MANAGEMENT OF POOR RESPONDERS IN IVF BY DR SHASHWAT JANI

1. Management Of
Poor Response
Facts Or Myths
Dr. Shashwat Jani.
M.S. ( Gynec)
Diploma In Advance Endoscopy.
Consultant Assistant Professor,
Smt. N.H.L. Municipal Medical College,
Sheth V. S. General Hospital, Ahmedabad.
Mobile : +91 99099 44160.
E-mail : drshashwatjani@gmail.com

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4. POOR RESPONDER ( ESHRE )
Two of the following three features
must be present:
Advanced maternal age (≥40 years) or any
other risk factor for POR;
A previous POR (≤3 oocytes with a
conventional stimulation protocol);
An abnormal ovarian reserve test (i.e. AFC <5–
7 follicles or AMH <0.5–1.1 ng/ml).
3-Sep-15 4Dr Shashwat Jani 9909944160

5. Bologna Criteria
( Ferraretti et al. ESHRE Consensus, Hum Reprod 2011 )
At least 2 of the following:
1 ) Advanced maternal age (≥40 years or risk
factor for POR)
2 ) Previous POR (≤3 oocytes with conventional
stimulation)
3 ) Abnormal ovarian reserve biomarker
AFC<5-7; AMH <0.5-1.1ng/Ml
Or:
• Two episodes of POR after maximal stimulation
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8. Management of Poor
Responders
“ One of the most
challenging tasks in
reproductive medicine...”
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10. 1. Identify Patient at
Risk…
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11. RISK FACTORS…
o Elder patients
o High FSH, Small Ovaries
o Previous poor response
o Ovarian surgery especially in case of endometrioma ,
o Genetic defects,
o Chemotherapy,
o Radiotherapy,
o Autoimmune disorders,
o Single ovary,
o Chronic smoking,
o Unexplained infertility.
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12. Moreover, New risk factors of low ovarian
response have been proposed:
o Diabetes mellitus Type I .
o Transfusion-dependent B - thalassemia ,
o Uterine artery embolization for the treatment
of uterine leiomyoma .
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13. “ Predicting ovarian
response before starting
hormonal stimulation is
the only way to
administer an efficient
and safe treatment…”
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14. Predictors of Poor Ovarian Reserve
 Age,
 Biochemical parameters
(basal FSH levels in the early follicular phase,
 Serum antimullerian hormone [AMH]),
 Morphological characteristics
(antral follicular count [AFC] and ovarian volume)
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15. • FSH: Cut - off point > 11 IU/L*
Sensitivity = 10%-30% (n false-negatives)
Specificity = 83%-100%
• AMH: Cut-off points <0.5-1.1 ng/mL
Sensitivity >75% (e false-negatives)
Specificity >85%
• AFC: Cut-off points <5-7
Sensitivity >60%
Specificity >85%
*Standardized assays by WHO IRP 78/549; Esposito et al. Hum Reprod 2002;
Bancsi et al. Fertil Steril 2002;
Kwee et al. Fertil Steril 2008; ASRM Practice Committee, Fertil Steril 2012
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16. 2. Individualized
Controlled Ovarian
Stimulation
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17. 1. GONADOTROPINS
• When standard dose ( 225 – 300 IU ) fails …
Dose increased up to 450 IU.
• This approach is used since years….
( CLASSICAL APPROACH )
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18. • But, Now,
RECENT STUDIES
( Prospective & Retrospective ) :
No enhancement in Ovarian
response OR
Better pregnancy rates.
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19. Which gonadotropin preparations
offer the highest oocyte yield?
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20. Recent Studies,
Increase of FSH starting dose does not result
in higher pregnancy rates and also found no differences
between the starting dose of 300UI, 450UI, and 600 UI
of gonadotropins in terms of retrieved oocytes, number
of embryos obtained, and pregnancy rates.
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21. 2. GnRH Analogues…
Since the era of Nineties….
Combination of Gonadotropins & GnRH agonists ,
started on the late luteal phase of previous cycle ,
considered the protocol of choice in Normo
responder pts.
Lower cancellation rates & Increased No. of
Pre ovulatory follicles & better pregnancy rates.
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22. But, in Poor Responders...,
It may induce
excessive ovarian suppression…
 For this reason, in patients
with poor ovarian reserve the
options could be…
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23. (i) To decrease the length of suppression by
decreasing the duration of GnRH agonist use
(short and ultrashort, mini- and microdose flareup
regimens).
(ii) To lower or to stop (after pituitary suppression)
the dose of GnRH agonists initiated during the luteal
phase .
(iii) To use the GnRH antagonists in combination
with gonadotropins to prevent premature LH rise
during the mid-late follicular phase .
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24. In a recent meta analysis…
• No statistically significant difference
was present in clinical pregnancy rates per
cycle randomized between the “GnRH
agonist stopped protocol” and the “ standard
agonist protocol” .
• Moreover, duration of stimulation
and total number of gonadotropins
ampoules required as well as number of
oocytes retrieved were not statistically
different between the two groups.
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25. 3. GnRH Antagonists
• Introduced 15 years ago …
Advantages :
 Increased Pt. Compliance.
 Decreased No. of days of stimulations
 Decreased amount of gonadotropins
 Reduction in OHSS.
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26. • Recent meta-analysis of 14 randomized
controlled studies,
“ GnRH antagonist protocols resulted in a
statistically significant lower duration of stimulation
compared with GnRH agonist protocols but there was
no significant difference in the number of oocytes
retrieved, in the cycle cancellation rate, and in the
clinical pregnancy rate.
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27. Advantages of Antagonists Over
Agonists…
 Possible to assess Ovarian Reserve by USG on D2 –
