European Journal of mellitus (T2DM), non-alcoholic fatty liver disease diabetes mellitus(T2DM),non-alcoholic fattyliverdisease insulin resistance(IR),anincreased prevalenceoftype2 a similaradversemetabolic phenotype, includingobesity, Interestingly, female AE and male AD are associated with by disease,obesity, medicationsortheageing process( androgen deficiency(AD),whichcanbeinheritedoracquired most commonlyresultinhypogonadismandconsequent disorder ( excess (AE),representsthemostcommonendocrine dysfunction, polycysticovarianmorphologyandandrogen syndrome(PCOS),atriad ofovulatory polycystic ovary reproductive andmetaboliccomplications.Inwomen, of circulating androgenconcentrations,andresultin disease leadtoalterations adrenal orhypothalamic–pituitary togonadal, Disturbances inandrogenmetabolismsecondary Introduction lipid accumulation,centralfatmassexpansionandinsulinresistance. female androgenexcessandmalehypogonadismaremetabolicallydisadvantageous,promotingadiposeliver on skeletalmusclemayconfermetabolicbenefits. We hypothesise that serumandrogenconcentrationsobservedin tissue dysfunction,witheffects onlipidmetabolism,insulinresistanceandfatmassexpansion,whileanaboliceffects metabolic phenotypeobservedinfemaleandrogenexcessandmaledeficiency. Androgensinduceadipose We conceptualisethatanequilibriumbetweenandrogeneffects onadiposetissueandskeletalmuscleunderpinsthe examining theassociationsbetweenmetabolicdiseaseanddisordersofandrogenmetabolisminmenwomen. an attempttounravelthecomplexmechanisticlinkswithmetabolicdysfunction;wealsoevaluateclinicalstudies increased riskofcardiovasculardisease.Here,wereviewtheimpactandrogensonmetabolictargettissuesin including abdominalobesity, insulin resistance,type2diabetesmellitus,non-alcoholicfattyliverdiseaseandan Female androgenexcessandmaledeficiencymanifestwithanoverlappingadversemetabolicphenotype, Abstract NHS FoundationTrust, Edgbaston,Birmingham,UK 2 1 Lina Schiffer human metabolicdisease The sexuallydimorphicrole ofandrogens in MECHANISMS INENDOCRINOLOGY Centre forEndocrinology, DiabetesandMetabolism,BirminghamHealthPartners,UniversityHospitals Institute ofMetabolismandSystemsResearch,UniversityBirmingham,Edgbaston,UK www.eje-online.org DOI: 10.1530/EJE-17-0124 www.eje- Review Open Access 10.1530/EJE-17-0124 online.org 1 ). In men, disturbances of gonadal function ). Inmen,disturbancesofgonadalfunction 1 , Punith Kempegowda

L Schiffer andothers Published byBioscientifica Ltd. 1 , Wiebke Arlt Printed inGreat Britain © 2017Theauthors © 2017Theauthors 1 , 2 2 and ). ). Michael W O’Reilly AE andAD. consequences ofmetabolicdysfunction inthecontextof of metabolictargettissues, and comparephenotype AD inmen,examinetherole ofandrogensinthefunction this article,wewilldiscussdisordersofAEinwomenand underpinning thesephenomenaarepoorlyunderstood.In ( metabolic consequences( androgen concentrationsthatareassociatedwithdeleterious the concept of a metabolically adverse window of circulating male ADmayoverlap,Escobar-Morreale serum (T) concentrationsin female AEand in the relationship between androgens and metabolism.As mortality ( (NAFLD), cardiovasculardisease(CVD)andevenpremature Androgens inmetabolicdisease i. 1 Fig. ). However, thecellularand systemic mechanisms 3 , 4 , 5 , 6 , 7 1 , , 2 8 ). This highlights a sexual dimorphism ). Thishighlightsasexualdimorphism Attribution 3.0Unported License This workislicensed under a

Downloaded fromBioscientifica.com at10/04/202101:06:55PM 9 ), or a ‘metabolic valley of death’ ), ora‘metabolicvalleyofdeath’ (2017) Endocrinology European Journal of [email protected] Email to MWO’Reilly should beaddressed Correspondence 177 177 : 3 177 et al :3 Creative Commons , R125–R143 . have proposed . haveproposed .

