 40 93 areassociatedwithserumE1and 95 ). ). In rodents, there appears to be ). However, atleastsomeofthe 94 97 ). Additionally, theGothenburg ). Themeanageofparticipants M Grossmann N Russelland 77 ). Evidencefrom 92 92 ). This also 77 ), butthe 40 ). Itisa , 82 97 ). ) cross-sectional study, mayberesponsiblefordifferencesin pubertal, testosteroneconcentrations,notmeasuredinthis unclear. The authors speculated that differences in earlier, mass. Thus, the mechanism of this association remains did notaccountfortheeffectofpolymorphismsonbone genotypes, andstatistically, testosteroneconcentrations measured by immunoassay, was no different between suggesting loweraromataseactivity, althoughserumE2, were associatedwithhighercross-sectionaltestosterone, polymorphisms associatedwithgreatercorticalbonesize (a functionofcross-sectionalareaandthickness)( the associationmediatedbydifferencesincorticalbonesize to beassociatedwitharomatasegenepolymorphisms, homogenous cohortof18-to20-year-oldmenwasshown resolved byMendelianrandomization. or intheattenuationofbonelossoldermenisnot most importantintheachievementofpeakbonemass with theseSNPs.WhethergeneticallydeterminedE2is week 6( withdrawn, andrepeatmeasurements weremadeat markers atweek3,either T, E2,both orneitherwere E2. Following baseline assessment of bone remodeling add-back of physiological doses of testosterone and analog plusAIin59healthyoldermenwithtransdermal In onesuchstudy, Falahati-Nini of BMDandsuppressionabnormalboneremodeling. the relativeimportanceofeachhormoneinmaintenance treatment andadd-backoftestosteroneorE2haveassessed hypogonadism inhealthymencombinedwithAI concentrations ( DHT, anon-aromatizableandrogenwhichlowersE2 E2 andincreasetestosterone( and theseparameters( microstructure andfracturesthanwithserumtestosterone E2, particularlynon-SHBG-boundandBMD, generally foundclosercorrelationsbetweenserum dependent. evidence suggeststhattheseeffectsaremostlyE2 microarchitecture ( bone remodeling and deterioration in bone density and Severe hypogonadism in oldermeninducesaccelerated of hypogonadism E2 andbonelossinoldermenmodels bone thickness. periosteal appositionleadingtothedifferencesincortical E2 inmen Short-term experimentsofGnRHanalog-induced Among oldermen,epidemiologicalstudieshave In the GOOD study, peak areal BMD in a large 90 ). Sexsteroidwithdrawalleads toanincrease 32 ), bothreduceBMDinmen. 91 ). Observational andexperimental ). Observational 99 Downloaded fromBioscientifica.com at09/26/202106:51:16AM , 100 102 , 101 ), andtreatmentwith t al. et 181 ). AIs,whichlower :1 usedaGnRH 98 ). The R30 via freeaccess European Journal of Endocrinology of participantshadanincident fracture( althoughfreeE2 wasnotreportedandonly10% 6 years, of E2 with change in BMD or incident fractures over men (meanage76.9 in1700 measuring sexsteroidsby mass spectrometry finding ( risks aremodest,andtheassociationisnotauniversal in oldermen( between serumE2,particularlyfreeandfracturerisk anassociation studieshaveobserved Many observational Serum E2andfracturesinmen arms was6.7%(95%CI3.7–9.7)infavorofE2. for 60participants,withanestimateddifferencebetween endpoint, 1-yearchangeinspineBMD,wasanalyzable years.Theprimary scans atbaselineandannuallyfor2 (DXA) dualenergyx-rayabsorptiometry who underwent prostate cancer( (castrate testosteroneandE2)inmenwithadvanced E2 (highE2,castratetestosterone)versusGnRHanalogs bone sub-study of an ongoing trial of ADT with transdermal because ofsteadystatecouplingtheseprocesses. term effectsofsexsteroidwithdrawalortreatment, resorption andformationcannotbeusedtoinferlong- studies revealingdifferentialchangesinbiomarkersof is primarilyduetoE2deficiency. However, short-term rate andbonelossthatoccursinmalehypogonadism ( short-term anti-resorptiveandpro-osteoblasticeffects reduced serum CTX and increased P1NP, consistent with analogs forprostatecancer, transdermalE2add-back men rendered chronically hypogonadal with GnRH replacement dose( in menwhoreceivedAIateachactivetestosterone quantitative computedtomographywhichweregreater 1 