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update on poor responder

aboubakr elnashar

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update on poor responder

  1. 1. LOWOVARIANRESPONSE Prof.AboubakrElnashar BenhauniversityHospital,Egypt ABOUBAKRELNASHAR CONTENTS 1.MEASUREOFSUCCESSofIVF 2.PREVALENCE 3.DEFINITION&CLASSIFICATION 4.CAUSE 5.PREDICTION 6.MANANAGEMENT 1.Challenging 2.Prognosis 3.Interventions 4.AccordingtoPOSEIDON CONCLUSIONABOUBAKRELNASHAR
  2. 2. 1.MEASUREOFSUCCESSofIVF ▪Cumulativelivebirthrate(CLBR)perstartedcycle ▪MostimportantmeasureofsuccessinIVF [Maheshwarietal,2015] ▪NumberofoocytesretrievedafterCOS ▪Greatlyinfluencestheclinicaloutcome [Drakopoulosetal,2016]. ▪Optimizationoftheoocytenumberbasedonthe ovarianreserveisessential. ABOUBAKRELNASHAR ▪Theidealnumberofoocytes,whichshouldbe retrievedafterCOStomaximizeLBRinfreshET cycles: ▪10accordingtoVerbergetal.[2009] ▪13accordingtoVanderGaastetal.[2006], ▪15accordingtoSunkaraetal.[2011]. ▪18accordingtoFatemietal.[2013] ▪Onaverage,then,10–15oocytes ABOUBAKRELNASHAR
  3. 3. ❑Idealnumberofoocytesaccordingto: woman’sagetoobtainatleastoneeuploid blastocyst ▪Aneuploidchromosomalconstitution ▪stronglyrelatedtothewoman’sage ▪representsthemainfactoraffectingembryo reproductivecompetence[Capalboetal,2017]. ▪Theclinicianshoulddecideatreatmentstrategy thatgiveatleastoneeuploidblastocyst ABOUBAKRELNASHAR ThemeaneuploidblastocystratesperMIIoocyteaccordingtotherangesofmaternal agehavebeenestimatedbasedonanaverage35%blastocystrateperMIIoocyte, whichisindependentfrommaternalage(GENERAdataunderreview),andonthe euploidyrateperblastocystreportedbyCapalboetal.[2017]. ABOUBAKRELNASHAR
  4. 4. Meannumberofoocytesneededtooptimizethelikelihoodofaeuploidblastocyst ABOUBAKRELNASHAR 2.PREVALENCE ▪9-24%[Ubaldietal,2014]. ▪dependsonthedefinition ▪Notahomogeneouspopulation ▪Increasing{manypatientspostponingconceptionsto thelatethirtiesorevenbeyond40}. ABOUBAKRELNASHAR
  5. 5. 3.DEFINITION&CLASSIFICATION ▪41differentdefinitionsoutof47RCTs: ▪Managementverydifficulttocompare ▪Anidealtreatmenthasneverbeendefined. (Polyzosetal,2011) ABOUBAKRELNASHAR ❑Classesofpatientsaccordingtoovarianresponse: 1.Poorresponder:3orlessoocytesretrieved 2.Suboptimalresponder:4to9oocytesretrieved 3.Normalresponder:10–15oocytesretrieved 4.Hyperresponder:15ormoreoocytesretrieved. ▪Theexactclassificationofthepatientinoneof thesegroupsisessentialtodefinethecorrectTT [Polyzosetal,2008]. ABOUBAKRELNASHAR
  6. 6. BolognaCriteria2011 ❑Atleast2of3featuresmustbepresent: 1.Age(≥40y)oranyotherriskfactorforPOR 2.PreviousPOR (≤3oocyteswithaconventionalstimulationprotocol) 3.AbnormalORT (AFC<5–7folliclesorAMH<0.5–1.1ng/ml). ❑2episodesofPOR aftermaximalstimulationinabsenceofadvancedmaternalage orabnormalORT. ABOUBAKRELNASHAR ❑Criticisms 1.Populationwastooheterogenousin 1.Woman’sage 2.Oocytecompetence 3.Riskfactors. 2.Noclearcut-offofAFC&AMH Valuesrangingfrom5-7forAFC&0.5-1.1ng/mLforAMH 3.Useof“othercauseofPOR”asoneofcriterion: thesecriteriaimprecise. {asovariansurgeryorhistoryofchemotherapyshouldbe evaluatedseparatelynotincludedinthesamecategory}. ABOUBAKRELNASHAR