R125 –R143 via freeaccess

European Journal of Endocrinology they derive from C21 precursor steroids and can be they derivefromC21precursor steroidsandcanbe by theadrenalglandandgonads inboth men and women; Androgens are 19-carbon (C19) steroid hormones produced metabolism Pre-receptor androgen synthesisand www.eje-online.org completeness ( resistance wasavailable,butvaluesareincludedfor testosterone inwomenwithtypeAformofsevereinsulin information aboutthemethodusedtodetermineserum female andfemale-to-maletransgenderpatients( hypogonadism andhypopituitarism( secondary hypogonadismduetoidiopathichypogonadotropic receiving testosteronesupplementation( with primaryhypogonadismduetoKlinefeltersyndromenot replacement ( women ( quantification: HealthywomenvsPCOS( recent publicationsusingmassspectrometry-based concentrations. Approximatehormonerangesaretakenfrom metabolically adversewindowofcirculatingandrogen leading totheconceptof‘metabolicvalleydeath’asa associated withsevereadversemetabolicconsequences excess andmenwithandrogendeficiencyoverlapare Serum testosteroneconcentrationsofwomenwithandrogen deficiency (PanelB)isshowninrelationtotestosteronelevels. from femalandrogenexcess(PanelA)ormale estimated metabolicriskfordifferent populationssuffering testosterone levelsandincreasingmetabolicrisk.The Sexually dimorphicassociationsbetweencirculating Figure 1 Review 30 ), womenwithCAHonstandardglucocorticoid 205 ). 201 ), healthyandobesemen( L Schiffer andothers 204 ), aswellmale-to- 203 ), menwith 200 70 202 ). No ), obese ), men pathway ( the classicsynthesispathway;so-calledbackdoor several alternativepathwaystoDHTsynthesisthatbypass is activated to DHT in peripheral target tissues. There are visualised in three interconnected pathways, which are schematically eliciting classicgenomicandrogenaction. and DHTbindactivatetheandrogenreceptor(AR), 5 can beconverteddownstreamtothemorepotentandrogen generated insmallamountsbytheadrenalgland( by 17 androgen exposure. In , A4 is converted to T expressing therequiredenzymes,therebymodulatinglocal from circulating androgen precursorsinperipheraltissues de novo inwomen( 10-fold higher than thoseobserved men, circulating Tconcentrations areapproximately 15 from precursorsinperipheraltissues( ovarian thecacellsinwomen,butmayalsobeactivated T isproduceddirectlyintesticularLeydigcellsmenand infemales.Active glands inbothsexes,andbytheovary androstenedione (A4)aresecretedmainlybytheadrenal precursor steroidsdehydroepiandrosterone(DHEA)and converted toC18steroids,theoestrogens.Theandrogen the significant contribution of 11-oxygenated androgens the significantcontribution of11-oxygenatedandrogens T inhealthypremenospausal women,whichdemonstrates shown tobeapproximatelyfour timeshigherthanthoseof ( of peripheral5 the affinityofTand11KThighlightingimportance is approximatelyoneorderofmagnitudehigherthan the AR,DHTand11KDHTalsohaveanARaffinitythat have comparablemaximumtransactivationpotentialfor biological androgenaction( for thesepreviouslyoverlookedandrogensinconveying potential ( and DHT, bothwithregardtoaffinityandtransactivation been showntohavethesameARactivatingpotentialas T and 11-keto-5 11-oxygenated androgens ( A4 viatheadrenalCYP11B1enzyme( 11 downstream ofthemajoradrenalandrogenprecursor of 5 T maybefurtheractivatedtoDHTbythetype1isoform also calledasaldoketoreductasetype1C3(AKR1C3),and Androgens inmetabolicdisease 21 α -dihydrotestosterone (DHT)by5 β ) thatdirectlysynthesiseDHTby-passingT. Inhealthy ). Importantly, the circulating levels of 11KT have been -hydroxyandrostenedione (11OHA4), generated from -hydroxyandrostenedione (11OHA4),generatedfrom α Androgens canbesynthesisedfromcholesterolvia Recently, ithasbeenshownthatsteroids -reductase ( β -hydroxysteroid dehydrogenasetype5(17 biosynthesis,activeandrogenscanbesynthesised 11 20 , Fig. 2 ), raising the possibility of an important role ), raisingthepossibilityofanimportantrole α 12 -dihydrotestosterone (11KDHT) ( α , 17 -reductase activity for androgen action -reductase activityforandrogen action 13 . TheclassicalpathwayproducesT, which ). ) andalternate5 Downloaded fromBioscientifica.com at10/04/202101:06:55PM 19 ). 11-keto-testosterone (11KT) ). 11-keto-testosterone (11KT) 21 ). While all four agonists ). Whileallfouragonists α α -reductase activity. T 177 -dione pathway( 10 :3 18 ), and can be ), andcanbe ), are active ), areactive 16 Fig. 2 ). Besides β -HSD5), R126 10 ) have ) have ). T ). T 14 via freeaccess , European Journal of Endocrinology dyslipidaemia, NAFLD,CVD andpotentiallypremature disorder, associatedwithIR,visceraladiposity andobesity, (AO) andAE.However, PCOSisalsoa majormetabolic polycystic ovarian morphology (PCO), anovulation required for diagnosis: ultrasound appearance of criteria ( PCOS is diagnosedaccording to the2003 Rotterdam affecting 5–10% of women of reproductive age ( PCOS isthemostcommoncauseofAEinwomen, Polycystic ovarysyndrome metabolic consequences Androgen excessinwomen andrelated pool ofcirculating active androgens( not onlytotheandrogenprecursorpool,butalso dehydrogenase/∆4–5 isomerase;11 5 allopregnanolone; An,androsterone;DHEA,dehydroepiandrosterone;DHEAS,dehydroepiandrosteronesulfate;DHP, 17-hydroxydihydroprogesterone; 17OH-PREG,17-hydroxypregnenolone;17OH-PROG,17-hydroxyprogesterone;AlloP, 11KA4, 11-keto-androstenedione;11OHDHT, 11 deficiency inobesemen.Steroidabbreviations:3 to theoestrogensestrone(E1)andestradiol(E2),respectively, byaromatase(CYP19A1),whoseactivitypossiblyenhancesandrogen to mutationsoftheco-factorsynthesisingPAPS synthase2leadstoaPCOS-likephenotype.AndrostenedioneandTcanbeconverted 17 boxes. EnzymesupregulatedinPCOScontributingtolocalandsystemicandrogenexcess(steroid5 17,20-lyase activity. Allandrogenreceptor-transactivating androgens(T, DHT, 11KTand11KDHT)arehighlightedinboldwhite androgens 11-keto-testosterone(11KT)and11-keto-dihydrotestosterone(11KDHT).CYP17A1capableofboth17 androstenedione (A4)to11 5 ∆4-precursors, leadtotheformationoftestosterone(T),whichcanbeconverteddihydrotestosterone(DHT).Thealternate is thecommonprecursorofallandrogenbiosynthesispathways.Theclassicalpathways,proceedingparallelfor∆5-and Overview ofthehumanandrogenbiosynthesispathways.Pregnenolone(PREG),producedbyside-chaincleavagecholesterol, Figure 2 α α Review -dione pathwayand‘backdoor’directlysynthesiseDHTby-passingT. The11-oxygenatedandrogenpathwayconverts -dihydroprogestrone; PROG,progesterone.Enzymeabbreviations:STS,steroidsulfatase;3 β -hydroxysteroid dehydrogenase,17 24 ), with two of the following three features β -hydroxyandrostenedione (11OHA4)byadrenal11 β HSD2, 11 L Schiffer andothers β HSD) arehighlightedinbold.Impairedactivityofsulfotransferase2A1(SULT, underlined)due 22 ). β -hydroxysteroid dehydrogenasetype2;cytb β -hydroxytestosterone; 17OH-AlloP, 17-hydroxyallopregnanolone;17OH-DHP, α -diol, 5 α 4 -androstanediol; 5 , 23 ). 