collagentelopeptide(CTX)anddeclinesinBMDby caused elevationsinserumbetacarboxyl-terminaltype of inducedhypogonadisminhealthyyoungermen but nottestosterone. and E2withdrawal,thiseffectwaspreventedby amino-terminal propeptide (P1NP), fell with testosterone study, theosteoblastlineagemarker, procollagentype1 model, testosteronehadnoindependenteffect.Inthis even without testosterone, and in ananalysis of variance Significant increaseswerepreventedbyE2add-back, 1 collagen,indicatingresorptionofmineralizedmatrix. deoxypyridinolineandN-telopeptideoftype in urinary 104 Review Longer-term interventional dataareavailablefroma Longer-term interventional In Finkelstein’s study(discussedabove)( ). Thesestudiessuggestthatthehighremodeling 108 , 109 100 , 105 110 103 , ). Thissub-studyenrolled74men 106 ± ). Ahigh-qualitylongitudinalstudy ). Inanother4-weekRCTenrolling

. years)showednoassociation 5.5 , 107 ). Ingeneral,attributable M Grossmann N Russelland 110 54 ), 16 weeks ). Alarge were attenuatedinmen receiving supraphysiological percentage bodyfatandsubcutaneousarea gains of testosteronereplacement dose.IntheAI-treatedmen, deficiency astheyoccurred in AI-treatedmen,irrespective abdominal fat( hypogonadism causedgainsinsubcutaneousandintra- independent effectofE2. below athresholdofapproximately6.9 These lossesweretestosteronedependent,decreasing analogs lostmusclemass,sizeandstrengthover16 weeks. healthy youngermenrenderedhypogonadalwithGnRH experimental data( and for skeletalhealthinmen,basedonobservational of 37–92 and22to174( (75–85 years) 23 to154 E2 range from 38 to 196 referencerangesforserum reported massspectrometry in whomhypogonadismhasbeenrigorouslyexcluded, genetic alterationsinserumtestosteroneonfracturerisk. 1.35; 95%CI1.18–1.55).Therewasnocausaleffectof with anincreased risk ofany self-reported fracture (OR serum E2 by 1SD (35.2 and self-reported17,650fractures.Ageneticallyreduced The menenrolledinthestudywereaged56.9 of Europeanorigin,capturedasparttheUKBiobank. reported ( testosterone-associated SNPs onfracture risk wasrecently Mendelian randomizationstudyofE2-associatedand or strength.InFinkelstein’s study(discussedabove)( level expressionofER expressed in human adipose tissue ( nearly allof these dataarefromwomen( expressed inthestromaofhumanadiposetissue,although ( In men,aromatase activity is reported in skeletal muscle Body composition:E2,muscleandfat lipid metabolism Body compositionandglucose predominantly importantforskeletalhealthinmen. effects onskeletalmuscle,E2appearstobethesexsteroid bone microstructure,andindirecteffectsthoughanabolic testosterone hasdirecteffectsonboneremodelingand E2 inmen 114 In thesamestudy, experimental profound E2 doesnotappeartobeimportantformusclesize In summary, theavailabledatasuggestthat,while Although further research is required in populations ) andadiposetissue( pmol/L have been suggested to be necessary pmol/L havebeensuggestedtobenecessary 111 mlL(57 years),22to166 pmol/L (65–75 ). This study useddata from 175,583 men 54 ). Thesewerepredominantly duetoE2 103 α inhumanskeletalmuscle( , Downloaded fromBioscientifica.com at09/26/202106:51:16AM 113 pmol/L) was robustly associated pmol/L in men aged ). > 9 85 years) ( 85 years) ). Aromataseisstrongly https://eje.bioscientifica.com 116 181 ) and there is low mmol/L, withno :1 115 112 ). ERsarealso ). Thresholds ± < 8.1 years 8.1 years 65 years, 65 years, pmol/L 117 R31 54 ). via freeaccess ),

European Journal of Endocrinology https://eje.bioscientifica.com an agonistatEr mechanism ofeffectisvia the DHTmetabolite3 studies. However, asdiscussedabove,another theoretical predominantly VAT, masscouldbeinferredfromthese testosterone, aspecificeffect ofE2inlimitingfatmass, aromatizable, andprofoundlysuppressesserumE2 not distinguishedinthisstudy. Because DHT isnon- group differencewasnon-significant. VAT andSAT were increase intheplacebogroup,althoughbetween- in fatmassby1.0–1.5 strength as expected ( mass by1.0–1.5 ofageorolder,healthy men50 years DHTincreasedlean RCT of DHT treatment to inhibit prostate growth in 114 to testosterone-treated