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Aromatase inhibitors in men 概要 Background1 Safety and concerns5 Aromatase inhibitors3 Aromatase2 Effects of aromatase inhibitior4BackgroundThe role of estradiolgainingandmaintainingbonemassclosingoftheepiphysesthefeedbackongonadotropinsecretionEstrogen excessprematureclosureoftheepiphysesgynecomastialowgonadotropinlowtestosteronelevels.7/1/2024 AromataseAromataseAromatase,alsoknownasestrogensynthetase,isthekeyenzymeinestrogenbiosynthesis.Theenzyme,localizedintheendoplasmicreticulumoftheestrogen-producingcell,isencodedbytheCYP19A1gene，whichislocalizedonchromosome15andcomprisesnineexons，thestartcodonfortranslationislocatedonexon2.CYP19 geneMenwithestrogendeficiencycausedbyamutationintheCYP19genesufferfrom：I.lowbonemineraldensity(BMD)II.unfusedepiphyses,III.highgonadotropinIV.hightestosteronelevels.Aromatase activitygonadsplacentabrainfattissuemusclehairbonevasculartissueIthasbeendemonstratedin:Estradiol productiondirecttesticularsecretionconversionoftesticularandrogensperipheralconversionofadrenalandrogens7/1/2024 Aromatase inhibitorsMechanismNonsteroidalenzymeinhibitorssuchasanastrozoleandletrozoleinhibitenzymeactivitybybindingwiththehemeironoftheenzyme.Incomplete efficacyAlthougharomataseinhibitionbyanastrozoleandletrozoleisreportedtobecloseto100%,administrationoftheseinhibitorstomenwillnotsuppressplasmaestradiollevelscompletely.Inmenthird-generationaromataseinhibitorswilldecreasethemeanplasmaestradiol/testosteroneratioby77%.Cause of incomplete efficacy Aromataseislesssuppressedinthetestiscomparedtoadiposeandmuscletissue.AdvantageItpreventsexcessivereductionofestrogenlevelsinmenandthepossibleassociatedadverseeffects.Inpostmenopausalwomenwithbreastcarcinoma,long-termuseofpotentaromataseinhibitorsreducescirculatingestradiollevelsby88%andisassociatedwithadverseeffectsonbone.Effects of aromatase inhibitiorEffect Loweringestradiollevels,byadministeringanaromataseinhibitorsuchasletrozole,isassociatedwithanincreaseinlevelsofLH,FSHandtestosteronethroughthefeedbackofhypothalamo-pituitary-gonadalaxis.Epiphysial closureLowerestradiollevelsandtherebyslowdownepiphysialmaturation.Aromataseinhibitors,mostlycombinedwithagonistsofGRHprovedeffectiveforthepreventionofprematureepiphysialclosureinboyswithpubertaspraecox.Thereisalsoevidencethataromataseinhibitorscanbeusedinboyswithidiopathicshortstatureandboyswithconstitutionaldelayofpubertytoincreaseadultheight.SpermatogenesisIncreasegonadotropinsecretionstimulateLeydigandSertolicellfunctionstimulatespermproductionClinical use Weinvestigatedwhetherletrozole(2.5mgperday)improvesspermcountinNOApatients.4menwereincludedinthisstudy,andtheyhadFSHandotherhormonelevelswithinthenormalrangeandnovaricocelesorchromosomalaberrations.Thesefourpatientswereadministeredletrozolefor3months.Clinical use Allpatientssufferedlossesoflibidodespitethesupra-physiologicallevelsofT,FSHandLH;however,inastudyonthesexualbehaviourofmenwitharomatasecongenitaldeficiency,alossoflibidooccurredevenwithsupra-physiologicallevelsoftestosterone.Thissuggeststhatoestrogenscouldhavearoleinsupportinglibido.Clinical useWepresentthecaseofaninfertilemanwithsmalltestesandanelevatedFSHlevel,whichwasdiagnosedasNOA,hypospermatogenesisprovenbytesticularbiopsy.Aftertakingletrozolefor3months,semenanalysesbycomputer-aidedspermanalysispresentthatthismanhadnormalspermatogenesis.Clinical useThestudygroupconsistedof29infertilemenwithalowserumT/E2ratio(10).Patientsweredividedintotwogroups.GroupAincluded15patientstreatedwith2.5mgletrozoleorallyoncedailyfor6months,andGroupBconsistedof14patientstreatedwith1mganastrazoleorallyeverydayfor6months.Clinical useTheincreaseinaverageTFSFintheletrozolegroupaftertreatmentcomparedwiththepretreatmentvaluewas31.6%,andtheincreaseinaverageTFSFintheanastrazolegroupaftertreatmentcomparedwiththepretreatmentvaluewas21.1%.Clinical useWeinvestigatedtheeffectofletrozole,anaromataseinhibitor,onbodymassindex,serumhormones,andspermparametersininfertilemenwithdecreasedT/E2ratios.Clinical use2ofthe10oligospermicmen(20%)achievedspontaneouspregnancyaftertheletrozoletreatment.In4of17azoospermicmen(23.5%),spermatozoaappearedintheejaculatewithameantotalmotilespermcountsof1.110.69million,although13men(76.5%)remainedazoospermicafterletrozoletreatment.Safety and concerns Long-termuseinpostmenopausalwomenisassociatedwithamoderateincreaseinboneresorptionandamodestdecreaseinBMDcomparedwithplacebo.Inmoststudiesutilizingaromataseinhibitorsinmenestradiollevelsdecreasedonlymoderately.Althoughmostoftherecentstudieswitharomataseinhibitorsinmendonotshowmajordetrimentaleffectsonbone,long-termskeletalsafetyremainsanissueofconcern.7/1/2024Thank you！
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