11-oxygenated androgens was similarly observed in 11-oxygenated androgens was similarlyobserved to PCOS-related AE. Of note, this increase in circulating ( of PCOSwomenconsisted of 11-oxygenatedandrogens half of the circulating androgen pool in a large cohort in arecentstudy, whichdemonstratedthat morethan origin in PCOS. The latter was explored for the first time 11-oxygenated androgens,areindicativeofAEadrenal DHEA sulfateesterDHEASand11OHA4,aswellactive risk ( assessment ofA4andTispredictiveadversemetabolic PCOS-related AE,aswelldemonstratingthatintegrated defined A4asamoresensitivemarkerfordetecting by measuring serum T ( circulating androgen burden has been typically evaluated is intimatelylinkedwithAE( mortality ( Androgens inmetabolicdisease 22 ), highlightingthesignificant adrenalcontribution 22 α -dione, 5 , β 27 -hydroxylase (CYP11B1)activity, generatingtheactive 3 ). Increasedcirculating concentrationsofthe , 4 ). PCOS-associatedmetabolic dysfunction α -androstanedione; 5-diol, androstene-diol; -androstanedione; 5-diol,androstene-diol; 5 , cytochromeb5. β -HSD, 3 Downloaded fromBioscientifica.com at10/04/202101:06:55PM α 25 -reductase, 5 β , -hydroxysteroid -hydroxysteroid 25 26 ) ( ), but recent work has Fig. 1 177 α α Red; Red; ). Conventionally, -hydroxylase and -hydroxylase and www.eje-online.org :3 R127 via freeaccess European Journal of Endocrinology www.eje-online.org mutations areoftenonlydiagnosed inearlyadulthood, present atbirthorinearlychildhood, patientswithmild patients withmajorloss-of-function mutationsusually the lossofnegativefeedback bycortisol( adrenal drivedueto enhanced hypothalamic–pituitary androgen biosynthesis,whichisfurtherincreasedby precursor steroidsareshunteddownthepathways of AE ( with onlymildglucocorticoiddeficiency, butrelevant deficiency frequentlyresultinginanon-classicCAHform 1:16 defect is21-hydroxylasedeficiency, with a frequencyof dehydrogenase type2deficiency. The most common 11 with AEinaffectedwomen:21-hydroxylasedeficiency, androgen secretion.ThreeCAHvariantsareassociated deficiency and variable impact on mineralocorticoid and recessive inheritancecharacterizedbyglucocorticoid represent agroupofinborndisorderswithautosomal The variantsofcongenitaladrenalhyperplasia(CAH) Women withmonogeniccausesofandrogen excess generation inPCOS. an importantroleforadiposetissueasorgan of androgen dysfunction andmetabolicissues( treatment to ameliorate PCOS-associated AE, ovulatory ( is higher than in body mass index (BMI)-matched controls AKR1C3 expressioninadiposetissuefromPCOSpatients obesity anddecreaseswithweightloss( is increasedinadiposetissuefrompatientswithsimple T fromA4viaits17 enzyme expressed in adipose tissue that can locally generate likely tocontributetissue-specificAE,asthisistheonly steroidogenic enzymeAKR1C3inPCOSadiposetissueis PCOS duringpuberty( phenotype andovarianmorphologycharacteristicof PCOS womenalsodevelopametabolicandbiochemical ( indaughtersofPCOSwomenearlychildhood observed activation ofTtoDHT; thisphenomenonisalready inPCOS( is observed burden. Systemicupregulationof5 activation anditsdysregulationcontributetolocalandrogen metabolic complications. whether androgenexcessprecedesthedevelopmentof obese and non-obese PCOS women, raising the question 35 31 Review β ). Weight losshasbeenshowntorepresentaneffective ). However, itiscontroversialwhetherdaughtersof -hydroxylase deficiencyand3 In addition to systemic AE, tissue-specific androgen In additiontosystemicAE,tissue-specificandrogen 39 000 innewborns( , 40 ). Asaconsequenceoftheenzymaticblock, β HSD activity( 28 37 32 , 29 , , 38 , 33 30 ) andistheonlyenzyme ). Overexpression of the ). Overexpressionofthe ); resulting in enhanced ); resultinginenhanced L Schiffer andothers 34 36 ). AKR1C3 expression ). AKR1C3expression ), further supporting ), furthersupporting α -reductase activity -reductase activity 34 β -hydroxysteroid ); furthermore, ); furthermore, 18 , 41 ). While present withaPCOS-likephenotype( 5 PAPSS2 deficiency(PAPSS2, 3 recommended inthework-upofPCOS. for CAHbybaselineserum17-hydroxyprogesteroneis identified assufferingfromnon-classicCAH( 2–3% ofwomenpresentingwithaPCOSphenotypeare PCOS representsadiagnosisofexclusionandonaverage the adversemetabolicphenotypefoundinPCOS.As insulin resistancehasbeen reported ( non-classic CAH,anincreasedprevalenceofobesityand and PCOappearanceoftheovaries.Inpatientswith early adulthood, including hirsutism, irregular periods but generallywithaPCOSphenotypeinadolescenceor patients usuallydonotpresentwithoutrightvirilisation, stimulation oftheadrenals,atexpenseAE.These is sufficientlyupheldbycontinuouslyincreasedACTH as their glucocorticoid and mineralocorticoid secretion tissue developmentresulting incongenitalcomplete obesity andconsequentIR, ordysfunctionaladipose transduction. Monogenicdisorders mayalsocausesevere the level of the insulin receptor or in post-receptor signal development. Defectsininsulinsignallingcan be foundat impacting oninsulinsignallingoradiposetissue obesity asaconsequenceofmonogenicgenedefects Severe insulinresistancecandevelopindependent of Women withmonogenic insulinresistance clinical manifestationasPCOS( the carrierofamajorloss-of-functionmutation,with but also in theheterozygousmother, co-incidentallyagain revealed significant AE not only in the affected children by PAPSS2 deficiencywasrecentlyidentified,andwork-up PCOS asayoungwoman( function mutationononeallele,hadpresentedwith heterozygous mother, whoharbouredamajorloss-of- AE withnon-detectableserumDHEAS.Interestingly, her amenorrhoea;investigationsrevealed cycles andsecondary presented with premature pubarche followed by irregular The firstreportedcase,ahomozygouslyaffectedyounggirl, rates ofconversionDHEAtowardsTandDHT( DHEA areinactivatedtoDHEAS,resultinginincreasing Consequently, fewermoleculesoftheandrogenprecursor impaired DHEAsulfotransferase(SULT2A1) activity( PAPS synthase2havebeenshowntoresultinsignificantly PAPS synthaseisoforms,andinactivatingmuationsin universal sulfatedonor, generatedbythetwohuman Androgens inmetabolicdisease ′ -phosphosulfate synthase 2), has been described to -phosphosulfate synthase2),hasbeendescribedto Recently, anothermonogeniccauseofAE, Downloaded fromBioscientifica.com at10/04/202101:06:55PM 45 ). A further family affected ). Afurtherfamilyaffected 47 ). 42 177 ′ -phosphoadenosine -phosphoadenosine , 43 :3 45 , ). PAPS isthe 44 4 ), mirroring ), screening Fig. 2 R128 46 via freeaccess ). ). ). European Journal of Endocrinology area. Congenitalhypogonadotropic hypogonadism cases arecausedbytumours of thehypothalamo–pituitary majorityofsuch androgen synthesis.Theoverwhelming stimulationoftesticular impaired hypothalamic–pituitary by lowTandreducedgonadotrophin secretiondueto HG,orhypogonadotropic HG,isdefined Secondary Secondary malehypogonadism like inKlinefeltersyndrome( as well as by autosomal or sex chromosome aneuploidies be causedbygonadaldysgenesisandcryptorchidism ( to theeugonadalstate( the likelihoodto progress toovertADwhencompared Compensated hypogonadismissubclinical,butincreases function thatisrescuedbyincreasedLHstimulation. hypogonadism, which represents impaired testicular Normal TandhighLHlevelscharacterizecompensated T incombinationwithincreasedluteinizinghormone(LH). malehypogonadism(HG)isdefinedbylowserum Primary Primary malehypogonadism cognitive functionandmooddisturbances( strength andenduranceaswellsometimesimpaired of low circulating T. Commonsymptomsareareduction physical symptomsofADwithbiochemicalevidence ( disease testicular pathologyorhypothalamic–pituitary of testicularTproduction,inthecontextprimary Male ADisaclinicalsyndromearisingfromfailure metabolic consequences Androgen deficiencyinmenand related profile andabsenceofhepaticsteatosis( leptin, adiponectinandSHBG,alongsideanormallipid which isaccompaniedbynormalorelevatedlevelsof clinically inthesettingofseverehyperinsulinaemia, discounted. Monogenic INSR mutations may be suspected of insulin-stimulatedandrogengenerationcannotbe and stromalcells( androgen biosynthesisbydirecteffectsofinsulinontheca hyperinsulinaemia may stimulate ovarian Compensatory and acanthosisnigricans,usually in theabsenceofobesity. dysfunction,PCO mutations presentwithAE,ovulatory monogenic lipodystrophyorinsulinreceptor(INSR) or partial lipodystrophy ( 2 Review ). Inadultmen,itisdiagnosedbythepresenceof libido and erectile strength, fatigue, reduced physical 49 ), althoughotherperipheralsources 51 ). Congenital primary HGcan ). Congenitalprimary 48 53 ). Patients with IR due to , L Schiffer andothers 54 ). 