men ( subcutaneous adiposetissue(SAT) orleanmasscompared increased visceraladiposetissue(VAT) withnochangein transdermal testosterone or placebo, DHT treatment years( older than40 9-month RCTrandomizingabdominallyobesemen adiposity ( orobesewithexcessabdominal generally overweight fat gain.Menwithcongenitalaromatasedeficiencyare to E2withdrawal( contributed tothebodycompositioneffectsattributed expected tolowerGH and IGF-1whichmighthave add-back inFinkelstein’s andJuang’s studieswouldbe systemic E2withdrawalinthecontextoftestosterone an E2-dependenteffect.Asothershavepointedout, the dutasterideandtestosterone-onlygroupssuggesting mass increasedandproportionfatdecreasedin and AIgroups,serumE2increased,proportionfat-free weeks.Comparedwiththeplacebo at baselineand14 (placebo group).BodycompositionbyDXAwasassessed A separate group received placebos for all four treatments (AI group),orplacebo(testosterone-onlygroup)( (dutasteride group),AItoinhibitaromatizationE2 with eitherdutasteridetoinhibitreductionDHT supraphysiological transdermaltestosteroneadd-back men withoutdiabeteswithaGnRHantagonistplus adipogenesis andtowardmyogenesis( ( increased musclemass,andlipolyticmyokineproduction to AR-mediated effectsonfatmassmightbesecondary doses ofnon-aromatizableandrogens( reporting reductionsoffatmassusingpharmacological AR-mediated effects.ThisisinagreementwithRCTs testosterone replacement,suggestiveofpharmacological 119 Review Other humandatasupportaroleforE2inlimiting In anRCT, Juang ) ordiversionofpluripotentstemcellsfrom 38 , β 39 kg togetherwithasmallincreaseingrip . Er , 122 β 40 isexpressedinhumanadipose tissue , 32 ). kg intheDHTgroupwithasmall 42 ). However, there was a decrease n , t al. et

= 44 31) totransdermalDHT, 123 , 45 treatedyoungobese M Grossmann N Russelland ). Inanother24-month , 46 120 , 48 32 ). , , 49 118 ). Inone ). Such β Adiol, 121 ). ).

E2 serum concentrations and urinary productionrates E2 serumconcentrationsandurinary feedback onLHproduction.Inthe1970shigherE1and elevates E2concentrations,whichincreasesnegative is thatinobesity, excessadiposetissuearomataseactivity inappropriately normalLH.Onehypothesizedmechanism free testosteronealsofalls,andthisisassociatedwithlowor and thereforetotaltestosterone,butasobesityincreases, mass indexinmen( linear correlation between serum testosterone and body studieshaveconsistentlyfoundanegative Observational Effects ofobesityonE2 compared toSAT ( expression ofER depot-specific effectsofE2aresupportedbydifferential gamma-induced adipogenesis( regulator ofperoxisomeproliferator-activated receptor- ( tissue and pancreatic islet cells ( other tissues,suchasthebrain, skeletalmuscle,adipose beneficial effects of E2 signaling on insulin sensitivity in insulin sensitivity( effects, actingviahepatic ER ( have insulinresistance,whichimproveswithE2treatment Men withcongenitalaromatasedeficiencyarereported to testosterone ( diabetes islowandremainsdirectlycorrelatedwithserum Dhindsa serum E2producedbyexcessiveadiposetissuearomatase, testosterone is due to negative feedback from elevated tothehypothesis thatthislow type 2diabetes.Contrary Subnormal serumtestosteroneisprevalentinmenwith Glucose metabolism concentrations werepositivelycorrelated. mostly didnothavediabetes( also intheEuropeanMaleAgingStudywhichmen normal serumfreetestosterone.InDhindsa’s study, and testosterone hadlowerE2concentrationsthanthosewith or normalserumfreeT( in obesemenwithtype2diabeteseithersubnormal equilibrium dialysis to accurately measure total and free E2 study byDhindsa the excessaromatization hypothesis. For example,a ( were reportedinobesemencomparedwithleancontrols E2 inmen 116 129 126 E2 mayhavebeneficialeffectsonglucosemetabolism. ) and in pre-clinical studies appears to be a negative ). Inmalemice,E2appearstohavedirectbeneficial ). However, there are little subsequent data tosupport t al. et 127 showedthatE2inmenwithtype2 β ). 