treatment of poor responders: review of systematic reviews 2016
TRANSCRIPT
Treatment of poor responders:
Review of Systematic reviews
2016
AboubakrElnashar
Benha University Hospital, Egypt
CONTENTS1. INTRODUCTION2. OBJECTIVE3. MATERIAL AN D METHODS4. RESULTS5. CONCLUSION
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1. INTRODUCTIONqDIAGNOSIS
(ESHRE: Bologna criteria 2011)
§ At least 2 of 3: § Age (≥40 y) or any other risk factor for POR§ Previous POR (≤3 oocytes with a conventional stimulation
protocol)§ Abnormal ORT (i.e. AFC <5–7 follicles or AMH <0.5–1.1
ng/ml).§ 2 episodes of POR
after maximal stimulation are sufficient to define a patient as poor responder in absence of advanced maternal age or abnormal ORT.
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qPREDICTION OF TREATMENT OUTCOME1. Female age2. Number of oocytes retrieved(Oudendijk et al, 2012)
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qINTERVENTIONS: 33(Most popular intervention first).(Papathanasiou et al, 2016)
1. Antagonist2. Microdose flare3. Long protocol4. LH added5. Letrozole + FSH+antagonist6. DHEA7. Short protocol8. Transdermal testosterone9. Growth hormone10.HCG added at stimulation
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11. Increase of FSH dose12. CC+ FSH/HMG + -antagonist13. Luteal FSH start14. Estrogen for luteal support15. Follicular flushing16. Long-stop protocol17. FSH/HMG only (no agonist
or antagonist)18. FSH dose 300 IU19. Late FSH start20. Metformin
21. Ultrashorta-antagonist22. Modified flare23. Low-dose aspirin24. Natural cycle25. Mini-long protocol26. Step-down of FSH dose27. Luteal phase antagonist28. Gamete intrauterine transfer29. Day of embryo transfer30. Early (Day 1) FSH start31. FSH dose 450 IU32. FSH dose 600 IU33. Clomiphene citrate onlyABOUBAKR ELNASHAR
qWhat are the most popular interventions?What are the recent Trends in last 5 years?
(Papathanasiou et al, 2016)
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qWHAT IS THE BEST EVIDENCE?
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qWhat is a systematic review?
§ A review of a clearly formulated question that uses systematic and explicit methods to
1. identify, select and critically appraise relevant research2. collect and analyse data from the studies that are
included in the review (Cochrane Reviewers’ Handbook 4.1.5)
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Systematicreview
Meta-analysis
Literaturereview
qWhat is Meta-Analysis? The use of statistical techniques in a systematic review to
integrate the results of included studies.
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2. OBJECTIVEReview SR in treatment of poor responders
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3. METHODS§Pub med:
From 2003 till April 2016§Key words
•Treatment of poor responders•ICSI•Systematic review•Meta analysis
§OutcomeCPR
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4. RESULTS§31SR:
oRandomized controlled trialsoCase control studiesoSelf controlled studies
§Classified into:I. COS:
1. Gnt type 2. Gnt dose 3. Protocol
II. AdjuvantsIII. Lab
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I. Controlled ovarian stimulation1. Gnt type
qRec FSH §Not improve outcome. (Tarlatzis et al, 2003)§Insufficient evidence to recommend one type of Gnt over another.(Nardo et al, 2013)
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2. Gnt doseqIncrease dose
Little or no benefit. (Tarlatzis et al, 2003)
qPatients who failed to conceive with 450 IU/d will not benefit from increasing dose to 600 IU (Haas et al.,2015)
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3. Protocol1. Natural cycle Vs long agonist protocols
No difference(Tarlatzis et al, 2003)
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2. Short Vs long agonistNo difference(Sunkara et al, 2007)
3. Flare up GnRHa Vs long agonist protocolBetter results(Tarlatzis et al, 2003)
4. Flare up GnRHa Vs Antagonist/Let protocolBetter(Song et al, 2014)
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5. GnRHa 'stop' Vs long protocolNo difference(Tarlatzis et al, 2003)
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6. Antagonist Vs long agonistBetter
Griesinger et al, 2006Franco et al, 2006
No differenceTarlatzis et al, 2003Sunkara et al, 2007Pu et al, 2011Xiao et al, 2013Nardo et al, 2013
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6. Antagonist Vs flare up protocols.Better
(Franco et al, 2006)
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II. Adjuvants1. GH
No significant improvement. §Tarlatzis et al, 2003§Yu et al, 2015
Significant improvement§Cochrane Database Syst Rev. 2003§Kyrou et al, 2009§Kolibianakis et al, 2009
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qDose:4-12 IU of GH SC on the day of stimulation
qEffects:§ stimulates steroidogenesis, follicular development and
responsiveness to FSH (Jia et al. 1986).