48 ). 50 ). 52 ), as lowTlevelsifanyformofclassicalcausesADcanbe (HPG) axisandcanleadtolate-onsetAD,whichisdefined prostate cancer( both metastatichormone-naiveandcastration-resistant deprivation therapyisanestablishedtreatmentoptionfor and obesity( pharmacological treatment,chronicillness,poorhealth systemortestis,radio-andchemotherapy,central nervous Acquired HGmaybecausedbylesionsortumoursofthe Acquired malehypogonadism cranio-facial abnormalities( syndrome, whichmaybeassociatedwithanosmiaand inKallmann gonadotrophin deficiencyasobserved dysplasia, butmorecommonlyisassociatedwithisolated hormone deficienciesinconditionssuchassepto-optic inthecontextofmultiplepituitary may beobserved after gonadectomywhereappropriate, therebyenabling the principle ofgenderreassiginment, both before and Replacement and blockade of sex hormones underpin transgender patients Androgens andmetabolic healthin of androgensinobesityhasbeensuggested( men andacontributionofleptinexcesstothereduction 68 cytokines( levels ofadipocyte-derivedinflammatory letrozole normalisesTlevels( ( suppress theHPGaxis,whichreducesgonadalTsynthesis reducing thelevelofactiveandrogens.Oestrogensmay by aromatase(CYP19A1, lead toenhancedaromatisationofandrogensoestrogens this association ( obesity–adipokine cycleisaproposedmechanismbehind hypogonadism ( Conversely, weightlosscanreverseobesity-associated associated withdisorderedgonadotrophinrelease( significantly increasestheage-relatedTdeclineandis starting duringthethirddecadeoflife( related decline of T levels of around 0.1 signalling ( pituitary to LHofLeydigcells,andinreducedhypothalamic– testicular failureduetoadecreasednumberandresponse excluded ( Androgens inmetabolicdisease 65 ) havebeenshowntoinhibittheHPGaxisinhealthy ). Treatment ofobesemenwith theCYP19A1inhibitor Ageing affects the hypothalamic–pituitary–gonadal Ageing affectsthehypothalamic–pituitary–gonadal Male ADcanalsobeinducedbyobesity( 57 ). Ageingcanresultingradualdevelopment of 2 ). Surgicalorpharmacologicalandrogen 56 50 62 ). , ). Theconceptofahypogonadal– 63 58 , 64 , Downloaded fromBioscientifica.com at10/04/202101:06:55PM Fig. 2 59 ): Obesity has been suggested to 55 ). Thismanifests in anage- ). 66 ) inadiposetissue,thereby ). Additionally, elevated 177 60 www.eje-online.org :3 nmol/L per year ). 69 61 ). ). Obesity R129 60 67 via freeaccess ). , European Journal of Endocrinology www.eje-online.org to beincreased( cerebrovascular diseasecompared tocontrolmenappear Prevalence rates of T2DM, thrombo-embolic disease and increased subcutaneousand visceralfatmass( reduced musclemassandtotalleanpercentage, but treatment developanadverselipidprofile( patients oncombinedestrogenandanti-androgen large dosesofoestrogen.Male-to-femaletransgender population is clouded by co-administration of relatively effects ofandrogendeprivationtherapyinthispatient < in thepre-gonadectomystage( anti-androgen treatmentisfrequentlyco-prescribed transgender patients, both before and after orchidectomy; treatmentforfeminizationofmale-to-female primary Oral ortransdermaloestrogensupplementationisthe Male-to-female genderreassignment phenotype inPCOS. that AEandnotovariandysfunctiondrivesthemetabolic polycystic ovarianmorphology( patients takingTshowovarianhyperplasia,butno with PCOS symptoms, female-to-male transgender female controlpopulations( also showanincreasedprevalenceofT2DMcomparedto dyslipidaemia ( including arterialstiffness,bloodpressure( have beenreportedtobeincreasedbyTadministration, increased ( while reducing subcutaneous fatmass( increases totalleanmass( T administrationforfemale-to-malegendertransition generally between 12 and 24 sexcharacteristics.Targetsecondary serumTlevelsare aiming toinducevirilisationandsuppressfemale both beforeandaftergenitalreconstructionsurgery, For female-to-male gender reassignment, T is administered Female-to-male genderreassignment patients ( to-female andfemale-to-malegenderreassignment inbothmale- replacement therapymaybeobserved metabolic consequencesforandrogendeprivationand reference rangeforthedesiredgender( be maintainedin the upper-normalphysiological the desiredgender. Circulating sexhormonesshould sexcharacteristicsofthe developmentofsecondary 1.9 Review nM arerecommended( 72 75 ). , 76 78 79 ). Surrogatecardiovascularriskfactors ). Female-to-maletransgenderpatients ). 71 73 79 ). Delineatingthespecific ) andvisceralfatmass, , nmol/L ( L Schiffer andothers 80 81 71 ). Despitepresenting ) furthersupporting ). SerumTlevels 70 74 70 , ); BMImaybe 71 ). Long-term 76 ). However, , 77 78 73 ) and ) with , 74 ). ). visceral andlessSCadiposetissue( have apredominantandroidfatdistribution,withmore with lessvisceralbutmoresubcutaneous(SC)fat;men In women,bodyfatisdistributedinagynaecoidmanner, body fatthanmen,whilemenhavegreatertotalleanmass. distribution, withwomenhavingahigherpercentage of There isaclearsexualdimorphisminpatternsofbodyfat Androgens, adiposetissueandlipidmetabolism glucose andlipidhomeostasis. compartments crucially involved in maintaining systemic tissues. Theseincludeadiposetissueandskeletalmuscle, drive, androgensexertkeyeffectsonmetabolictarget maintenance ofmaleandfemalereproductionsex In additiontotheircentralroleinthedevelopmentand target tissues The role ofandrogens inmetabolic intracellular stressandinflammation( could induceadipocytedysfunctionmanifestedinIR, mechanism to increase adipose tissue mass, which may lead to adipocyte as a compensatory impairment ofadipocyteproliferationanddifferentiation glucose uptake( a humanSCpreadipocytecelllineandtoenhancebasal been showntoinhibitproliferationanddifferentiationof both sexes( preadipocyte lineage, and adipocyte differentiation in effects on multipotent stem cell commitment to the cells andpreadipocytes( proliferation and differentiation of mesenchymal stem major determinantsofmetabolicdysfunction( lipid indifferentiatedadipocytes;bothprocessesare and hypertrophy, which is driven by accumulation of preadipocytes and their differentiation into adipocytes, (adipogenesis), whichisdrivenbyproliferationof tissue expansionisaconsequenceofbothhyperplasia insulin-sensitizing effects.However, women withPCOS effect onadiponectinsecretion, whichhassystemic male andfemaledonors ( of humanabdominalSCand omentaladipocytesfrom cultures Incubation withactiveandrogensinprimary the secretionofcytokinesbyadiposetissuearelacking. studies evaluatingthedirecteffectsofandrogenson profile ( proinflammatory, diabetogenic andatherogenicserum Androgens inmetabolicdisease Hypertrophic, dysfunctionaladipocytesinducea Androgens impair adipogenesis by inhibiting 90 ). However, comprehensivehuman 87 , 88 89 ). Inaddition,DHEA,butnotDHEAS,has ). Klöting Downloaded fromBioscientifica.com at10/04/202101:06:55PM 86 ). DHT and T have inhibitory ). DHTandThaveinhibitory 88 t al et ) showednosignificant . hypothesisethatan 82 177 90 , :3 ). 83 , 84 85 ). Adipose ). in vivo R130 via freeaccess

