aboubakr elnashar

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. 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
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3. ❑Idealnumberofoocytesaccordingto:
woman’sagetoobtainatleastoneeuploid
blastocyst
▪Aneuploidchromosomalconstitution
▪stronglyrelatedtothewoman’sage
▪representsthemainfactoraffectingembryo
reproductivecompetence[Capalboetal,2017].
▪Theclinicianshoulddecideatreatmentstrategy
thatgiveatleastoneeuploidblastocyst
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ThemeaneuploidblastocystratesperMIIoocyteaccordingtotherangesofmaternal
agehavebeenestimatedbasedonanaverage35%blastocystrateperMIIoocyte,
whichisindependentfrommaternalage(GENERAdataunderreview),andonthe
euploidyrateperblastocystreportedbyCapalboetal.[2017].
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4. Meannumberofoocytesneededtooptimizethelikelihoodofaeuploidblastocyst
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2.PREVALENCE
▪9-24%[Ubaldietal,2014].
▪dependsonthedefinition
▪Notahomogeneouspopulation
▪Increasing{manypatientspostponingconceptionsto
thelatethirtiesorevenbeyond40}.
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5. 3.DEFINITION&CLASSIFICATION
▪41differentdefinitionsoutof47RCTs:
▪Managementverydifficulttocompare
▪Anidealtreatmenthasneverbeendefined.
(Polyzosetal,2011)
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❑Classesofpatientsaccordingtoovarianresponse:
1.Poorresponder:3orlessoocytesretrieved
2.Suboptimalresponder:4to9oocytesretrieved
3.Normalresponder:10–15oocytesretrieved
4.Hyperresponder:15ormoreoocytesretrieved.
▪Theexactclassificationofthepatientinoneof
thesegroupsisessentialtodefinethecorrectTT
[Polyzosetal,2008].
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6. BolognaCriteria2011
❑Atleast2of3featuresmustbepresent:
1.Age(≥40y)oranyotherriskfactorforPOR
2.PreviousPOR
(≤3oocyteswithaconventionalstimulationprotocol)
3.AbnormalORT
(AFC<5–7folliclesorAMH<0.5–1.1ng/ml).
❑2episodesofPOR
aftermaximalstimulationinabsenceofadvancedmaternalage
orabnormalORT.
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❑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}.
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7. POSEIDON(Humaidanetal,2017)
(Patient-OrientedStrategiesEncompassingIndividualizeDOocyteNumber)
Thegroupcomprises12opinionleadersinreproductivemedicinefrom7countries
▪Moredetailedstratificationforpatientsby
▪Reducedovarianreserveor
▪Lowresponsetoovarianstimulation.
▪Movingfromapoorovarianresponsetoalow
prognosisconcept
▪Consideringnotonlythe
▪Numberofoocytesretrieved,butalso
▪Age-relatedaneuploidyrateand
▪Ovarian‘sensitivity’toGnTABOUBAKRELNASHAR
▪4groupsbasedonoocytequantity&quality
ABOUBAKRELNASHARABOUBAKRELNASHAR

8. ABOUBAKRELNASHAR
PrevalenceofPOSEIDONpatientsattendingaFertilityClinic&
distributionbygroupcategory.
(Androfert:(N.=432)-year2017).
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9. 4.CAUSESofdiminishedovarianreserve
•Itisunclearwhetherrepresentsapathologiccondition
resultingfrom:
1.Abnormallyrapidatresiainanormalpoolofoocytes.
2.Normalatresiaofanabnormallysmallinitialpoolofoocytes.
▪Ovarianaging:DOR
▪fewerfollicles,whichareinhypoxicenvironment&consistof
fewergranulosacells,withpossiblyimpairedfunction(Pelliceretal.
1998)
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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
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10. 5.Iatrogenic
▪Exposuretochemotherapy
▪Exposuretoradiotherapy
▪Previousovariansurgery
▪Salpingectomyforectopic,hydrosalpinx,etc
▪Uterinearteryembolization&ligation
6.Environmental:
▪Pollutants
▪Oxidativestress
▪Smoking
7.Idiopathic:Inoverhalfofthesepatients
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❑PreventionofDOR
▪Avoidsmoking
▪Carefulsurgicaltechnique&strictadherenceto
principlesofmicrosurgery
▪LODshouldbeavoidedinpatientswithlowAMH
eveniftheovariesarepolycysticinappearance.
▪Beforechemotherapyorradiotherapy:various
methodsoffertilitypreservation
▪Useofapoptosisinhibitorslikesphingosine-1-
phosphatehasbeenproposed.ABOUBAKRELNASHAR