  7. 7. POSEIDON(Humaidanetal,2017) (Patient-OrientedStrategiesEncompassingIndividualizeDOocyteNumber) Thegroupcomprises12opinionleadersinreproductivemedicinefrom7countries ▪Moredetailedstratificationforpatientsby ▪Reducedovarianreserveor ▪Lowresponsetoovarianstimulation. ▪Movingfromapoorovarianresponsetoalow prognosisconcept ▪Consideringnotonlythe ▪Numberofoocytesretrieved,butalso ▪Age-relatedaneuploidyrateand ▪Ovarian‘sensitivity’toGnTABOUBAKRELNASHAR ▪4groupsbasedonoocytequantity&quality ABOUBAKRELNASHARABOUBAKRELNASHAR
  8. 8. ABOUBAKRELNASHAR PrevalenceofPOSEIDONpatientsattendingaFertilityClinic& distributionbygroupcategory. (Androfert:(N.=432)-year2017). ABOUBAKRELNASHAR
  9. 9. 4.CAUSESofdiminishedovarianreserve •Itisunclearwhetherrepresentsapathologiccondition resultingfrom: 1.Abnormallyrapidatresiainanormalpoolofoocytes. 2.Normalatresiaofanabnormallysmallinitialpoolofoocytes. ▪Ovarianaging:DOR ▪fewerfollicles,whichareinhypoxicenvironment&consistof fewergranulosacells,withpossiblyimpairedfunction(Pelliceretal. 1998) ABOUBAKRELNASHAR 1.Genetic ▪Abnormalities(45X,FMR-premutations) ▪PolymorphismofGnT&theirreceptors ▪LH-bsubunitvariant ▪GallelecarriersofacommonFSHreceptor (FSHR)polymorphism(p.N680SA>G,rs6166) 2.Autoimmunedisorders,likeAddison’sdisease 3.Metabolic:Galactosemia 4.Infectious:Mumpsoophoritis ABOUBAKRELNASHAR
  10. 10. 5.Iatrogenic ▪Exposuretochemotherapy ▪Exposuretoradiotherapy ▪Previousovariansurgery ▪Salpingectomyforectopic,hydrosalpinx,etc ▪Uterinearteryembolization&ligation 6.Environmental: ▪Pollutants ▪Oxidativestress ▪Smoking 7.Idiopathic:Inoverhalfofthesepatients ABOUBAKRELNASHAR ❑PreventionofDOR ▪Avoidsmoking ▪Carefulsurgicaltechnique&strictadherenceto principlesofmicrosurgery ▪LODshouldbeavoidedinpatientswithlowAMH eveniftheovariesarepolycysticinappearance. ▪Beforechemotherapyorradiotherapy:various methodsoffertilitypreservation ▪Useofapoptosisinhibitorslikesphingosine-1- phosphatehasbeenproposed.ABOUBAKRELNASHAR
  11. 11. 5.IDENTIFICATIONOFPATIENTATRISK PREDICTION (Fiedler&Ezcurra,2012) HighresponseLowresponse 164TotalAFC 40.5AMHng/ml 48.9FSHIU/L ABOUBAKRELNASHAR 6.MANAGEMENT 6.1.Challenging ▪Doctor ▪Expectationsofsuccessfulpregnancyarelow ▪Guidelinesarelacking ▪CochraneSR:(Oudendijketal,2012) ▪insufficientevidencetosupporttheroutine useofanyparticularinterventions ABOUBAKRELNASHAR
  12. 12. ▪Couple 1.CostofIVFishigher ▪Higheramountofdrugsadopted ▪RepeatTTcycles. 2.Emotional,physical,&financialdistress, particularlywhenmultipleTTcyclesarerequired. 3.Drop-outamongtheaffectedpatientsishigh ABOUBAKRELNASHAR 6.2.Prognosis(Oudendijketal,2012) ▪variesgreatlydependingon ▪Age ▪Numberofoocytesretrieved ABOUBAKRELNASHAR