European Journal of Endocrinology with geneticandfunctional markersofmitochondrial in reducingproteinoxidation ( replacement inhypogonadal menconfirmstheeffectofT in skeletalmuscleproteinsynthesis ( men receiving intramuscular T injections exhibit increases stem cellsviaanAR-dependentpathway( and inhibitadipogenesisofpluripotentmesenchymal Additionally, androgensinducemyogenicdifferentiation which can subsequently fuse with the adjacent myofiber. proliferation anddifferentiationofsatellitecells( compared tonon-steroidusers( of musclerepairinhumanskeletalathletes growth, andproportionofcentralnucleiindicative from fusion with satellite cells and promoting muscular androgens increasesthenumberofmyonuclei,resulting of Tincombinationwithnon-aromatisablesynthetic and mitochondrial function ( lipid oxidation,insulinsensitivityandglucoseusage myotubes, aswellskeletalmuscleproteinsynthesis, Androgens enhancethedifferentiationofstemcellsto Androgens, skeletalmuscleandinsulinsensitivity tissue aresummarisedin lipid metabolism( pathways, includingoxidativestress,inflammationand PCOS showdistinctchangesinseveralbiological comparing adipocytesfromwomenwithandwithout The adiposegeneexpressionstudiesbyCorton of proteinkinaseCviaanAR-mediatedmechanism( stimulated glucoseuptakebyimpairingphosphorylation in femaleSCadipocytes on adiposeinsulinsensitivity. TdirectlyinducesIR accumulation. at a possible role of androgens in promoting adipose lipid revealing hints at enhanced lipogenesis ( to the profile of obese controls with normal androgens profile of omentaladipocytesin obesewomenwithAE Conversely, Corton in asex-anddepot-specificmanner( DHEAS havebeenshowntostimulatelipolysisinhumans date haveshown conflicting results. Tanditsprecursor catabolism andlipidaccumulation.However, studiesto androgens inadiponectinsecretion. than eugonadalmen( ( have lowerlevelsofadiponectinthanhealthycontrols 91 Review ), andhypogonadalmenshowhigheradiponectin Androgens alsoexertdirectandindirecteffects Androgens maymodulatethebalancebetweenlipid 98 et al ). Effectsofandrogensonadipose 92 . havecomparedtheexpression Fig. 3 ) suggestingapotential role for in vitro 64 . 106 , L Schiffer andothers 101 , andinhibitsinsulin- 102 ). Inmen,Tcorrelates 105 ) ( ). Tstimulatesthe 93 Fig. 3 ). IntramuscularT , 98 94 , 104 , 99 ). Theintake 95 ) andthus ). Healthy , 96 t al et , 103 100 97 ). ), ). . function inskeletalmuscle( effect infemales( sex-specific gradualdifferences, hintingatastronger skeletal musclecells,inboth menandwomenbutwith stimulate insulinsensitivity andglucoseutilisationin In summary, currentevidence suggeststhatandrogens in rat( administration leadstoincreasesinmuscleglycogenlevels synthesis orthepentosephosphatepathway( channelling itintothepathwaysofglycolysis,glycogen glucose, thereby impairing its release from the cell and free glycolysis, andhexokinase,whichphosphorylates enzymeof phosphofructokinase, thekeyregulatory signalling ( to theplasmamembraneaswellintracellularinsulin DHEA enhancesGLUT4expressionandtranslocation ( leads toanupregulationofinsulinreceptorsubstrate-2 and maintenanceinskeletalmuscleofmice( reporting apositiveeffectofTonmitochondrialbiogenesis resulting infatmassexpansion.Athigherconcentrations,as Androgens mayexertpro-lipogeniceffects onadiposetissue, skeletal muscleandimplicationsforglobalmetabolism. Differential effects ofandrogensonadiposetissueand Figure 3 testosterone (11KT),11-keto-dihydrotestosterone(11KDHT). disease. Testosterone (T),dihydrotestosterone(DHT),11-keto- phenotype, andgiverisetometaboliccardiovascular and anincreaseinabdominalobesitydrivethesystemic excess andmaleandrogendeficiency, alossofmusclemass circulating androgenlevelsintherangeoffemale increasing skeletalmusclebulkpredominate.However, with observed inthehealthymalerange,netanaboliceffects on Androgens inmetabolicdisease 110 Incubation of primary human muscle cells with T Incubation of primary ). Inculturedratmusclecells,theadditionofTand 112 ) duetoreducedglycogen breakdown ( 111 ). TandDHEAstimulate the activityof 110 ). Downloaded fromBioscientifica.com at10/04/202101:06:55PM 107 ), consistentwithfindings 177 www.eje-online.org :3 108 , 111 109 R131 113 ). T ). via freeaccess ). European Journal of Endocrinology Dyslipidaemia andCVR NAFLD IR andT2DM Body composition Metabolic outcomes/Sex Table 1 www.eje-online.org M M M F F F M M F F M M M/F F M M Review