11. 5.IDENTIFICATIONOFPATIENTATRISK
PREDICTION
(Fiedler&Ezcurra,2012)
HighresponseLowresponse
164TotalAFC
40.5AMHng/ml
48.9FSHIU/L
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6.MANAGEMENT
6.1.Challenging
▪Doctor
▪Expectationsofsuccessfulpregnancyarelow
▪Guidelinesarelacking
▪CochraneSR:(Oudendijketal,2012)
▪insufficientevidencetosupporttheroutine
useofanyparticularinterventions
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12. ▪Couple
1.CostofIVFishigher
▪Higheramountofdrugsadopted
▪RepeatTTcycles.
2.Emotional,physical,&financialdistress,
particularlywhenmultipleTTcyclesarerequired.
3.Drop-outamongtheaffectedpatientsishigh
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6.2.Prognosis(Oudendijketal,2012)
▪variesgreatlydependingon
▪Age
▪Numberofoocytesretrieved
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13. ❑Follicle-to-oocyteindex(FOI)forpoorresponders.
(Alviggietal.2016)
▪PORischaracterizedbyareducednumberof
FolliclesOutputRate(FORT)
▪Reflectthedynamicnatureoffolliculargrowthin
responsetoCOS,comparedtothetraditional
markersofovarianreserve.
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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. 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)
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15. ▪Nostandardmanagement,intermsofprotocol&
drugs,hasbeendefined[Patrizioetal,2015].
▪Thebestprotocol
▪Noconsensus.
▪Debatedissue.
▪Lines:
I.COS:
1.Type2.dose3.protocol4.triggering
II.Addson
III.Lab
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I.Controlledovarianstimulation
1.Gnttype
❑RecFSH
▪Notimproveoutcome(Tarlatzisetal,2003)
▪InsufficientevidencetorecommendonetypeofGnt
overanother(Nardoetal,2013)
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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
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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. 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. ▪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)
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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
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❑Dose:
4-12IUofGHSConthedayofstimulation
❑Effects:
▪stimulatessteroidogenesis,folliculardevelopment&
responsivenesstoFSH(Jiaetal.1986).
▪ActssynergisticallywithFSH(Adashi&Rohan1993)
▪mayimprovethenumberofoocytes
❑Disadvantages:
Expensive&routineusecannotbejustified
(CochraneSR.2002)
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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. ▪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. 4.rLH
Beneficial
▪CochraneSystRev.2007
▪Nardoetal,2013
Notbeneficial
▪Bosdouetal,2012
▪Fanetal,2013
▪Jeve,Bhandari,2016
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5.LutealphaseE2
Beneficial
▪Changetal,2013
▪Reynoldsetal,2013
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24. EstrogenPrimed
AntagonistProtocol
•Pretreatmentcycleisanaturalcycle(noBCP).
•Aboutaweekafterovulation
–GnRHan{preventprematurerecruitmentoffollicles}
–Estrogen
{providestheyoungfolliclesanoptimalconditiontogrowinthefuture}.
•Onday3ofthenextmenses.
–Stimulationmedicationsarestarted
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6.OCPpretreatment
▪Tarlatzisetal,2003
▪±helpovarianresponse.
❑Nardoetal,2013
▪GnRHancycles:
•AdverselyaffectsIVFoutcome
▪GnRHacycles.
•Noeffect
ABOUBAKRELNASHAR

25. 7.Corticosteroids
▪Reducestheincidenceofpoorovarianresponse
(Tarlatzisetal,2003)
▪BritishFertilitySociety,2014
Thereislimitedevidence
ABOUBAKRELNASHAR
❑Dexamethasone
▪1mg/dorallytillretrieval
▪directlyinfluencegranulosacellsviaisoformorby
increasingGH&IGF-1
▪improvetheendometrialmicroenvironment.
(Smithetal.2000,Keayetal.2001)
ABOUBAKRELNASHAR

26. 8.Nitricoxidedonors
▪Limiteddata(Tarlatzisetal,2003)
ABOUBAKRELNASHAR
9.Aromataseinhibitors
Notbeneficial
(fourtrials;n=223)(Jeve,Bhandari,2016)
▪ESHRE,2019:
▪Theadditionofletrozoletogonadotrophinsinstimulation
protocolsisprobablynotrecommendedforpredictedpoor
responders.
ABOUBAKRELNASHAR

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. 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. ❑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. 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. 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. 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. 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. 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. ▪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. 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. 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. 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. ▪Useofaspirinbeforeand/orduringOSisnotrecommendedin
thegeneralIVF/ICSIpopulationandforpoorresponders.
▪Useofsildenafilbeforeand/orduringOSisnotrecommended
forpoorresponders.
ABOUBAKRELNASHAR
▪Thefollowinginterventionsarepromising
{Littleevidence:Possiblyeffective:moreevidence
needed}
▪FlareupGnRHaprotocol
▪Dualtriggering
▪EstrogenPrimedAntagonistProtocol
▪GH
▪DHEAsupplementation
▪Transdermaltestoeterone
▪Embryotransferonday2
ABOUBAKRELNASHAR

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. 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