  13. 13. ❑Follicle-to-oocyteindex(FOI)forpoorresponders. (Alviggietal.2016) ▪PORischaracterizedbyareducednumberof FolliclesOutputRate(FORT) ▪Reflectthedynamicnatureoffolliculargrowthin responsetoCOS,comparedtothetraditional markersofovarianreserve. ABOUBAKRELNASHAR 6.3.INTERVENTIONS:Many:33 ▪Mostpopularintervention(Papathanasiouetal,2016) 1.Antagonist:Mostcommonstrategy(Jeve,Bhandari,2016) 2.Microdoseflare 3.Longprotocol 4.LHadded 5.Letrozole+FSH+antagonist 6.DHEA 7.Short(flareup)protocol 8.Transdermaltestosterone 9.Growthhormone 10.HCGaddedatstimulation ABOUBAKRELNASHAR
  14. 14. 11.IncreaseofFSHdose 12.CC+FSH/HMG+-antagonist 13.LutealFSHstart 14.Estrogenforlutealsupport 15.Follicularflushing 16.Long-stopprotocol 17.FSH/HMGonly(noagonistor antagonist) 18.FSHdose300IU 19.LateFSHstart 20.Metformin 21.Ultrashorta-antagonist 22.Modifiedflare 23.Low-doseaspirin 24.Naturalcycle 25.Mini-longprotocol 26.Step-downofFSHdose 27.Lutealphaseantagonist 28.Gameteintrauterinetransfer 29.Dayofembryotransfer 30.Early(Day1)FSHstart 31.FSHdose450IU 32.FSHdose600IU 33.ClomiphenecitrateonlyABOUBAKRELNASHAR ❑WhataretherecentTrends?(Papathanasiouetal,2016) ABOUBAKRELNASHAR
  15. 15. ▪Nostandardmanagement,intermsofprotocol& drugs,hasbeendefined[Patrizioetal,2015]. ▪Thebestprotocol ▪Noconsensus. ▪Debatedissue. ▪Lines: I.COS: 1.Type2.dose3.protocol4.triggering II.Addson III.Lab ABOUBAKRELNASHAR I.Controlledovarianstimulation 1.Gnttype ❑RecFSH ▪Notimproveoutcome(Tarlatzisetal,2003) ▪InsufficientevidencetorecommendonetypeofGnt overanother(Nardoetal,2013) ABOUBAKRELNASHAR
  16. 16. 2.Gntdose ❑Increasedose: ▪Littleornobenefit(Tarlatzisetal,2003) ▪Patientswhofailedtoconceivewith450 IU/dwill notbenefitfromincreasingdoseto600 IU(Haaset al.,2015) ▪ESHRE,2019: ▪Itisunclearwhetherahighergonadotrophindoseis recommendedover150IUforpredictedpoor responders. ▪Dose≥300IUisnotrecommendedforpredictedpoor responders.ABOUBAKRELNASHAR ❑CochraneSR,2018 ▪Nodifferenceinpregnancyoutcomesbetweenlow dosesofGnT&GnTcombinedwithoral compounds(CCorLet)comparedwithhighdoses ofGnTinovarianstimulationregimensinPOR ABOUBAKRELNASHAR
  17. 17. 3.Protocol 1.NaturalcycleVslongagonistprotocols ▪Nodifference(Tarlatzisetal,2003) ▪Theuseofmodifiednaturalcycleisprobablynot recommendedoverconventionalOSforpredictedpoor responders(ESHRE,2019) 2.MildCOS(CC/Gn/GnRHan)Vslongagonist Nodifference(Songetal,2016) 3.FlareupVslongagonistprotocol ▪Betterresults(Tarlatzisetal,2003) ▪Nodifference(Sunkaraetal,2007)ABOUBAKRELNASHAR 4.FlareupVsAntagonist/Letprotocol Better(Songetal,2014) 5.GnRHa'stop'Vslongagonistprotocol Nodifference(Tarlatzisetal,2003) 6.AntagonistVsflareupprotocols. Better(Francoetal,2006) ABOUBAKRELNASHAR
  18. 18. 7.AntagonistVslongagonist Better Griesingeretal,2006 Francoetal,2006 Nodifference Tarlatzisetal,2003 Sunkaraetal,2007 Puetal,2011 Xiaoetal,2013 Nardoetal,2013 Jeve,Bhandari,2016 ESHRE,2019 GnRHantagonistsandGnRHagonistsareequallyrecommended forpredictedpoorresponders.ABOUBAKRELNASHAR ▪ESHRE,2019: ▪shouldonlybeusedinthecontextofclinicalresearchonly ▪canbeconsideredforurgentfertilitypreservationcycles. 8.Doublestimulation(Ubaldietal,2015) ABOUBAKRELNASHAR