Selected studieshighlightingtheeffects ofandrogensonmetabolicdysfunctioninmenandwomen. 2301 PCOS(evidenceofAEin88%) 40 PCOSvs20normoandrogeniccontrols PCOS onhypocaloricdietandflutamid( Cross-sectional population-basedstudyof Prospective cohortstudyof55menwith Retrospective cross-sectionalobservation Prospective casecontrolstudywith29PCOS Prospective cross-sectionalstudyinvolving 156 obese,hypogonadal,diabeticmenonT 1413 men,age 15 PCOSonresveratroltreatmentvs 86 PCOSgroupedaccordingtoseverityof 17 female-to-maletranssexualsonT 130 nonsmokingmen,age21–70 60 PCOS(biochemicaland/orclinicalAE)vs 139 PCOSgroupedaccordingtocombination Study design followed over20 years or placebo( 1912 men chronic spinalcordinjury study of495healthyKoreanmen women and29controls 314 PCOSwomenand74controls therapy followedover6 years PCOS placebocontrols and BMI) AE vs43controls(matchedforage supplementation followedover1 year 60 controlsmatchedforage,race,BMI of PCO,AOandAE L Schiffer andothers 19 ≥ ) treatment 20

17 Androgens inmetabolicdisease ) ISI: Fasting insulin: T, DHEAS: T andA4,IGT, fastinginsulin,HOMA-IR: HDL: TG: Body fatdistribution: T levels: Body fatmass,%bodyfat,WC,vicadiposity: Fat–lean–mass ratio: Lean mass:Nodifference % bodyfat: WHR: WHR: BMI: Nodifference Parameters assessed T2DM, MI,angina,HF, stroke,CVrelated CIMT: HDL: Trend for Vis/SC fatTG,cholesterol,LDL: A4, DHEAS: Serum T, serumDHEAS,ultrasonographyliver: Serum T, ultrasonographyliver, HOMA-IR:Low Serum testosterone,BMI,HDL,TG:Lowserum HOMA-IR, MRIliver, MRS:Differences inliver Various liverfibrosisscores,HOMA-IR, Lipid profile:Ameliorated Fasting insulin,glycatedHb,WC,weight, T levels,Prevalenceofdiabetes:Negative ↑ Negatively associatedwithTandDHEAS PCO +AOAE population MI, anginacomparedtolocalmale death: T, A4andDHEAS and highDHEAS Hepatic steatosiswasassociatedwithlowT T wasindependentlyassociatedwithNAFLD independent ofvisfatandIR T wasassociatedwithhigherriskofNAFLD differences inobesityandinsulinresistance fat remainedapparentafteradjustingfor syndrome women withratherthanwithoutmetabolic than thecontrolgroup,aswellinPCOS were allsignificantlyhigherinthePCOS HOMA- blood pressure: with abnormallylowT diabetes persistinguponexclusionofmen association: FreeT, bioavailableTand withseverityofAE ↑ ↑ byresveratrol ↓ ↑ ↑ ↑ inPCOS;CorrelationwithtotalT, free inPCOS ingroupswithAE,highest ↑ ↑ β age-specificprevalenceofT2DM, tosupraphysiollevels , QUICKI:Indicesofhepaticsteatosis ↓ byresveratrol ↓ ↑ secondarytoflutamide inPCOS ↑ ↓ byresveratrol ↓ ↑ ↓ inPCOS Downloaded fromBioscientifica.com at10/04/202101:06:55PM : SC, Main outcome ↑ visfat ↓

177 :3

(Continued) Reference ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( R132 172 164 141 155 208 154 152 151 128 207 119 206 121 131 135 25

) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) via freeaccess European Journal of Endocrinology factor forT2DM( consequently, AE inwomenhasbeensuggestedasrisk diabetes diagnosiscriteria, BMI andwaist-to-hipratio; women with T2DM even after adjustment for age, race, 117 but obesitydeterioratesthediabeticphenotype( higher prevalence of IGTandT2DM than controls, obese andnon-obesePCOSwomenwithAEshow a obesity significantlyincreasesthisrisk( impaired glucosetolerance(IGT)andtoT2DM, trend toprogressfromnormalglucosetolerance to with insulinresistance.Women withPCOS showa The presence of AE in PCOS is closely correlated Female androgen excessandinsulinresistance in discussed inthefollowingsectionsaresummarised systemic insulin resistance. Studies selected from those of theexaggeratedpancreaticbeta-cellresponseto Frank hyperglycaemiaoccursafterdecompensation disturbances inhepaticandadiposelipidmetabolism. response innormallylessresponsivetissues,aswell hyperinsulinemia, leadingtoanexaggeratedinsulin synthesis ( promotion oflipogenesis,aswellproteinandglycogen uptake andmetabolism,suppressionoflipolysis metabolic responsetoinsulin,whichincludesglucose Insulin resistanceisdefinedastheimpairedsystemic and androgen statusinmenandwomen Insulin resistance, type2diabetesmellitus circumference; WHR,waist–hipratio. sensitivity checkindex;Ref,reference;SC,subcutaneous;T, testosterone;T2DM,type2diabetesmellitus;TG,triglycerids;vis,visceral;WC,waist magnetic resonanceimaging;MRS,spectroscopy;NAFLD,non-alcoholicfattyliverdisease;QUICKI,quantitativeinsulin resistance; ISI,insulinsensitivityindex;LDL,lowdensitylipoprotein;MACE,majoradversecardiovascularevent;MI,myocardialinfarct;MRI, failure; HOMA- risk; DHEA,dehydroepiandrosterone;DHEAS,dihydroepiandrosteronesulfate;HbA,haemoglobinA;HDL,highdensitylipoprotein;HF, heart A4, androstenedione;BMI,bodymassindex;CIMT, carotidintima-mediathickness;CRP, C-reactiveprotein;CV, cardiovascular;CVR,cardiovascular Metabolic outcomes/Sex Table 1 F F Review

Table 1 ). Conversely, Tlevelsaresignificantly higherin Continued. . 114 β , homeostaticmodelassessmentof ). IRisaccompaniedbycompensatory 118 ). WhengroupingPCOSpatients 4736 menwithlowTsupplementedto 255 hypogonadalmenreceivingTtherapy Study design 3 years persistently low, normalorhighTfor for 60 months L Schiffer andothers β -cell function;HOMA-IR,homeostaticmodelassessmentofinsulinresistance;IR, 115 ). Both 116 , spectrum orincreasingandrogenburden( and risk of overt hyperglycaemia increases acrossa according toseverityofAE,insulinsensitivitydecreases to improvetheinsulinsensitivityindex( resveratrol hasbeenshowntoreducefastinginsulinand circulating androgenburden inPCOSbytreatmentwith hypogonadal men( sensitivity and diabetes in obese and non-obese ( between totalandfreeT IRparametersobserved healthy controls,withsignificantnegativecorrelations glucose, leptinlevelsandHOMA-IRcomparedto androgen deprivationtherapyhavehigherBMI,fasting independent ofobesity. Menwithprostate canceron This identifieslowTlevelsasariskfactorforT2DM, men whencomparedtoBMI-matchedcontrols( prevalence of subnormal T has been found in diabetic after adjustment for IR ( of thiscorrelationisattenuated,butstillsignificant, levels predictinghyperglycaemia( found theinverseassociationinwomen,withhigherT significantly lowerTlevelsinmenwithT2DMalso associated withIR( established diagnosisofT2DM,lowTisindependently sensitivity ( In men,Tlevelsarepositivelyassociatedwithinsulin Male androgen deficiencyandinsulin resistance cells byresveratrol( and androgenproductionofratovariantheca-interstitial studies demonstratedselectiveinhibitionofproliferation Androgens inmetabolicdisease 126 MACE (stroke,MI,death): HDL: HbA, CRP, liverenzymes: TG, LDL,bloodpressure,glucose,glycated T levels: Parameters assessed ). Androgenreplacementtherapy improvesinsulin for highTcomparedtonormal compared topersistenlylowT; ↑ ↑ tophysiologicallevels 107 , 121 120 127 122 ) and even in men with an ). Downloaded fromBioscientifica.com at10/04/202101:06:55PM , : ). Ameta-analysiscorrelating Main outcome 128 123 ↓ ↓ innormalT ). , 124 ↑ strokerisk 118 ). An increase in the 177 ). Thesignificance www.eje-online.org :3 25 119 ). Lowering Reference ). ( ( In vitro R133 198 209 125

) ) via freeaccess ). ).

