多囊卵巢综合征患者的生育治疗选择卵母细胞冷冻保存(英文版)

FertilityTreatmentOptionsforWomenwithPCOS

&Oocyte

CryopreservationObjectivesToreviewthemenstrualcycleandwhywomenwithPCOShave

ANOVULATIONTodiscusstreatmentoptionsfor

ovulationinductionTooptimizecounselingPCOSptsabout

therisksofclomiphenecitrate(CC),aromataseinhibitors(letrozole),gonadotropinswithinseminationandinvitro

fertilizationStein-leventhalSyndrome(1935)Report 7caseswitholigo/amenorrheaandbilateralpolycystic

ovariesThreewere

obeseFivehirsute(oneobese)andone

thinacneicWedgeresectionresultedintwopregnancies,andregularcyclesinremainingStein&Leventhal.AmJObstetGynecol29:181,

1935BackgroundWomenwithPCOSmaybe

sub-fertileANOVULATIONWhy?Inflammatory+endocrineabnormalities

on:Ovulatory

functionOocytequalityEndometrial

receptivityHyperandrogenismand

hyperinsulinemia

prematuregranulosacell

luteinizationD.A.Dumesicetal.PolycysticovarysyndromeandoocytedevelopmentalcompetenceObstetGynecolSurv,63(2008),pp.

39–48.Whatarethefeaturesof

PCOS?Androgen

Excess:Biochemical(i.e.

hyperandrogenemia)Clinical(e.g.hirsutism,

acne)IrregularPeriodsAbnormal

MenstruationDiagnosisof

PCOS(The2003RotterdamESHRE/ASRMsponsored

PCOSconsensus

workshop)Atleast2ofthefollowing3

features:Oligo/

anovulationHyperandrogenismPolycystic

ovariesExclusionofother

etiologiesLateonsetadrenal-hyperplasia

(CAH)AndrogensecretingtumorsHyperprolactinemia/thyroid

disorderTheRotterdamESHRE/ASRM-SponsoredPCOSconsensusworkshopgroup.FertilSteril81:19-25,2004;&HumReprod19:41-7,

2004Ovulatory

DysfunctionPolycysticOvarySyndrome

(PCOS)70%Prematureovarianfailure10%Hypothalamicamenorrhea10%Hyperprolactinemia10%ReindollarRH.AmJObstetGynceol1986;155:

531-43.Howdowedetect

ovulation?–BasalBody

Temperature–OvulationPredictor

Kits–Day21-24

Progesterone–Follicleon

Ultrasound8122428Body

TemperatureMenstruation16

20OVULATION360 43736.836.636.436.237.237.437.637.838o

LHTheeffectiscausedbyadirectcentraleffectofprogesterone(fromthenewlyformed

CL)Ovulation

DetectionOvulationDetection

DevicesOvulationpredictor

kits/MonitorsOvulationmayoccur

anytimewithinthe2days

thereafterFalse-positive

testMonitorscannotbeused

intreatment

cyclesDay22-24

ProgesteroneMidlutealphase>

3ng/mlPreferably>10

ng/mlCervical

MucousPregnancyratesatpeakmucous(38%)

vs.(15%to

20%)Notrecommendedduringtreatment

cycles(Clomidor

Gonadotropins)Pretreatment

EvaluationCompleteHistoryandPhysical

examSemenanalysisHysterosalpingogramBaselineFSH,estradiol,AMH,

LHConsiderendometrial

biopsy-Ruleoutendometrial

hyperplasia(amenorrhea

>6mo)LifestyleFactorsThat

MayImpact

OvulationLongertimeto

conceiveWeightSmokingFertilitydecreasesAlcoholDrugsToxinsCounselingPCOS

Patients:Pregnancy

OutcomesAhigherincidence

of:GestationalDM:40%to

50%Fetal

macrosomiaGestationalhypertensivedisorders:

5%Small-for-gestational-agebabies:10%

to15%BoomsmaCMetal.Ameta-analysisofpregnancyoutcomesinwomenwithpolycysticovarysyndromeHumReprodUpdate,12(2006),pp.