  19. 19. ▪Sfakianoudisetal,SR&MA,2019 ▪DuoStimiscorrelatedwithahighernumberof ▪Retrievedoocytes,matureMIIoocytes ▪Goodqualityembryos ▪incomparisontoconventionalstimulation. ▪LPStimulation ▪correlatedwithanequaloranevenhigher overallperformanceincomparisontoFPS. ▪notcorrelatedwithahigheraneuploidyrate. ❖DuoStim promisingtreatmentofPORpatientsbyenablinga higheroocyteyieldduringasinglemenstrual cycle.ABOUBAKRELNASHAR 4.Triggering. ❑DualTriggering statisticallysignificantincreasein ▪numberofretrievedoocytes ▪matureoocytes ▪fertilizedembryos ▪PR ▪IR ▪newborn/transferredembryorate. (Oliveiraetal,2016) ABOUBAKRELNASHAR
  20. 20. II.Adjuvants 1.GH Nosignificant improvement. ▪Tarlatzisetal,2003 ▪Yuetal,2015 ▪ESHRE,2019: ▪UseofGHbeforeand/or duringOSisprobablynot recommendedforpoor responders. Significantimprovement ▪CochraneSystRev.2003 ▪Kyrouetal,2009 ▪Kolibianakisetal,2009 ▪Jeve,Bhandari,2016 ▪Lietal,2017 ABOUBAKRELNASHAR ❑Dose: 4-12IUofGHSConthedayofstimulation ❑Effects: ▪stimulatessteroidogenesis,folliculardevelopment& responsivenesstoFSH(Jiaetal.1986). ▪ActssynergisticallywithFSH(Adashi&Rohan1993) ▪mayimprovethenumberofoocytes ❑Disadvantages: Expensive&routineusecannotbejustified (CochraneSR.2002) ABOUBAKRELNASHAR
  21. 21. ▪Clonidinetest ▪Clonidineactscentrallytostimulatealpha-adrenergic receptors,whichareinvolvedinregulatingGHrelease. ▪SerumGHlevelsareobtainedatbaselineandat60 minutesand90minutesaftertheoraladministrationof clonidine0.1mg/kg. ▪Clonidinenegative:failuretoincreaseGHconcentration ▪GHincreaseovarianresponse&generatedPRandLBRin clonidinenegativePORpatientsbutnotinclonidine positiveinfertilepatients ABOUBAKRELNASHAR 2.DHEAsupplementation Notbeneficial ▪Bosdouetal,2012 ▪Narkwicheanetal,2013 ▪CochraneSR,2015(excluding biasedstudies) ▪Quinetal,2016 ▪Jeve,Bhandari,2016 ▪Qinetal,2017ofRCT Beneficial ▪Fouany,Sharara,2013 ▪Lietal,2015 ▪CochraneSR,2015 ▪Zhangetal,2016 ▪CochraneSR,2019 ▪ESHRE,2019: ▪UseofDHEAbeforeand/orduringOSisprobablynot recommendedforpoorresponders.ABOUBAKRELNASHAR
  22. 22. ▪Mildandrogen ▪Dose:75mg–100mg/d foratleast12w ▪Effects:(Zhangetal,2016) ▪IncreaseinAMHlevels ▪DecreaseinbaselineFSH ▪Improvesoocytenumbers ▪embryoquality ▪spontaneousPR ▪IVFPR ▪Advantages: ▪Availableover counter ▪Minimalside effects ▪Inexpensive ABOUBAKRELNASHAR 3.Transdermaltestoeterone Beneficial ▪GonzálezComadranetal,2012 ▪Bosdouetal,2012 ▪Luoetal,2014 ▪CochraneSR,2015 ▪Jeve,Bhandari,2016 Insufficientevidence ▪Sunkaraetal,2011 ESHRE,2019:UseoftestosteronebeforeOSisprobablynot recommendedforpoorrespondersABOUBAKRELNASHAR
  23. 23. 4.rLH Beneficial ▪CochraneSystRev.2007 ▪Nardoetal,2013 Notbeneficial ▪Bosdouetal,2012 ▪Fanetal,2013 ▪Jeve,Bhandari,2016 ABOUBAKRELNASHAR 5.LutealphaseE2 Beneficial ▪Changetal,2013 ▪Reynoldsetal,2013 ABOUBAKRELNASHAR