European Journal of Endocrinology www.eje-online.org negative associationsbetween Tandtotalbodyfatmass, associated with decreased androgen levels ( associated withtotalTin men ( free T( ( increased fatmasscomparedtoeugonadalcontrols consistently support the association between low Tand men acrossdifferentagesandobesevsnon-obese Cross-sectional studiesanalysingage-advancedmen, correlate inverselywithBMIandvisceraladiposity. In comparisontowomen,circulating androgensinmen Male androgen deficiency andbodycomposition ( decreases androgen levels and the visceral-to-SC fat ratio on ahypocaloricdietwiththeanti-androgenflutamide android pattern ( with a shift in fat distribution from a gynaecoid to an lean mass correlating with serum T and A4 ( Studies onPCOSwomenwithAEdescribeanincreased mass andobesityinpre-pubertalpubertalgirls( correlation betweencirculating androgenswithbodyfat controls ( higher increasesinBMIduringearlyadulthoodthan presenting withisolatedhirsutismshowsignificantly in thepresenceofAEPCOS( waist circumference and waist-to-hip ratio are higher and systemic5 with andwithoutPCOS,BMIcorrelatestheFAI associated withmetabolicrisk( higher bodyfat-to-leanmassratio,whichispositively They haveanincreasedbodyfatmassresultingina in additiontotheincreasedglobaladiposity( amounts ofvisceralfatdepotsinwomenwithPCOS women andmen,Borruel study comparinghyperandrogenicPCOSwomen,healthy adiposity comparedtocontrolcohorts( general femalepopulation( of AEshowahigherprevalenceobesitythanthe PCOS women with clinical and/or biochemical evidence Female androgen excessandbodycomposition of androgensonbodycomposition. effects on systemic IR, there are sexually dimorphic effects forandrogen Similar tothegender-specificeffectsobserved status inmenandwomen Body compositionandimpactofandrogen 140 107 Review , , 141 142 142 ). 136 , 143 , 144 ). Arecentstudyfoundasignificantpositive ). BMInegativelycorrelates withtotaland α -reductase activity( ), andwaistcircumference isnegatively 132 ). The treatment of PCOS women t al et 4 ) andanincreasedglobal . demonstratedincreased L Schiffer andothers 133 131 142 25 , , ) andbodyweight, ). Althoughageis 134 132 129 , ). Forwomen ). Inadetailed 135 143 138 ). Women , , 144 130 139 137 ), ), ). ), ). have increasedvisceralfatmass( controls, butnotinSCdepots;hypogonadalmenalso of visceralandretroperitonealfatcomparedto ( adipose tissuearemaintainedafteradjustmentforage body fatpercentage, waistcircumference and visceral ranges from intra-hepatic accumulation of TG or simple ranges fromintra-hepaticaccumulationofTGorsimple of significantalcoholconsumption.TheNAFLDspectrum inducedbyobesityandIR,intheabsence hepatic injury NAFLD isanumbrellatermencompassingaspectrumof and malefemaleandrogen status Non-alcoholic fattyliverdisease(NAFLD) T2DM ( and reduces vis adiposity in men with and without hypogonadal menleadstoincreasesinleanbodymass controls ( is lowerinhypogonadalmencomparedtoeugonadal underlying PCOS-relatedNAFLD remaintobeelucidated. function ( products havebeenshown to developderangedhepatic female ratsfedwithadietrich inadvancedglycationend and visceral and intra-abdominal fat ( due toPCO to normoandrogenicPCOSwomen(diagnosedwith significantly higherinhyperandrogenicPCOScompared to theRotterdamcriteriaandfoundthatliverfatwas PCOS womenwithandwithoutAEdiagnosedaccording Jones which was attributed to younger age of the cohort ( find anydifferenceintheprevalenceofhepaticfibrosis, the healthyfemalepopulation.However, theydidnot of Mediterranean women with PCOS when compared to higher prevalenceofhepaticsteatosisinalargecohort ( of NAFLDcomparedtocontrolswithsimpleobesity with PCOShaveanalmost4-foldhigherprevalence population; a recent meta-analysis found that patients those inBMI-matchedindividuals from thebackground Prevalence ratesofNAFLDinPCOSappeartobehigherthan Female androgen excessandNAFLD frequent causeoflivertransplantationintheWestern world. major metaboliccomplicationsandemergingasthemost advanced hepaticfibrosisandcirrhosis( steato-hepatitis (NASH),withariskofprogressionto steatosis, todiffusetissueinflammationornon-alcoholic Androgens inmetabolicdisease 150 121 ). Polyzos and colleagues reported a significantly ). Tadministrationinmenreducesaccumulation t al. et 127 153 146 comparedseveralmetabolicparametersin , + 148 ). However, putativecausativemechanisms AO), evenafteradjustmentforobesity, IR , ). 147 ). T replacement therapy of Downloaded fromBioscientifica.com at10/04/202101:06:55PM 145 177 152 ). Leanbodymass 149 :3 ). Androgenised ). NAFLD is a ). NAFLDisa R134 151 via freeaccess ). European Journal of Endocrinology PCOS withnon-hyperandrogenic women showed an increased CVR( disorders appear to be altered in PCOS, indicating an systemic inflammation,oxidativestressandcoagulation inter-study heterogeneity, profilesofcirculating markersfor and gonadotrophinsecretion( tonormalisation ofovulation A4 levelsprobablysecondary obese andnon-obesewomenleadstodecreasesinT flutamide improves the dyslipidaemic phenotype in both studies. Nevertheless,treatmentwiththeanti-androgen confounded byco-existentobesityandIRinmostPCOS the directassociationsbetweenAEanddyslipidaemia is levels, butdoesnotaffect TG andLDLlevels ( associated with higher total cholesterol and lowerHDL According toarecentmeta-analysis,AEinPCOSis Female androgen excessandcardiovascular risk androgen status Cardiovascular riskandmalefemale adverse metabolicconsequencesmayarise. relatively narrowphysiologicalwindowoutsideofwhich steatosis inmen( Synthetic anabolicsteroidusehasbeenlinkedtohepatic may alsoadverselyimpactonriskofNAFLDinmen. replacement andsupraphysiologicalserumandrogens Mirroring femaleAE,however, excessiveandrogen 1, whichisamajorregulatorofbeta-oxidation( and negativeregulatorofcarnitinepalmitoyltransferase increased malonylco-A,asubstratefor malonyl coAdecarboxylaseexpression.Thisresultsin peroxisome proliferator-activatedreceptor-alphaand acetyl coAcarboxylase,coupledwithareductionin elementbindingprotein-1cand of sterolregulatory This appearstobedueactivationandupregulation develop hepaticsteatosisandIRwithahighfatdiet. liver metabolism. Liver-specific male AR knock-out mice studies haveunderpinnedadirectroleforandrogenson hypogonadism, wereinitiallyhypothesised,recent such asincreasedvisceraladiposityinthecontextof hepatic steatosis( reported aninverseassociationbetweenserumTand IR ( for traditionalriskfactorssuchasvisceraladiposityand associated withNAFLDinKoreanmendespiteadjusting Kim Male androgen deficiencyandNAFLD Review 154 Luque-Ramirez et al. ). A large observational studyofGermanmenalso ). Alargeobservational reportthatlowserumTlevelwasindependently 91 157 , 155 160 t al et ), againsuggestingthepresenceofa ). Althoughindirectmechanisms, , 161 . comparinghyperandrogenic , 162 140 , L Schiffer andothers , 163 141 ). , de novo 159 ). Despite large ). Despitelarge 158 lipogenesis ). Studying ). Studying 156 ). T andA4asmajordeterminantsofCIMT( in PCOS,independentofobesity, andindentifiedtotal increased meancarotidintimalmediathickness(CIMT) 170 PCOS womenthanthebackgroundpopulation( and age at death may not be significantly higher in for BMI( heart disease and stroke, even after adjustment coronary prevalence ofMIandangina( 170 describe increasesintheprevalenceofhypertension( myocardial infarction (MI)orstroke( large vesseldisease( Some studies conclude that there is no increased risk for term cardiovasculareventsinPCOSareinconsistent. due toimpairedvasodilation( with PCOSandAEalsoexhibitmicrovasculardysfunction total and free T with HDL ( cholesterol and LDL as well as a positive correlation of profile. AninverserelationbetweenTandTG,total In men,lowTlevelsareassociatedwithadyslipidaemic Male androgen deficiencyandcardiovascular risk subjects withpersistentlylow T( levels reducestherateofstroke, MIordeathcomparedto Supplementing menwithinitially lowTlevelstonormal mortality comparedtotheir eugonadal counterparts( adenomas hadincreased of non-functioningpituitary men withgonadotrophindeficiencyafterthetreatment cardiovascular diseaseandcancer( between Tlevelsandprospectivemortalityduetoallcauses, mortality ( 193 severity isnegativelycorrelatedwithTlevels( disease presentwithlowerTlevels( by T supplementation ( controls, whichcanberapidlybutincompletelyrescued hypogonadal mencomparedtoage-andweight-matched ( cytokine balancetowardsastateofreducedinflammation men, andTreplacementhasbeenshowntoshiftthe protein in normal ageing ( exists betweenserumTandhigh-sensitiveC-reactive on thelipidprofile( therapy inhypogonadal men exhibitsbeneficialeffects dyslipidaemia ( was described. ADT for the treatment of PCa also induces Androgens inmetabolicdisease 184 ). Male AD is associated with a higher risk of all-cause ). MaleADisassociatedwithahigherriskofall-cause , ) andcerebrovasculardisease( Increased arterial stiffness has been reported in Increased arterialstiffnesshasbeenreportedin , 174 188 ). ). 173 194 ). Generalandcause-specificmortality , 181 195 , 127 ), and an inverse correlation exists ), andaninversecorrelationexists 167 182 , ), abdominalaorticplaque( Downloaded fromBioscientifica.com at10/04/202101:06:55PM 189 184 , 175 186 ). Men with coronary artery artery ). Men withcoronary 183 , 185 , ) and hypogonadal ( 165 ), whileTreplacement 198 172 176 ). Aninversecorrelation 171 , , 196 ) andintheriskof , 166 177 199 ), intheage-specific 177 190 169 www.eje-online.org ). We foundthat :3 ). Dataonlong- ). , , 178 , 164 191 170 , ). Women 190 179 ) and its ) andits 167 ). Others R135 , , , 168 197 187 180 169 168 192 via freeaccess ), ). ). ) ) , , ,