1 isoforms,whicharereducedinVAT 116 et al. 125 130 ). employed mass spectrometry and employedmassspectrometry ). InsulinresistancelowersSHBG Downloaded fromBioscientifica.com at09/26/202106:51:16AM ). Rodentstudiesalsosuggest 127 ). Menwithsubnormalfree α 128 inthelivertoimprove 124 ), testosteroneandE2 ). Thehypothesisof 131 181 :1 ). E2 may also R32 via freeaccess European Journal of Endocrinology ( increased comparedtoplacebo, withnochangeinLDL-C with benignprostatichyperplasia, TC,HDL-CandTG controlled trialofGnRH analog therapyin50men lipoprotein cholesterol (HDL-C). In a6-monthplacebo- ( density lipoprotein cholesterol (LDL-C) and an increase increase ( eitheran triglycerides (TG)(25%).Thesestudiesobserved modest increaseintotalcholesterol(TC)(7–10%)and controlled studiesreportthatADTisassociatedwith a physical activity. Most( changes inbodycomposition,insulinresistanceand uncontrolled, andlikelyconfoundedbyADT-induced parameters. Additionally, many ofthesestudies were aboutchangesinlipid heterogeneous observations have beennon-randomizedbynecessityandmade from thedyslipidemiaofmetabolicsyndrome.Studies concentrations, appearstoalterlipidsinapatterndistinct which reduces both testosterone and E2 to castrate In menwithprostate cancer, ADTwith GnRH analogs, Lipid metabolism peripheral insulinsensitivityimproved. sensitivity whichisinhibitedbyDHT. Bothglobaland The authorsinferaneffectofE2inimprovinginsulin or AI group (GnRH analog plus testosterone plus AI). the testosterone-only (GnRH analog plus testosterone) increases ininsulinsensitivitywhichwerenotseen (GnRH analogplustestosteronedutasteride)showing change ininsulinsensitivity, withthedutasteridegroup There weresignificantbetween-groupdifferencesin hyperinsulinemic glucose clamp at baseline and 14 weeks. ( increase intestosteronewhichconfoundsinterpretation. analog tosuppressgonadotropins),treatmentresultsinan However, asinotherstudiesofAIalone(withoutGnRH letting theauthorsinferaskeletalmuscleeffect( mediated suppression of endogenous glucose production, peripheral glucosedisposalbuthadnoeffectoninsulin- or placebo,AItreatmentreducedinsulin-stimulated clamp study in healthy young men randomized to AI concentrations ( without measurablechangesincirculating sexsteroid and increased WAT E2 concentrations and expression of of aromatasetargetedtowhiteadiposetissue(WAT) have intracrineactions;inmalemice,overexpression 121 138 134 Review In the study by Juang ), insulin sensitivity was measured by euglycemic– ). Lipids returned to baseline after the intervention. ). Lipidsreturnedtobaseline aftertheintervention. ) (upto20%)ornochange( Irs1 , associatedwithimprovedinsulinsensitivity, 134 , 135 132 ) (up to 7%) or no change ( ). Inahyperinsulinemic–euglycemic 134 , 135 t al. et 135 M Grossmann N Russelland , 136 , 136 (described above) ) butnotall( ) inhigh-density 136 ) in low- Glut4 133 137 ). )

at baseline. The intervention produced testosterone at baseline. The intervention serum testosteroneconcentrationswere14.9–17.3 (T+E2 (T patch ornopatch.Fourgroupswereanalyzed:IMplacebo add-back orplacebo,AIandtransdermalE2 antagonist followedbyrandomizationtoIMtestosterone 74 menwererenderedacutelyhypogonadalbyaGnRH in bodycomposition and physical activity. Over 3 weeks, ( markersinhealthyoldermen lipids andinflammatory to isolatetheeffectofphysiologicalE2concentrationon aromatization-dependent effects. changes, but the study was not designed to differentiate or TG( HDL-C compared to placebo with no change in LDL-C hypogonadism usingaGnRHanalogincreasedTCand In anotherRCTenrolling15healthymen,inductionof on musclemassarelargelya directeffectviaARsignaling. including VAT, butthattheanaboliceffectsoftestosterone are mediatedviaaromatization ofE2tolimitadiposity, beneficial effects of testosterone on body composition atherosclerosis progressioninmen( are inconclusive as to whether E2 has effects on nitric oxideproduction( to vasoconstrictorsandenhancesbasalendothelial dose oralE2add-backbeneficiallyreducesresponses for treatmentofprostatecancersuggeststhatlow Experimental evidenceinmenrenderedhypogonadal Vascular reactivityandatheroscleroticplaque rather thanphysiologicalactionsorotherconfounders. body compositionoractivitychanges,pharmacological