  24. 24. EstrogenPrimed AntagonistProtocol •Pretreatmentcycleisanaturalcycle(noBCP). •Aboutaweekafterovulation –GnRHan{preventprematurerecruitmentoffollicles} –Estrogen {providestheyoungfolliclesanoptimalconditiontogrowinthefuture}. •Onday3ofthenextmenses. –Stimulationmedicationsarestarted ABOUBAKRELNASHAR 6.OCPpretreatment ▪Tarlatzisetal,2003 ▪±helpovarianresponse. ❑Nardoetal,2013 ▪GnRHancycles: •AdverselyaffectsIVFoutcome ▪GnRHacycles. •Noeffect ABOUBAKRELNASHAR
  25. 25. 7.Corticosteroids ▪Reducestheincidenceofpoorovarianresponse (Tarlatzisetal,2003) ▪BritishFertilitySociety,2014 Thereislimitedevidence ABOUBAKRELNASHAR ❑Dexamethasone ▪1mg/dorallytillretrieval ▪directlyinfluencegranulosacellsviaisoformorby increasingGH&IGF-1 ▪improvetheendometrialmicroenvironment. (Smithetal.2000,Keayetal.2001) ABOUBAKRELNASHAR
  26. 26. 8.Nitricoxidedonors ▪Limiteddata(Tarlatzisetal,2003) ABOUBAKRELNASHAR 9.Aromataseinhibitors Notbeneficial (fourtrials;n=223)(Jeve,Bhandari,2016) ▪ESHRE,2019: ▪Theadditionofletrozoletogonadotrophinsinstimulation protocolsisprobablynotrecommendedforpredictedpoor responders. ABOUBAKRELNASHAR
  27. 27. 10.COENZYMEQ10 ▪Rationale: ▪Oxidativestress&mitochondrialdysfunctionare possiblepathophysiologicalmechanisms ▪CoQ10antioxidant ▪enablesfortheelectrontransportinmitochondrial respiration&oxidativephosphorylationnecessary foradenosinetriphosphate(ATP)production ABOUBAKRELNASHAR ▪CoQ10supplementationtoCOS ▪Improvedpatients’responsetoovulationinduction ▪Decreasedfetalaneuploidyinolderpatients(El Refaeeyetal,2014). ▪POSEIDONclassificationgroup3(Xuetal,RCT,2018). ▪Pre-treatmentfor2monthsbeforeCOSforIVF ▪Moreoocyteswereretrieved ▪Fertilizationrate&numberofhigh-quality embryoswashigher ▪HigherCPR&LBR/ETdidnotreach statisticalsignificanceABOUBAKRELNASHAR
  28. 28. StudyTypeNuOutcome Sfakianoudisetal, 2019,GynecolObstet Invest. Case series 3Withina3-monthinterval,FSH decreasedby67.33%,AMH increasedby75.18%.improved embryoquality.Natural conceptionat24successfullive birth. Farimanietal,2019Case series 19Themeannumbersofoocytes beforeandafterPRPinjection were0.64and2.1.Two spontaneousconceptions.The thirdcaseachievedclinical pregnancy 11.Platelet-richplasma ▪Poorresponders ABOUBAKRELNASHAR StudyType of study No of pt outcome Sillsetal, 2018,Gyn endocrinology Case series 4Improvedovarianfunctioninallcases, IncreaseAMH,DecreaseFSHorboth.IVF: retrievalof5.3±1.3MIIoocytes. Nataliiaetal, 2020,Rep science observ ational cohort 38Significantimprovementinhormonelevels;6 babieswereborn,10pregnancieswere achieved,and4outofthe10werefromnatural conception. Singhetal, 2020,ESHRE observat ional cohort 30NobenefitinincreasingAMH,AFC,ovarian responsetoovarianstimulationorIVFoutcome Melloetal, 2020.JAssist ReprodGenet Controll edNon R 46SignificantimprovementinFSH,AMHandAFC, nochangeinthecontrolgroup.biochemical (26.1%vs5.4%,P=0.02)andclinical pregnancy(23.9%vs5.4%,P=0.03)were higherinthePRPgroup,nodifferencein miscarriageandLBR ▪Diminishedovarianreserve ABOUBAKRELNASHAR
