来曲唑 芳香化酶抑制剂概要课件

Aromataseinhibitorsinmen

Aromataseinhibitorsinmen

1概要

Background1

Safetyandconcerns5

Aromataseinhibitors3

Aromatase2

Effectsofaromataseinhibitior4概要Background12BackgroundBackground3Theroleofestradiol

gainingandmaintainingbonemass

closingoftheepiphyses

thefeedbackongonadotropinsecretionTheroleofestradiolgaining4Estrogenexcess

prematureclosureoftheepiphyses

gynecomastia

lowgonadotropinlowtestosteronelevels.Estrogenexcessprematureclos511/11/2022

Aromatase11/10/20226Aromatase

Aromatase,alsoknownasestrogensynthetase,isthekeyenzymeinestrogenbiosynthesis.Theenzyme,localizedintheendoplasmicreticulumoftheestrogen-producingcell,isencodedby

the

CYP19A1

gene，whichislocalizedonchromosome15andcomprisesnineexons，thestartcodonfortranslationislocatedonexon2.AromataseAromatase,als7CYP19gene

MenwithestrogendeficiencycausedbyamutationintheCYP19genesufferfrom：

lowbonemineraldensity(BMD)

unfusedepiphyses,

highgonadotropinhightestosteronelevels.CYP19geneMenwithestrog8Aromataseactivity

gonads

placenta

brain

fattissue

muscle

hair

bone

vasculartissueIthasbeendemonstratedin:AromataseactivityIthasbeen9来曲唑芳香化酶抑制剂概要课件10Estradiolproduction

directtesticularsecretion

conversionoftesticularandrogens

peripheralconversionofadrenalandrogensEstradiolproductiondirectte1111/11/2022

Aromataseinhibitors11/10/202212来曲唑芳香化酶抑制剂概要课件13Mechanism

Nonsteroidalenzymeinhibitorssuchasanastrozoleandletrozoleinhibitenzymeactivitybybindingwiththehemeironoftheenzyme.MechanismNonsteroidalenz14Incompleteefficacy

Althougharomataseinhibitionbyanastrozoleandletrozoleisreportedtobecloseto100%,administrationoftheseinhibitorstomenwillnotsuppressplasmaestradiollevelscompletely.Inmenthird-generationaromataseinhibitorswilldecreasethemeanplasmaestradiol/testosteroneratioby77%.IncompleteefficacyAlthou15Causeofincompleteefficacy

Aromataseislesssuppressedinthetestiscomparedtoadiposeandmuscletissue.

Causeofincompleteefficacy16AdvantageItpreventsexcessivereductionofestrogenlevelsinmenandthepossibleassociatedadverseeffects.

Inpostmenopausalwomenwithbreastcarcinoma,long-termuseofpotentaromataseinhibitorsreducescirculatingestradiollevelsby88%andisassociatedwithadverseeffectsonbone.

AdvantageItpreventsexces17EffectsofaromataseinhibitiorEffectsofaromataseinhibitio18Effect

Loweringestradiollevels,byadministeringanaromataseinhibitorsuchasletrozole,isassociatedwithan

increaseinlevelsofLH,FSHandtestosteronethroughthefeedbackofhypothalamo-pituitary-gonadalaxis.EffectLoweringestradio19Epiphysialclosure

Lowerestradiollevelsandtherebyslowdownepiphysialmaturation.

Aromataseinhibitors,mostlycombinedwithagonistsofGRHprovedeffectiveforthepreventionofprematureepiphysialclosureinboyswithpubertaspraecox.Thereisalsoevidencethataromataseinhibitorscanbeusedinboyswithidiopathicshortstatureandboyswithconstitutionaldelayofpubertytoincreaseadultheight.EpiphysialclosureLower20来曲唑芳香化酶抑制剂概要课件21来曲唑芳香化酶抑制剂概要课件22SpermatogenesisIncreasegonadotropinsecretionstimulateLeydigandSertolicellfunction

stimulatespermproductionSpermatogenesisIncreasegonado23来曲唑芳香化酶抑制剂概要课件24ClinicaluseWeinvestigatedwhetherletrozole(2.5mgperday)improvesspermcountinNOApatients.4menwereincludedinthisstudy,andtheyhadFSHandotherhormonelevelswithinthenormalrangeandnovaricocelesorchromosomalaberrations.Thesefourpatientswereadministeredletrozolefor3months.ClinicaluseWeinvestigatedw25来曲唑芳香化酶抑制剂概要课件26Clinicaluse