inotherstudies might bedueto lipid changesobserved needed toconfirmthesefindings,theysuggestthatthe testosterone concentrations. While larger studies are and apolipoproteinBwereunrelatedtoserumE2or showed thatTC,LDL-C,HDL-C,TG,lipoprotein(a) the physiologicalrange,linearregressionanalysis 80-fold range of serum E2 concentrations encompassing group and301 in testosterone then 4 serum E2concentrationswere77–99 three groupsreceivingtestosteroneadd-back.Mean group, differentfromthe25.9to29.3 concentrations of5.7 E2 inmen 140 − E2 Roelfsema In summary, thedatasuggestthatmetabolically ). Thisdesignavoidedconfoundingeffectsofchanges − − pmol/L in the testosterone+E2 ) andIMTplusAIE2patch(T+E2++).Mean ); IMTplusoralplacebo(T+E2+);AI 139 ). Testosterone replacementpreventedthese et al. pmol/L intheT+/E2++group.Despitean − E2 − performed a short-term clamp study group,115 nmol/L inthetestosterone-E2 Downloaded fromBioscientifica.com at09/26/202106:51:16AM 141 https://eje.bioscientifica.com ). Observational data ). Observational pmol/L intheT+E2+ 142 181 pmol/L atbaseline, − group, 35 :1 , 143 nmol/L inthe ). nmol/L pmol/L R33 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com However, biological mechanisms contributing to gender an importantroleinhuman brainmasculinization( and heterosexualorientation suggestingthatER male lackingafunctionalER masculinization ( that AR-mediatedactionsareimportantinhumanbrain serum testosteroneandE2concentrations,demonstrating with CAIShaveafemalegenderidentitydespiteelevated heterosexual orientation( deficiency, wherereported,havemalegenderidentity and behavior ( copulatory treatment duringgestationdisruptednormalmale are lessimportant( development whileanyaromatization-dependent effects acting viatheAR,isimportantinmalegender genes ( un-methylating epigeneticallyrepressedmasculinizing formed from gonadal testosterone, is responsible for production occursprenatally( because uniquelyinthemale,significantgonadalsteroid has higherbrainE2concentrationsthanthefemale adulthood, isaromatizationdependent.Themalefetus defined by subsequent male-typical sexual behavior in testosterone-induced masculinizationofthebrain, several otheranimalspecies( steroids fromthefetaltestis( (prenatal in primates, early postnatal in rodents) to sex masculinization dependentontime-criticalexposure phenotype is considered to befemale, with of sexchromosome-encodedgenes( differences in gonadal hormone secretion, and the effects to reproduction.Thesedifferencesareattributable distinctions pertaintostructuresandbehaviorsrelevant and behavior, are sexually dimorphic. The greatest Brain structure and physiology, and resultant cognition related behavior Antenatal effectsonbrainstructureandgender- Brain designed studies. atherosclerosis arelimitedduetothelackofappropriately active tissues.Inferencesoneffectslipidsand part, mediatedviaE2signalinginmultiplemetabolically in malerodentsand men indicatethatthese are, atleastin insulin sensitivityandglucosemetabolism,experiments With respecttosexsteroid-mediatedbeneficialeffectson Review Observations in humans suggestthat testosterone, Observations In mammalianbraindevelopment,thedefault 149 ) leadingtobrainmasculinization. 151 146 150 ). Furthermore, the single reported ). Unlikeinrams,whichAI ), men with congenital aromatase 47 , α 51 hadamalegenderidentity 147 ). Conversely, XYwomen 146 147 M Grossmann N Russelland ). Inrodents( ), perinatal,gonadal 144 ). BrainE2,locally , 145 , 146 148 ). α ), and lacks 35 ). limited. Whether sex steroids have effects on cognition is with testosteronesignalingviatheAR,althoughdataare men, brainmasculinizationappearstotrackmoreclosely brain masculinization during development inrodents, in ineffective atimprovingcognitionover12 months( impairmentwas mildly lowtestosteroneandmildmemory ( not improvecognitioninthespecificdomainstested men receivingGnRHanalogsforprostatecancer, E2did term randomizedtrialsoforalE2versusplaceboinolder and E2canbedelineated.Intwosmall( exist inmenwhichthecognitiveeffectsoftestosterone studies