  29. 29. ❑ZhangetalSR,2020 ▪46trials,6312womenwere ▪WithregardtoCP:DHEAandCoQ10:significantlyhigher ▪Withregardtothenumberofretrievedoocytes:HCG,E2 andGHtreatmentshadthehighestnumber ▪Withregardtothenumberofembryostransferred: Testosterone&GHtreatmentledtothehighestnumber ▪GH:highestE2levelontheHCGday ▪CC,letrozole&GHgroupsusedthelowestdosagesofGnT ▪CoQ10:lowestcancelationrate ABOUBAKRELNASHAR ❖ForpatientswithPOR,COSprotocolsusingadjuvant treatmentwithDHEA,CoQ10&GHshowedbetter clinicaloutcomesintermsofachievingpregnancy& lowerdosageofGnT ABOUBAKRELNASHAR
  30. 30. III.Lab 1.Assistedhatching Nobenefit(Tarlatzisetal,2003) 2.Embryotransferonday2Vsday3 improveCPR(Kyrouetal,2009) 3.Follicularflushing ▪Doesnotincreasenumberofretrievedoocytes ▪LowerIR&CPR(NeumannK,Griesinger,2017) ABOUBAKRELNASHAR 6.4.TreatmentAccordingToThePOSEIDON Stratification(Drakopoulosetal,2020) Group1&2 ▪G1:Youngwomen(<35years)withnormalovarian markers(AMH1.2;AFC5) ▪G2:Oldwoman(>35years)withnormalovarian markers(AMH1.2;AFC5) ▪Issue:Unexpectedpoorresponse: -HyposensitivityofgranulosacellstostandardFSHdoses -FSHreceptorpolymorphisms ABOUBAKRELNASHAR
  31. 31. I.COS: 1.Protocol ▪BothGnRHlongagonist&antagonistprotocols maybeused{studieshasshowncomparable efficacy} ▪Theyperformbettercomparedwiththeshort flare-upprotocol ABOUBAKRELNASHAR ▪Dualstimulation ▪Giventhatoocyte&embryoaneuploidyratesare higherinthisgroupcomparedwithwomen<35years:higher oocyteyieldisrequiredtoobtainaneuploidembryo. ▪oocytes/embryosderivedfromlutealphasestimulation showsimilarcompetenceasfollicularphasestimulation- ones ▪Maximizingthetotalnumberofoocytesinonemenstrual cycle:higherprobabilitytogetageneticallynormalembryo :thecumulativeLBRwouldbeincreased. ABOUBAKRELNASHAR
  32. 32. 2.Typeofgonadotropins ▪{Themainproblembehindunexpected suboptimal/poorresponseisthattheoocyteyieldis notconsistentwithovarianreserve} ▪Toretrievemoreoocytes,amore“potent”GnT. ▪SeveralRCTs&meta-analyses:rFSH:significantly moreoocytescomparedwithurinarypreparations (Devroeyetal,2012;Santietal,2017)suggestingthat rFSHmaybetheGnTofchoiceforPoseidon groups1and2. ABOUBAKRELNASHAR 3.Dose:Increaseofinitialdoseofstimulation ▪higherrFSHstartingdose(225IU)inwomenhomozygousforSer680(SS):significantlyhigherserum E2comparedwithSSwomentreatedwithalower(150IU)doseandsimilarserumE2levelswith womenhomozygousforAsn680(AA)/heterozygous(AS)treatedwith150IUofrFSH. ▪Anincreaseinthestimulationdoseofthesecond IVFcycle:significantlyhigheroocyteyield. ▪Anincreaseby50unitsintheinitialdose:onemore oocyte. ▪EachadditionaloocytemayincreasetheLBRby 5%(Martinetal,2010) ABOUBAKRELNASHAR