Allpatientssufferedlossesoflibidodespitethesupra-physiological

levels

of

T,FSH

and

LH;

however,

in

a

study

on

the

sexual

behaviour

of

menwitharomatase

congenitaldeficiency,alossoflibidooccurred

even

with

supra-physiological

levels

of

testosterone.This

suggests

that

oestrogenscouldhavearoleinsupportinglibido.ClinicaluseAllpatient27来曲唑芳香化酶抑制剂概要课件28Clinicaluse

WepresentthecaseofaninfertilemanwithsmalltestesandanelevatedFSHlevel,whichwasdiagnosedasNOA,hypospermatogenesisprovenbytesticularbiopsy.Aftertakingletrozolefor3

months,semenanalysesbycomputer-aidedspermanalysispresentthatthismanhadnormalspermatogenesis.ClinicaluseWepresentth29来曲唑芳香化酶抑制剂概要课件30Clinicaluse

Thestudygroupconsistedof29infertilemenwithalowserumT/E2

ratio(<10).Patientsweredividedintotwogroups.GroupAincluded15patientstreatedwith2.5mgletrozoleorallyoncedailyfor6months,andGroupBconsistedof14patientstreatedwith1mg

anastrazoleorallyeverydayfor6months.ClinicaluseThestudygro31来曲唑芳香化酶抑制剂概要课件32来曲唑芳香化酶抑制剂概要课件33ClinicaluseTheincreasein

averageTFSFintheletrozolegroupaftertreatmentcomparedwiththepretreatmentvaluewas31.6%,andtheincreaseinaverageTFSFintheanastrazolegroupaftertreatmentcomparedwiththepretreatmentvaluewas21.1%.ClinicaluseTheincrease34来曲唑芳香化酶抑制剂概要课件35Clinicaluse

Weinvestigatedtheeffectofletrozole,anaromataseinhibitor,onbodymassindex,serumhormones,andspermparametersininfertilemenwithdecreasedT/E2

ratios.ClinicaluseWeinvestigat36来曲唑芳香化酶抑制剂概要课件37来曲唑芳香化酶抑制剂概要课件38Clinicaluse

2ofthe10oligospermicmen(20%)achievedspontaneouspregnancyaftertheletrozoletreatment.In4of17azoospermicmen(23.5%),spermatozoaappearedintheejaculatewithameantotalmotilespermcounts

of1.11±0.69million,although13men

(76.5%)remainedazoospermicafterletrozoletreatment.Clinicaluse2ofthe1039SafetyandconcernsSafetyandconcerns40Long-termuseinpostmenopausalwomenisassociatedwithamoderateincreaseinboneresorptionandamodestdecreaseinBMDcomparedwithplacebo.Inmoststudiesutilizingaromataseinhibitorsinmen

estradiollevelsdecreasedonlymoderately.Long-termuseinpostmenopausa41Althoughmostoftherecentstudieswitharomataseinhibitorsinmendonotshowmajordetrimentaleffectsonbone,long-termskeletalsafetyremainsanissueofconcern.Althoughmostoftherecentst4211/11/2022

Thankyou！11/10/2022Thankyou！43Aromataseinhibitorsinmen

Aromataseinhibitorsinmen

44概要

Background1

Safetyandconcerns5

Aromataseinhibitors3

Aromatase2

Effectsofaromataseinhibitior4概要Background145BackgroundBackground46Theroleofestradiol

gainingandmaintainingbonemass

closingoftheepiphyses

thefeedbackongonadotropinsecretionTheroleofestradiolgaining47Estrogenexcess

prematureclosureoftheepiphyses

gynecomastia

lowgonadotropinlowtestosteronelevels.Estrogenexcessprematureclos4811/11/2022

Aromatase11/10/202249Aromatase

Aromatase,alsoknownasestrogensynthetase,isthekeyenzymeinestrogenbiosynthesis.Theenzyme,localizedintheendoplasmicreticulumoftheestrogen-producingcell,isencodedby

the

CYP19A1

gene，whichislocalizedonchromosome15andcomprisesnineexons，thestartcodonfortranslationislocatedonexon2.AromataseAromatase,als50CYP19gene