European Journal of Endocrinology androgen levels observed inseverefemaleAEandmaleAD, androgen levelsobserved fat distributionandreducedmetabolicrisk;atcirculating and elevated oestrogens lead to predominant gynaecoid Inhealthywomen,lowandrogenconcentrations observed. disturbances inmetabolismandbodycompositionare physiological windowinbothsexes,outsideofwhich serum andtissue-specificconcentrations,withanarrow tissue andmusclemaylargelybegovernedbycirculating References Fellowship 099909,toMOR,andProjectGrant092283,WA). This workwassupportedbytheWellcome Trust (ClinicalResearchTraining Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest dissect thesecomplexassociations. account sexdifferences,arerequiredtounderstandand and epidemiologicalstudiesappropriatelytakinginto Further human-basedstudies,including body mass, muscle bulk and reducing fat mass ( in healthymen,thiseffectisdissipatedbyincreasinglean whileathigherandrogenconcentrationsseen is observed, preferential accumulationofcentralandvisceraladiposity www.eje-online.org in metabolism( highlighting the complexity of the role of androgens deficiency exhibitoverlappingmetabolicphenotypes, and disease.Femaleandrogenexcessmale Androgens playamajorroleinhumanmetabolichealth Conclusions 6 2 1 5 4 3 Review Coffin D&JonesTH.Systematicliterature reviewoftherisk 2015 Metabolism in men. 0253) ofEndocrinology Journal statement fromtheEuropeanSocietyofEndocrinology. Pasquali R HF, FranksS,GambineriA,KelestimurF, MacutD,Micic and late-onsethypogonadism. Metabolism in anunselectedpopulation. syndrome BO. Theprevalenceandfeaturesofthepolycysticovary (doi:10.1210/er.2003-0004) a prematureassociation? Zarotsky V, Huang MY, Carman W, Morgentaler A,SinghalPK, Bhasin S&BasariaS.Diagnosisandtreatmentofhypogonadism Conway G,DewaillyD,Diamanti-KandarakisE,Escobar-Morreale Corona G,Vignozzi L,SforzaA,Mannucci E&MaggiM.Obesity Azziz R,Woods KS,ReynaR,KeyTJ,KnochenhauerES&Yildiz syndromeandcardiovascular disease: Legro RS.Polycysticovary 418 Best PracticeandResearch ClinicalEndocrinologyand 120–133. et al 2004 2011 i. 1 Fig. . The polycystic ovary syndrome:aposition . Thepolycysticovary 89 25 2745–2749. 251–270. (doi:10.1016/j.mce.2015.06.031) ). Effectsofandrogensonadipose 2014 Endocrine Reviews 171 Journal ofClinicalEndocrinologyand Journal (doi:10.1016/j.beem.2010.12.002) Molecular andCellularEndocrinology (doi:10.1210/jc.2003-032046) P1–P29. L Schiffer andothers (doi:10.1530/EJE-14- 2003 in vitro 24 302–312. , European i. 3 Fig. in vivo ).

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