Treatment of poor responders: Review of Systematic reviews 2016

1. Treatment of poor
responders:
Review of Systematic
reviews
2016
Aboubakr
Elnashar
Benha University
Hospital, Egypt

2. CONTENTS
1. INTRODUCTION
2. OBJECTIVE
3. MATERIAL AN D METHODS
4. RESULTS
5. CONCLUSION
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3. 1. INTRODUCTION
qDIAGNOSIS
(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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4. qPREDICTION OF TREATMENT OUTCOME
1. Female age
2. Number of oocytes retrieved
(Oudendijk et al, 2012)
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5. ABOUBAKR ELNASHAR

6. qINTERVENTIONS: 33
(Most popular intervention first).
(Papathanasiou et al, 2016)
1. Antagonist
2. Microdose flare
3. Long protocol
4. LH added
5. Letrozole + FSH+antagonist
6. DHEA
7. Short protocol
8. Transdermal testosterone
9. Growth hormone
10.HCG added at stimulation
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7. 11. Increase of FSH dose
12. CC+ FSH/HMG + -antagonist
13. Luteal FSH start
14. Estrogen for luteal support
15. Follicular flushing
16. Long-stop protocol
17. FSH/HMG only (no agonist
or antagonist)
18. FSH dose 300 IU
19. Late FSH start
20. Metformin
21. Ultrashorta-antagonist
22. Modified flare
23. Low-dose aspirin
24. Natural cycle
25. Mini-long protocol
26. Step-down of FSH dose
27. Luteal phase antagonist
28. Gamete intrauterine transfer
29. Day of embryo transfer
30. Early (Day 1) FSH start
31. FSH dose 450 IU
32. FSH dose 600 IU
33. Clomiphene citrate onlyABOUBAKR ELNASHAR

8. qWhat are the most popular interventions?
What are the recent Trends in last 5 years?
(Papathanasiou et al, 2016)
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9. qWHAT IS THE BEST EVIDENCE?
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10. 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 research
2. collect and analyse data from the studies that are
included in the review
(Cochrane Reviewers’ Handbook 4.1.5)
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11. Systematic
review
Meta-analysis
Literature
review
qWhat is Meta-Analysis?
The use of statistical techniques in a systematic review to
integrate the results of included studies.
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12. 2. OBJECTIVE
Review SR in treatment of poor responders
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13. 3. METHODS
§Pub med:
From 2003 till April 2016
§Key words
•Treatment of poor responders
•ICSI
•Systematic review
•Meta analysis
§Outcome
CPR
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14. 4. RESULTS
§31SR:
oRandomized controlled trials
oCase control studies
oSelf controlled studies
§Classified into:
I. COS:
1. Gnt type
2. Gnt dose
3. Protocol
II. Adjuvants
III. Lab
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15. I. Controlled ovarian stimulation
1. 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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16. 2. Gnt dose
qIncrease 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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17. 3. Protocol
1. Natural cycle Vs long agonist protocols
No difference
(Tarlatzis et al, 2003)
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18. 2. Short Vs long agonist
No difference
(Sunkara et al, 2007)
3. Flare up GnRHa Vs long agonist protocol
Better results
(Tarlatzis et al, 2003)
4. Flare up GnRHa Vs Antagonist/Let protocol
Better
(Song et al, 2014)
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19. 5. GnRHa 'stop' Vs long protocol
No difference
(Tarlatzis et al, 2003)
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20. 6. Antagonist Vs long agonist
Better
Griesinger et al, 2006
Franco et al, 2006
No difference
Tarlatzis et al, 2003
Sunkara et al, 2007
Pu et al, 2011
Xiao et al, 2013
Nardo et al, 2013
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21. 6. Antagonist Vs flare up protocols.
Better
(Franco et al, 2006)
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22. II. Adjuvants
1. 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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23. 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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24. 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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25. q Mild androgen
q Dose:
75 mg – 100mg/d for at least 12 w
q Effects:
(Zhang et al, 2016)
Increase in AMH levels
Decrease in baseline FSH
Improves oocyte numbers
embryo quality
spontaneous PR
IVF PR
q Advantages:
Available over the counter
Minimal side effects
Inexpensive
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26. 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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27. 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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28. 5. Luteal phase E2
Beneficial
§Chang et al, 2013
§Reynolds et al, 2013
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29. Estrogen Primed
Antagonist Protocol
§ Pretreatment cycle is a natural cycle (no BCP).
§ About a week after ovulation
ú 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.
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30. 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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31. 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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32. 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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33. 8. Nitric oxide donors
§The limited data are encouraging.
(Tarlatzis et al, 2003)
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34. III. Lab
1. Assisted hatching
No benefit
(Tarlatzis et al, 2003)
2. Embryo transfer on day 2 Vs day 3
improve CPR
(Kyrou et al, 2009)
3. Follicular flushing
§does not increase the number of oocytes
retrieved
§lower IR and CPR.
(Mok-lin et al, 2013)
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35. 5. CONCLUSIONS
qAccording 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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36. ABOUBAKR ELNASHAR
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