673–683.FauserBCetal.Consensusonwomen’shealthaspectsofPolycysticovarysyndrome

(PCOS):theAmsterdamESHRE/ASRM-Sponsored3rdPCOSConsensusWorkshopGroup.FertilSteril2012

Jan;97(1):28-38.e25.ImprovementsinFertility

RatesInducedByDietCrosignani.HumReprod.2003;

18(9):1928-32Menstrual

cycleOvulatory

cycleCumulative

pregnancy(N=33)ProspectivestudyofPCOSpatients

(N=33)1200kcal/day

diet76%lostatleast5%

oftheirbodyweight33%lost

10%PR=30%Ovulationinductionforwomen

withPCOSLife-stylemodification(exerciseand

diet)Clomiphenecitratewithor

withoutInseminationMetforminClomiphene+Adjuvant

regimensAromatase

InhibitorsLaparoscopicOvarian

drillingGonadotropinsInvitro

FertilizationClomiphene

Citrate(CC)ApprovedbytheFDAin

1967Non-steroidal

derivativePharmacologyandMechanismof

ActionSelectiveestrogenreceptormodulator

(SERM)***RequiresanintactHPO

axisoccupiesestrogenreceptorsand"deceives"thehypothalamusintosensingalowestrogen

environmenthypothalamusinturnsignalsthepituitaryviapulsatileGnRHtoincreasegonadotropin(FSHandLH)

releaseSide

EffectsTransienthot

flashesMood

swingsHead

AchesBreast

tendernessPelvicpain/

pressureNauseaVisualdisturbances(blurredordoublevision,scotomata,andlightsensitivity,rareoptic

neuropathy)–MaybeprudenttoabandonRxforalternativemethodofovulation

inductionPurvinV:Visualdisturbancesecondarytoclomiphenecitrate.ArchOphthalmol113:482,

1995Risksof

CCMultiplepregnancyoverallriskis

increasedSpontaneous:1in80

(1.25%)Twins

7-10%Triplets

0.3-0.5%Quadruplets

0.3%Quintuplets

0.1%KEYPOINT:Onceovulatory,higherdosesdonotimproveresultsandonlyincreaseriskofsuperovulationandmultiple

pregnancyAdashiEY(1996)Ovulationinduction:clomiphenecitrate.InAdashiEY,RockJAandRosenwaksZ(eds)ReproductiveEndocrinology,SurgeryandTechnology.Lippincott–Raven,Philadelphia/NewYork,USA,pp

1181–1206.OvarianHypsterstimulationSyndromeOHSSusuallymildsymptoms-abdominaldiscomfort,n/v,

diarrhea,abdominal

distensionRisksof

CCOvarianCancer

riskincreasedin

infertilewomenBecauseofobservationsthatpregnancyratesarelowafter6cyclesofCCandmorethan12cyclesmayincreasetheriskofovarianneoplasma,ACOGhassuggestedthatCCbelimitedtofewerthan12cyclesina

lifetime.RossingMAetal.Ovariantumorsinacohortofinfertilewomen.NewEngJofMedicine

1994;331:771.CCTreatment

Regimens50mgPOdailyfor

5-daysIncreaseby50mgincrementsuntil

ovulationachievedDosesupto150mgis

reasonableLongerdurationcansucceedinsome

womenifnopractical

alternativeResponsetoRxBBTLateluteal

Progesterone>3ng/mLMustbeappropriatelytimed(betweenCD22-25issafe)Whentocounselthepatient

toexpect

ovulation?LHsurgetypicallyoccurs5-12daysafterRxends(CD16-17usuallywhenCCgivenCD

5-9)–Ovulationusuallyoccurs14-26hrsafter

LHsurgeMeta-analysisontheuseof

CCvsplaceboCCis6Xmorelikelytoresultinpregnancythan

placebo75%ofthepregnanciesachievedwithinfirst3cyclesof

treatmentVanSantbrinkEJetal.OvulationInductioninnormogonadotropic

anovulation.ClomipheneCitrate

ProtocolClomipheneCitrateDay3-7or

5-9MensesUltrasoundDay

10hCG10,000

IUTherationaleistodrivemorethanoneoocytetoovulatewitheachcycleinordertoincreasetheoddsofapregnancy.Likewise,intrauterineinseminationofwashed

spermincreasesthenumberofmalegametespotentiallyreachingthe

oocytes.Newer

Protocol“Stair-step”treatment

protocol–Shortentimerequiredtoachieve

ovulationandidentifythosewhorequiredifferent

Rx–CCCD5-9(50mg)