Few relevant,appropriatelycontrolledintervention Cognition by psychologicalandsocialfactors. identity andsexualorientationinhumansareobscured the exposureispre-pubertal, prematureepiphysealclosure gynecomastia, hypogonadotropic hypogonadism,and,if Excess exposure to estrogens in men can cause Effects ofexcessE2in men therapy, reducedhotflushfrequency-severity scores( transdermal E2add-backinmenreceivingGnRHanalog 6 months (8vs46%)( men in the E2 arm had a lower incidenceof hot flushes at dose transdermalE2versusstandardGnRHanalogtherapy, RCT comparingtwomodesofADTforprostatecancer, high- < were unabletopreventhotflushesifserumE2remained even supraphysiologicserumtestosteroneconcentrations AI, menreceivingAIhadagreaterincidenceofVMS,and with differentialadd-backoftestosteroneorwithout experimental testosteroneandE2depletioninyoungmen dissipation effectors( hypothalamic neurokininB,aparacrineregulatorofheat women E2withdrawalhasbeenshowntocausereleaseof women, E2withdrawalisthemediatorofthiseffect.In the majorityofmen( GnRH analogsproducesvasomotorsymptoms(VMS)in The profound sex steroiddeficiencyinducedbyADTwith Vasomotor stability not clear. E2 inmen 152 mlL ( 37 pmol/L In summary, while E2, actinglocally, iscriticalfor , 153 ). Testosterone treatmentofoldermenwith 157 ). In a preliminary report of an ongoing reportofanongoing ). Inapreliminary 53 155 156 ). Finally, ina4-weekRCT, low-dose Downloaded fromBioscientifica.com at09/26/202106:51:16AM ). In men, as in perimenopausal ). Inmen,asinperimenopausal ). InFinkelstein’s paradigmof 181 :1 n 52) short- =25–27) 104 154 R34 ). ). via freeaccess

European Journal of Endocrinology this treatment appears to be well tolerated and safe, and does nothavethiseffect( there isongoinginterestinhigh-dose parenteralE2which factors by the first-pass metabolism orthese estrogens, of thrombosiscausedbyupregulation ofhepaticclotting use oforalestrogenshasstoppedbecausethehighrisk locally advancedandmetastaticprostatecancer. Whilethe hypogonadotrophic hypogonadism as a way of controlling and parenteralE2havebeenusedtoinduceprofound mechanism ofwhichisnotestablished. an increaseinaromatizationofavailabletestosterone,the did haveanincreasedcirculating E2/Tratio,suggesting ( sufficient accuracyinthelowmalerangeareconsidered present ifonlystudiesusinghigh-qualityE2assayswith studies usinginaccurateassaytechnologiesandisnot analysis has reported that thisassociation was driven by absolute excesscirculating E2.However, arecentmeta- ( testosterone morethanitdoesfreeE2)( more avidlythanE2,SHBGelevationreducesfree thyrotoxicosis oraging(becauseSHBGbindstestosterone conditions inwhichSHBGisincreasedsuchas E2 is reduced ( or wheretheratioofcirculating freetestosteroneto circumstances wherethere isabsoluteandrogendeficiency extrapolated tomen( androgens inhibitit( AR. Infemales,estrogensstimulatebreasttissue,whereas estrogen excess. Male breast tissue expresses both ERand ( in transgenderwomenandmenwithprostatecancer intentional pharmacological use of estrogens including exposures, abuseofaromatizableandrogenicsteroidsand by hepatocellularcarcinoma ( Jegher Syndrome( tumors ( been describedincasesofestrogen-secretingtesticular to the aromatase excess syndrome, gynecomastia has exposure toestrogensinboysandmen.Inaddition been notedsinceantiquity( familial gynecomastia, likely due to this syndrome have rearrangements weredescribedin2003( that enhancearomatasetranscription.( that resultsfromsubchromosomalrearrangements rare, autosomaldominant,aromataseexcesssyndrome leading toshortstature.Thisphenotypeoccursinthe 164 169 168 Review Since the1940s, high dosesof synthetic oralestrogens Klinefelter syndromecommonlycausesgynecomastia Gynecomastia is the most consistent effect of excess ). Gynecomastiaisalsoseenwithoutabsolute ). Inthisanalysis,menwithKlinefeltersyndrome ). Ithastraditionallybeenconsideredaconditionof 161 ) andSertolicellproliferationinPeutz 164 162 ). Examples of the latter include 165 166 ), excessaromataseexpression ). Thisunderstandinghasbeen 170 ). Gynecomastiacanoccurin 160 ). Otherthangynecomastia, ). M Grossmann N Russelland 163 167 ), occupational 159 158 ). ) butcasesof ). Thefirst