§ acts synergistically with FSH (Adashi & Rohan 1993) § may improve the number of oocytes
qDisadvantages:§ expensive and routine use can not be justified
(Cochrane SR, Kotarba et al. 2002)
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2. DHEA supplementation
Not beneficial§Bosdou et al, 2012§Narkwichean et al, 2013
Beneficial§Fouany , Sharara, 2013§Li et al, 2015§Cochrane Database SR, Nagels et al, 2015§Zhang et al, 2016
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q Mild androgenq Dose:
75 mg – 100mg/d for at least 12 w
q Effects:(Zhang et al, 2016)Increase in AMH levelsDecrease in baseline FSH Improves oocyte numbers
embryo qualityspontaneous PRIVF PR
q Advantages:Available over the counterMinimal side effectsInexpensive
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3. Transdermal testoeterone
Beneficial§GonzálezComadran et al, 2012§Bosdou et al, 2012§Luo et al, 2014§Cochrane Database SR, Nagels et al, 2015
Insufficient evidence§Sunkara et al, 2011
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4. rLH
Beneficial§Cochrane Database Syst Rev. 2007§Nardo et al, 2013
Not beneficial§Bosdou et al, 2012§Fan et al, 2013
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5. Luteal phase E2Beneficial
§Chang et al, 2013§Reynolds et al, 2013
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Estrogen Primed Antagonist Protocol
§ Pretreatment cycle is a natural cycle (no BCP).§ About a week after ovulationú GnRHan is started {prevent premature recruitment of
follicles}ú Estrogen {provides the young follicles an optimal condition
to grow in the future}. § Stimulation medications are started on day 3 of the
next menses.ABOUBAKR ELNASHAR
6. OCP pretreatment§Tarlatzis et al, 2003§±help ovarian response.
qNardo et al, 2013§GnRHan cycles:
•Adversely affects IVF outcome§GnRHa cycles.
•No effect
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7. Corticosteroids §Reduces the incidence of poor ovarian response(Tarlatzis et al, 2003)
§British Fertility Society, 2014 There is limited evidence
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qDexamethasone§ 1mg/d orally till retrieval § directly influence granulosa cells via isoform or
by increasing GH & IGF-1§ improve the endometrial microenvironment. (Miell et al. 1993, Polak 1993, Smith et al. 2000, Keay et al. 2001)
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8. Nitric oxide donors §The limited data are encouraging. (Tarlatzis et al, 2003)
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III. Lab1. Assisted hatching
No benefit(Tarlatzis et al, 2003)
2. Embryo transfer on day 2 Vs day 3improve CPR
(Kyrou et al, 2009)3. Follicular flushing§does not increase the number of oocytesretrieved§lower IR and CPR.
(Mok-lin et al, 2013)
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5. CONCLUSIONSqAccording to available SR:The following interventions are associated with increase CPR in poor responders:§Flare up GnRHa protocol§Estrogen Primed Antagonist Protocol§DHEA supplementation§Transdermal testoeterone§Embryo transfer on day 2
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