USCD11-14

100mg

ifnodominantfolliclehasemerged(>15mm)

repeatUS1wklater

ifstillnodominantfollicle,150mg

repeatUS1

wklaterContraindicationsPrudenttopostponeRxwithlarge

cystorgrosslyenlargedovariesResultsofCC

RxOvulationinducedin70-80%of

properlyselected

womenResponsedecreases

withIncreasing

ageIncreasing

BMIExtentof

hyperandrogenemiaCyclefecundity

~15%Cumulativepregnancyratesof70-75%can

beexpectedover6-9cyclesof

RxWhyaresomewomen

Clomid-resistant?Inorderof

importance:HyperandrogenemiaObesityOvarian

volumeMenstrual

dysfunctionWhatdowedowith

Clomid-resistant

patients?Ifnopregnancyafter3-6

CC-inducedovulatorycycles,theinfertilityevaluationshouldbeexpandedtoexcludeotherinfertility

factorsChangestrategyifevaluation

alreadycompletedProlongedCCRxis

inappropriateEspeciallyin

women>35yoAdjuvantand

CombinationTreatmentCC-resistantanovulatoryinfertilewomenmayrespondtocombo

RxOptionsMetforminPretreatwith

OCPsGlucocorticoidshCGtotrigger

ovulationCC+lowdose

gonadotropins****IDEALforsomecoupleswhoarereluctantorunabletodoInjectablegonadotropinsbecauseofcosts,logisticdemands,riskofOHSS,riskofmultiple

pregnancyCC+

MetforminAnovulatoryinfertilewomenwithPCOSandhyperinsulinemia

aretypicallymoreresistantto

ClomidMetformin–Biguanideoralinsulin-sensitizingagentthatactsbyreducinghepaticgluconeogenesis,butalsodecreasesintestinalabsorptionofglucoseandincreasesperipheralglucoseuptakeandutilizationSafetyinPregnancycontroversialCombinedRxwithmetformin+CCdeservesconsiderationfor

CC-resistantwomenbeforeproceedingtoovariandrillingor

hMGPreliminaryOCPSuppressionAnovulationreflectsadysfunctionalHPAaxis

reasonabletothinkanintervalofprelimsuppressiveRxmighthelp

restoreharmonyCansuppressLHandandrogen

levelsCC+

GlucocorticoidsStudieshaveshownit’seffectivein

womenwithelevatedDHEA-SandinunselectedpopulationofCC-resistant

womenCC+

GlucocorticoidsMechanismof

glucocorticoidAndrogen

suppressionGlucocorticoidsmaybejustifiedfor3-6cycleswhenitresultsinsuccessful

ovulationContinuousorlimitedtofollicularphase(CD

3-12)Prednisone(5mg

daily)Dexamethasone(0.5-2mg

daily)DexamethasoneforClomipheneResistance:ARCTof80

WomenDexamethasonehighdoseshort

course(2mg/day

D3-12)N=80ElnasharA.HumReprod.2006

;21(7):1805-8.21.81.61.41.210.80.60.40.2001020304050607080CC/

DEX CC/

PlaceboOvulationRatePregnancy

Rate*CC/DEX CC/PlaceboFollicle>18

mm**Dexamethasone+

CCConclusion:InductionofovulationbyaddingDEXtoCCinCC-resistantPCOSwithnormalDHEASisassociatedwithnoadverseanti-estrogeniceffectontheendometriumandhigherovulationandpregnancyratesinasignificantnumberofpatientsCochranereviewreportedthattheuseofDEXasanadjuncttoCCappearspromising(Beck2005)ElnasharA,etal.HumReprod2006;