MenwithestrogendeficiencycausedbyamutationintheCYP19genesufferfrom：

lowbonemineraldensity(BMD)

unfusedepiphyses,

highgonadotropinhightestosteronelevels.CYP19geneMenwithestrog51Aromataseactivity

gonads

placenta

brain

fattissue

muscle

hair

bone

vasculartissueIthasbeendemonstratedin:AromataseactivityIthasbeen52来曲唑芳香化酶抑制剂概要课件53Estradiolproduction

directtesticularsecretion

conversionoftesticularandrogens

peripheralconversionofadrenalandrogensEstradiolproductiondirectte5411/11/2022

Aromataseinhibitors11/10/202255来曲唑芳香化酶抑制剂概要课件56Mechanism

Nonsteroidalenzymeinhibitorssuchasanastrozoleandletrozoleinhibitenzymeactivitybybindingwiththehemeironoftheenzyme.MechanismNonsteroidalenz57Incompleteefficacy

Althougharomataseinhibitionbyanastrozoleandletrozoleisreportedtobecloseto100%,administrationoftheseinhibitorstomenwillnotsuppressplasmaestradiollevelscompletely.Inmenthird-generationaromataseinhibitorswilldecreasethemeanplasmaestradiol/testosteroneratioby77%.IncompleteefficacyAlthou58Causeofincompleteefficacy

Aromataseislesssuppressedinthetestiscomparedtoadiposeandmuscletissue.

Causeofincompleteefficacy59AdvantageItpreventsexcessivereductionofestrogenlevelsinmenandthepossibleassociatedadverseeffects.

Inpostmenopausalwomenwithbreastcarcinoma,long-termuseofpotentaromataseinhibitorsreducescirculatingestradiollevelsby88%andisassociatedwithadverseeffectsonbone.

AdvantageItpreventsexces60EffectsofaromataseinhibitiorEffectsofaromataseinhibitio61Effect

Loweringestradiollevels,byadministeringanaromataseinhibitorsuchasletrozole,isassociatedwithan

increaseinlevelsofLH,FSHandtestosteronethroughthefeedbackofhypothalamo-pituitary-gonadalaxis.EffectLoweringestradio62Epiphysialclosure

Lowerestradiollevelsandtherebyslowdownepiphysialmaturation.

Aromataseinhibitors,mostlycombinedwithagonistsofGRHprovedeffectiveforthepreventionofprematureepiphysialclosureinboyswithpubertaspraecox.Thereisalsoevidencethataromataseinhibitorscanbeusedinboyswithidiopathicshortstatureandboyswithconstitutionaldelayofpubertytoincreaseadultheight.EpiphysialclosureLower63来曲唑芳香化酶抑制剂概要课件64来曲唑芳香化酶抑制剂概要课件65SpermatogenesisIncreasegonadotropinsecretionstimulateLeydigandSertolicellfunction

stimulatespermproductionSpermatogenesisIncreasegonado66来曲唑芳香化酶抑制剂概要课件67ClinicaluseWeinvestigatedwhetherletrozole(2.5mgperday)improvesspermcountinNOApatients.4menwereincludedinthisstudy,andtheyhadFSHandotherhormonelevelswithinthenormalrangeandnovaricocelesorchromosomalaberrations.Thesefourpatientswereadministeredletrozolefor3months.ClinicaluseWeinvestigatedw68来曲唑芳香化酶抑制剂概要课件69Clinicaluse

Allpatientssufferedlossesoflibidodespitethesupra-physiological

levels

of

T,FSH

and

LH;

however,

in

a

study

on

the

sexual

behaviour

of

menwitharomatase

congenitaldeficiency,alossoflibidooccurred

even

with

supra-physiological

levels

of

testosterone.This

suggests

that

oestrogenscouldhavearoleinsupportinglibido.ClinicaluseAllpatient70来曲唑芳香化酶抑制剂概要课件71Clinicaluse

WepresentthecaseofaninfertilemanwithsmalltestesandanelevatedFSHlevel,whichwasdiagnosedasNOA,hypospermatogenesisprovenbytesticularbiopsy.Aftertakingletrozolefor3

months,semenanalysesbycomputer-aidedspermanalysispresentthatthismanhadnormalspermatogenesis.ClinicaluseWepresentth72来曲唑芳香化酶抑制剂概要课件73Clinicaluse

Thestudygroupconsistedof29infertilemenwithalowserumT/E2

ratio(<10).Patientsweredividedintotwogroups.GroupAincluded15patientstreatedwith2.5mgletrozoleorallyoncedailyfor6months,andGroupBconsistedof14patientstreatedwith1mg

anastrazoleorallyeverydayfor6months.ClinicaluseThestudygro74来曲唑芳香化酶抑制剂概要课件75来曲唑芳香化酶抑制剂概要课件76ClinicaluseTheincreasein

averageTFSFintheletrozolegroupaftertreatmentcomparedwiththepretreatmentvaluewas31.6%