  33. 33. II.Addson ▪rLHII. ▪To ▪stimulateearlystagesoffolliculargrowth ▪improveFSHreceptorexpressioningranulosacells ▪improvethesensitivitytoFSHdose&recruitability ▪MainlybenefitspatientswhoarecarriersofLH–β& presentovarianresistancetoGnT. ▪showingabenefitintermsofoocyteyield&PR ▪2:1ratioofrFSH:LH,(75–150IUoncedaily) ▪Startingat ▪Mid-follicularphaseinanattempttorescuetheongoing cycleor ▪fromday1ofthefollowingIVFcyle. ABOUBAKRELNASHAR ▪Androgenssupplementation ▪DHEAsupplementationfor8weeksbeforeCOSwere foundtohavesignificantlyhigherLBR&lowermiscarriage rate(Tartagnietal,2013) ABOUBAKRELNASHAR
  34. 34. Group3&4 G3:Youngwomen(<35years)withpoorovarianreserve markers(AFC<5;AMH<1.2ng/ml) G4:Oldwomen(>35years)withpoorovarianreserve markers(AFC<5;AMH<1.2ng/ml) ▪Issue DepletionofovarianreserveintermsofAFC ABOUBAKRELNASHAR I.COS 1.Protocol ▪AntagonistprotocolwithSynchronizingfolliclewave beforestartingCOSwith 1.E2for5dayspriortomenses 2.ShortGnRHanpre-treatmentatbeginningofthe cycle 3.Oralcontraceptives 4.Progestinsfor12–14daysaspretreatment ▪LongGnRHaprotocol,albeitnon-significantly,increasedthenumberofmature oocytesbyoneoocyteascomparedwiththeGnRHanprotocol{follicular synchronizationfollowinglutealFSHsuppression&inhibitionofearlyfollicular recruitmentobtainedwithdownregulationusinganagonistprotocol}(Sunkaraet al,2018) ABOUBAKRELNASHAR
  35. 35. ▪Doublestimulationinamenstrualcycle(DuoStim) {Multiplefollicularwavesduringonemenstrualcyclehas offerednewpossibilitiesforovarianstimulation} ABOUBAKRELNASHAR 2.GnTtype: ▪insufficientevidencetofavortheuseofonetypeof GnTratherthananotherinPOR(ESHRE,2019),making thisdecisionsubjecttoavailability,convenience& costs. 3.GnTdose:[Berkkanogluetal,2010]. ▪FSH300IUdaily. ▪Higherdoseswillnevercompensatetheabsence offollicles{GnTcanonlysupportthecohortoffollicle responsivetothestimulation,butcannotgeneratefollicles denovo} ABOUBAKRELNASHAR
  36. 36. II.Addson ▪AddingLH:(Alviggietal,SR2018) ▪benefitwasmorepronouncedin ▪unexpectedPORs ▪women36–39yearsofage ▪whileitsuseingeneralPORpopulationremains controversial ABOUBAKRELNASHAR ▪Insignificantimprovetheovarianreserve. ▪Growthhormone[Eftekharetal,2013] ▪DHEA[Yeungetal,2016] ▪Testosterone[Bosdouetal,2016] ▪CoQ10:2mpriortoCOS(Zhangetal.,RCT2020)inPOSEIDON group3 ▪significantlyhighernumberofretrievedoocytes ▪SignificantlylessconsumedFSH ▪{CoQ10wouldreducemitochondrialoxidativestress: improvedoocytecompetence} ABOUBAKRELNASHAR
  37. 37. CONCLUSION ▪PoorprognosispatientschallengeIVFclinicians ▪Bolognacriteriadescribedaveryheterogenousgroup withhighlydifferentsuccessratesafterART. ▪POSEIDONcriteriaforPOR,stratifyingpatientsinto morehomogenoussub-groups,andimportantly,giving recommendationsforclinicalTT. ▪TreatmentoftheexpectedPORpatientdemandsan individualizedapproachincludingallstepsofART,pre- treatmentstrategy,ovarianstimulationstrategyand ovulationtriggerstrategyABOUBAKRELNASHAR ▪Despitethetwodecadesoftrying,thereisstillno consensusonwhatisbestforpoorresponders ▪Nosingletreatmentcanberecommendedover another,astheevidenceforallofthemisinsufficient. ABOUBAKRELNASHAR