21:1805-8.ShouldweaddhCG

trigger?hCGusedasa

surrogateLHsurge

totrigger

ovulationNormally,preovulatoryfollicletriggersitsownovulatorystimulusatthepeakofmaturitybymaintainingtheE2

levelsthatarerequiredtoinducetheLH

surgehCGbestpostponeduntilthepreovulatoryfollicle

reachesorexceeds

20mmOvulationoccurs34-46hrsafterhCGinjectionsoIUI

usuallyperformed36hrs

laterWhenLHsurgedetectable,hCGhasNOvalueand

addsunnecessaryexpenseand

inconvenienceAromatase

InhibitorsAromatase

InhibitorsLetrozoleSuppressestrogenbiosynthesisbyblockingtheactionofaromatase,whichconvertsandrostenedione

estrogensIncreasesfollicularsensitivitytoFSH

stimulation–KeyPoint:LESSinhibitionofestrogenstimulatedCERVICALMUCUSandENDOMETRIAL

PROLIFERATIONMitwallyMetal.PotentialofAromataseInhibitorsforOvulationandSuperovulationInductioninInfertileWomen.Drugs2006;66(17):

2149-2160.LetrozoleTreatment

RegimensGiven2.5-7.5mgdailyfor5daysCycleDay

3-7Optimaldosagehasnotbeen

establishedfirmlyHigherdosemayresultingreater/longersuppressionofestrogen

couldlimitEndometrialproliferationLaparoscopicOvarianDrillingOvarian

DrillingAnothertreatmentoptionforCC-resistant,hyperandrogenic,anovulatory

womenMethods(noevidenceforsuperiorityofany

method)Electrocauteryorlaser

vaporizationMultiple

biopsiesMechanism:causefocaldestructionofovarianstromainefforttodecreasebothintraovarianandsystemicandrogen

concentrationRisksofOvarian

DrillingPostoperativeadnexal

adhesionsRiskofaffectingovarianreserveandpredisposingtoearlymenopause

hasnotbeenstudied

specificallyExogenous

GonadotropinsGonadotropin

UsehMG1970hMG(IM

only)1986Human-derivedFSH(IM

only)1996Human-derived

HP-FSH(SC

only)2000+Bravelle,Ovidrel,LuverisandDelivery

Systems1999Repronex®(IM,SC)1997Repronex®(IM);rFSHfromCHOcells

(IM,SC)FSH/hMGRisksof

GonadotropinsRiskofmultiplesAnovulatorywomen:

15%Superovulation:

30%–10%higherorder

multiplesRiskofOHSSRiskofSpontaneous

MiscarriageGonadotropins:20-25%(AMAand

obesity)HigherthangenerallyobservedSpAbrate

15%NOevidenceofcongenital

anomaliesWhenshould

cliniciansCANCELthe

cycle?BEST

guidelines:Estradiolisabove

1500pg/mL≥4follicleslargerthan

10-14mmSelectiveFetalReduction

CounselingShouldweperformanIntrauterineInsemination

whenadministering

gonadotropins?NobelPrizein

MedicineOctober4th,

2010LouiseBrown(bornin1978)andRobertG.Edwards,

Ph.D.InVitroFertilizationIVFICSIConclusionsGoalofovulationinductioninwomenwPCOS

is

monofollicular

developmentWesuggestweightlossforwomanwithBMIgreaterthan

27kg/m2ClomiphenecitrateisusedtoinduceovulationinPCOSpatients. Adjuvantsmaybeaddedtoresistantpatients.ProgressivedeclineinfecunditywithadvancingageisarealityIndividualizedtreatmentplansareidealdependingon

awoman’sageandbaselineline

testsEgg

FreezingSperm

FreezingEmbryo

FreezingFertility

PreservationHopeForThe

FutureWhento

considerSocial

indicationsInsurancepolicyforfuturehopesof

familyMedical

indicationsPriortocancertreatment(chemotherapyand

radiation)Priortoextensivepelvic

surgeryPriortoaggressivetreatmentforautoimmune

disorderFertility

PreservationProtectandpreservecurrent

fertilityTechnique:

VitrificationIdenticaltoIVFcycleE