EDCs canact through diverse mechanisms, including However, causationinhumanshasnotbeenprovenand illustrated bytheefficacyof5 ( thus increasingironavailabilityforredcellproduction AR-mediated reductioninhepatichepcidinproduction, Themechanismsappear tobevia action onerythropoiesis. range forhemoglobinreflectstheimpactofandrogen produce penilegrowth( syndrome, andtopicalDHT, whichisnotaromatized,can occur inXYmaleinfantswithpartialandrogeninsensitivity genitalia is AR mediated.Micropenis and hypospadias can predominant. The In certaintissues,AR-mediatedactionsareclearly independent ofaromatization Tissues inwhichandrogenactionis for anyparticularclinicaleffectinmen. estrogenic effectsofparticularEDCsthatareresponsible Therefore, itisimpossibleatpresenttoisolateparticular toxic effectsonendocrineandreproductivetissues. inhibition ofandrogenproductionandaction,direct evidence tosupportsimilareffectsinhumans( effects in rodent studies and there is epidemiological others, haveobesogenic,diabetogenicandreproductive Pre- andperinatalexposuretosomeoftheseEDCs, biphenyls (PCBs,nowbanned)bindtoandactivateERs. perfluorooctanoic acid(PFOA),andpolychlorinated dichlorodiphenyltrichloroethane (DDT, now banned), action’ ( of chemicals,thatinterfereswithanyaspecthormone chemical (EDC) as an ‘exogenous chemical or mixture The EndocrineSocietydefinesanendocrine-disrupting Endocrine-disrupting chemicals associated withcastrationusingGnRHagonistsorsurgery. may prevent skeletal fracture and vasomotor symptoms not with non-aromatizable androgens, selective androgen hypogonadal men should be replacement with T ( men hasclinicalapplications. Firstly, standardtherapyin Knowledge thatE2hasimportant physiologicalrolesin Clinical implicationsofE2physiologyinmen treating androgenicalopecia( E2 inmen 173 ). Male-pattern body hair growth is also AR mediated, ). Male-patternbodyhairgrowthisalso AR mediated, 171 ). ManyEDCs,suchasbisphenolA,p,p in utero Downloaded fromBioscientifica.com at09/26/202106:51:16AM 172 development of male external developmentofmaleexternal ). The higher male reference ). Thehighermalereference 174 α https://eje.bioscientifica.com -reductase inhibitors for -reductase inhibitorsfor ). 181 :1 175 R35 ), and 6 via freeaccess ). ′ - European Journal of Endocrinology https://eje.bioscientifica.com in differentiatingtherarecauses ofdeficientE2action in theevaluationofpossible E2excess( in theclinic,ideallywith mass spectrometry, isuseful in menundergoingsuchtherapy ( suggests E2therapyiseffectiveforvasomotorsymptoms analog therapy ( symptoms andbonemetabolicsideeffectsofGnRH low-dose transdermaladd-backtomitigatevasomotor E2 as the method of achieving medical castration or as investigation, eitherintheformofhigh-dosetransdermal in menrequiringADTforprostatecancercurrentlyunder but boneagedidnotadvance. BMD improvedinassociationwithraloxifenetreatment, with congenital aromatase deficiency ( proved ineffectiveinfusingepiphysesayoungman monthsofraloxifene transdermal E2 treatment, 12 maturity hasnotyetbeenattained.Unlikesubsequent raloxifene, is an inadequate substitute for E2 when skeletal ( designed toprovidedefinitiveevidenceforclinicaluse been relativelysmall,shorttermandhavenot such astheskeleton.Clinicaltrialstodatehoweverhave to AIs,havesomeERagonisticactivityinsomatictissues responsiveness,but,incontrast hypothalamic–pituitary testosterone productioninmenwithpreserved in ( low testosterone is alsounder investigation (reviewed modulators (SERMs) in middle aged and older men with remain ( concerns overskeletalsafetyofAIsinboysandmen men withgynecomastiaduetoE2excess( AIs andantiestrogensarealsoclinicallyusefulinboys which casestheyappeartoimproveadultheight( to testotoxicosis,andpossiblyidiopathicshortstature,in with aromataseexcesssyndrome,precociouspubertydue with DHT( ( treated with AI despite increases in serum testosterone with lowserumtestosterone,BMDdeclinedinthose 12-month RCTofAItherapyinoldersymptomaticmen