  38. 38. Youcangetthislecturefrom: 1.MyscientificpageonFacebook:Aboubakr ElnasharLectures. https://www.facebook.com/groups/2277448840913 51/ 2.Slidesharewebsite 3.elnashar53@hotmail.com 4.Myclinic:Althwarast,Mansura ABOUBAKRELNASHAR ▪Clomiphenecitratealoneorincombinationwithgonadotrophins andgonadotrophinstimulationaloneisequallyrecommended forpredictedpoorresponders. ▪NostudieswerefoundcomparingareducedFSHdose(<150 IU/day)toconventionalFSHstimulationinpoorresponders. ABOUBAKRELNASHAR
  39. 39. ▪Useofaspirinbeforeand/orduringOSisnotrecommendedin thegeneralIVF/ICSIpopulationandforpoorresponders. ▪Useofsildenafilbeforeand/orduringOSisnotrecommended forpoorresponders. ABOUBAKRELNASHAR ▪Thefollowinginterventionsarepromising {Littleevidence:Possiblyeffective:moreevidence needed} ▪FlareupGnRHaprotocol ▪Dualtriggering ▪EstrogenPrimedAntagonistProtocol ▪GH ▪DHEAsupplementation ▪Transdermaltestoeterone ▪Embryotransferonday2 ABOUBAKRELNASHAR
  40. 40. ▪Routineuseofadjuvantmetforminbeforeand/orduringOSis notrecommendedwiththeGnRHantagonistprotocolfor womenwithPCOS. ▪UseofadjuvantGHbeforeand/orduringOSisprobablynot recommendedforpoorresponders. ▪UseoftestosteronebeforeOSisprobablynotrecommended forpoorresponders. ▪Useofdehydroepiandrosteronebeforeand/orduringOSis probablynotrecommendedforpoorresponders. ▪Useofaspirinbeforeand/orduringOSisnotrecommendedin thegeneralIVF/ICSIpopulationandforpoorresponders. ▪Useofsildenafilbeforeand/orduringOSisnotrecommended forpoorresponders. ▪Thereisnoevidence,i.e.controlledstudiesorrandomised controlledstudies(RCTs),addressingtheefficacyandsafetyof adjuvantindomethacinuse,tosupportarecommendationon theuseofindomethacinduringOS. ABOUBAKRELNASHAR 1.InPORpatientswithborderlineGHdeficiency (Clonidinenegativepatients),theadditionofGHtoCOH mayimproveIVFresults. 2.InPORpatientswithevidenceofautoimmunityto variousglandsandorgans(thyroid,adrenal...), suggestinganautoimmunepathophysiologytotheir POR,aprotocolcombiningglucocorticoids,long GnRHa,andhighdosegonadotropinsmayimprovethe numberofretrievedoocytes,andpossiblyalsotheIVF results.Evenincaseswherethere wasasignificantincreaseintheyieldofgeneratedova andembryabythisprotocol,themaximalrecommended attemptsisthree—sinceallthepregnanciesachieved byusingthiscombinationweresuccessfulwithinthree attempts(1–3). Inaddition,thepreliminaryoptimisticreportson ABOUBAKRELNASHAR
  41. 41. 1.SynchronizingfolliclewavebeforestartingCOSwith E2,progestin,OCP 1.GnRHantagonist 2.IncreasingFSHdailydose ▪FSHdosedoesnotreachminimumthresholdforadequate follicularrecruitment 4.AddingLH(75–150IUoncedaily) ▪Tostimulateearlystagesoffolliculargrowth ▪ToimproveFSHreceptorexpressioningranulosacells ▪ToimprovethesensitivitytoFSHdose&recruitability ABOUBAKRELNASHAR ▪Ifahyporesponseisprecociouslydiagnosedin groups1&2POSEIDON(days5–8ofCOS) ▪IncreaseofFSHdoseand ▪AddLHactivity ▪couldbeeffectiveinpreventinglowfollicular outputrate(FORT). ABOUBAKRELNASHAR

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