circulating gonadotrophinsarealreadyhigh.Ina organic hypogonadism where or indeed in primary organichypogonadism are noteffectiveinsecondary responsivenessand AIs requirehypothalamic–pituitary not correct the deficiency ofestrogen action. Moreover, testosterone production.Theselatterapproachesdo receptor modulatorsorAIstoenhanceendogenous 102 178 Review Secondly, therearepotentialrolesforE2 treatment The clinicalutilityofselectiveestrogenreceptor Thirdly, measurement ofserumE2concentration 178 ). SimilarnegativeeffectsonBMDhavebeenshown ). Furthermore,limiteddatasuggestthattheSERM, )). LikeAIs,SERMscanenhanceendogenous 176 32 ). ). AIsdohaveoff-labelclinicalrolesinboys 170 ). Some clinical evidence already M Grossmann N Russelland 180 ). 177 179 177 ). However, ). Forearm , 181 ) and 176 ). concentrations reflectsufficiencyofestrogeniceffectsin a paracrinefashion,itisuncleartowhatextentserumE2 and diffuselyinaromatase-containingtissues,acts accurately measured,becauseE2inmenisproducedlocally present inmen( tends to overestimate E2 at the low serumconcentrations measurement byimmunoassayishighlyinaccurateand clinical useisstilllimitedformanyclinicians,and E2measurementtechniquesforroutine spectrometry testosterone. Accesstovalidatedgoldstandardmass actionable informationbeyondthatofcirculating is noevidencethatE2measurementsprovideclinically such as hypogonadism orosteoporosis because there part oftheroutineevaluationclinicalconditions synthesis ( aromatase deficiencyandrarecombineddefectsofsteroid osteoporosis. Thisdifferentialincludesestrogenresistance, leading to persistent linear growth, delayed bone age and recapitulate physiology. Moreresearch isneeded tobetter and thedesignof experimental studies does not always current studiesinmenare relativelysmall,shortterm, effects ofADTgiventomen withprostatecancer. Most promising treatmenttomitigate someoftheadverse to conventionalGnRHanalog-basedADT, maybea also suggestthatE2,eitherassoleADToradd-back off labelbysomepractitionersforthispurpose.They the tissue-specificeffectsofSERMs,whicharealsoused and emphasizestheneedforbetterunderstanding of aromatizable androgensandAIsformalehypogonadism, the useofselectiveandrogenreceptormodulators,non- E2. Conversely, this evidence raises caution regarding provides ‘threehormonesinone’–testosterone,DHT, hypogonadism is best achieved with testosterone, which data isthatclinicallyefficacioustreatmentofmale insulin resistanceandVMS.Therelevanceofthese E2. The data are strongest for effects on bone, fat mass, at leastinpart,mediatedbyitsaromatizationproduct actions historically attributed to testosterone are instead, Recent evidencehasdemonstratedthatmanybiological Conclusion the utilityofserumE2measurementsinclinicalpractice. assays,areneededtodefine available massspectrometry of E2inmalehealth,furtherstudies,usingincreasingly proposed ( sufficiency ofestrogenactioninvarioustissueshavebeen any particulartissue.SerumE2thresholdsestablishing E2 inmen At present,serumE2measurementshouldnotbe 182 170 ). ). Clearlyhowever, giventheimportance 183 ). Evenifcirculating E2canbe Downloaded fromBioscientifica.com at09/26/202106:51:16AM 181 :1 R36 via freeaccess European Journal of Endocrinology References Higher DegreeScholarship. Nicholas Russellissupported by an AustralianGovernmentResearch Acknowledgements Australia (NHMRC)grants1099173and1062073. This work was supported by the National Health and Research Council of Funding Besins from honoraria speaker’s Healthcare andOtsuka.NicholasRussellhasnothingtodisclose. and Lilly Watchers, Weight Novartis, Mathis Grossmann hasreceivedresearchfunding from BayerPharma, Declaration ofinterest biologic rolesofcirculating versuslocallyproducedE2. somatic andreproductivestudiestodissecttherelative understand the relative roles of testosterone versus E2 in 11 10 9 8 6 5 4 3 2 1 Review 7 Sartorius G, Spasevska S,Idan A,Turner L, Forbes E,Zamojska A, Hart RJ, Doherty DA,McLachlan RI,Walls ML, Keelan JA, Kelch RP, Jenner MR,Weinstein R, Kaplan SL&Grumbach MM. 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