D3 of cycle in which COS is planned.
 With Antagonists , to prevent premature LH Surge ,
a new gonadotropins, a hybrid molecule with
prolonged half life - Corifollitropin Alfa can be used.
 It could exploit fully the reduced ovarian reserve by
the rapid increase in the serum FSH concentration that
would result in a significantly higher exposure of the
small antral follicles to constant high levels of FSH
during the early follicular phase.
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28. To Strengthen the effect of
Exogenous Gonadotropins….
Proposed alternative
Approaches…
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29. 1. ROLE OF GH
 GH and IGF-1 levels in follicular fluid (FF)
• Higher in successful IVF attempts
• Decrease with ageing
• Lower in poor responders
 GH administration increases IGF-1 levels
• IGF-1 enhances LH-mediated androgen production within the
thecal compartment as well as FSH-mediated aromatization in
GC (beneficial effect on steroidogenesis)
 E2 levels in FF increased by GH therapy (beneficial effect on
oocyte quality)
Mendoza et al. Hum Reprod 2002; 2Bahceci et al. Eur J Obstet Gynecol Reprod Biol. 2007; 3Lucy MC. Reprod
Fertil Dev. 2011; 4Speroff & Fritz 2005; 5Tesarik et al. Hum Reprod 2005.
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30. There are no very recent and
robust data suggesting routine
addition of GH in ovarian
stimulation protocols for poor
responders patients...!!!
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31. 2. Estradiol in Luteal Phase
 Luteal Estradiol priming could improve
synchronization of the pool of follicles available
to controlled ovarian stimulation.
 In a recent meta analysis of 8 selected
studies from 1227 initially searched, the
addition of estradiol in the luteal phase with or
without the simultaneous use of GnRH
antagonist decreases the risk of cycle
cancellation and increases the chance of
clinical pregnancy in poor responder patients.
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32. 3. Recombinant LH
 In a very recent meta-analysis of 40
randomized controlled studies , significantly more
oocytes were retrieved and significantly higher
clinical pregnancy rates were observed with
r-hFSH plus r-hLH VERSUS r-hFSH treatment in
poor responders, suggesting that there is a
relative increase in the clinical pregnancy rates of
30% in poor responders and that the addition of
r-hLH to r-hFSH may be beneficial for women
with poor ovarian response.
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33. Rationale of LH supplementation
• Action of LH at the follicular level in a dose
dependent manner increases androgen production
• Androgens are then aromatized to estrogens and
help restore the follicular milieu.
• Action of LH at the GC level enhance responsiveness
to FSH.
• LH has also a direct positive effect on final oocyte
maturation.
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35. 4. ANDROGENS
 Produces by Theca cells.
 Critical role in adequate follicular steroidogenesis
and early follicular and granulosa cell development.
 Increase FSH receptor expression in granulosa
cells amplifying the effect of FSH and thus
potentially enhance responsiveness of ovaries to
FSH.
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36. DHEA
A recent meta-analysis of four
randomized controlled trials of adjuvant
androgens (DHEA and testosterone) in poor
responder patients showed a significantly
higher ongoing pregnancy rate in the androgen
supplementation group.
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37. TESTOSTERONE
 Increased No. small preantral /antral follicles and
granulosa/ theca cell proliferation by androgen treatment in
primates.
 PCOS-like morphological/functional changes by
exposure to extra ovarian androgens (e.g., congenital adrenal
hyperplasia, androgen-producing tumors, transsexuals)
 Basal T level related to No. large follicles on hCG day and
pregnancy outcome in poor responders.
 Up-regulation of FSH receptor density by androgens
(increased ovarian sensibility to FSH).
• 1Weil et al. J Clin Endocrinol Metab 1999; 2Hugues & Durnerin. Reprod Biomed Online 2005;
• 3Frattarelli & Peterson. Fertil Steril 2004.
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38. 5. ASPIRIN
 Increased intra ovarian vascularity has been
linked to improved delivery of gonadotropic hormones
or other growth factors required for folliculogenesis.
 On the other hand, impaired ovarian blood flow
could contribute to poor ovarian response.
 Based on this rationale, by enhancing ovarian
vascularization with vasoactive substances such as
aspirin, the ovarian response could theoretically
improve.
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39.  The conclusion of a meta-analysis and a
systematic review was that clinical pregnancy
rate per embryo transfer was not found to be
different between patients who received low-
dose aspirin and the control group.
 On the basis of updated evidence, a low
dose of aspirin has no substantial positive
effect on the likelihood of pregnancy and it
should not be routinely recommended for
women undergoing IVF.
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40. 6. NATURAL CYCLES IVF
 Natural cycles IVF with or without minimal
stimulation can be considered as an easy and
cheap approach in the management of poor
responders.
 In younger women ( < 35 years ) results
are encouraging with pregnancy rate 18 % per
started cycle, 29 % per transfer, 31% per
patients.
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41. 7. Oocyte Cryopreservation
 Breakthrough in ART technologies.
 Major societies like ESHRE, ASRM , ASCO
acknowledged recently oocyte cryopreservation as a
non experimental procedure which provides the
required legal and moral support for widespread
application.
 Moreover, oocyte cryopreservation can also
be used to preserve the fertility of all those women
at risk to lose their ovarian potential over the time.
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42. 3. Management of poor responders in
the IVF lab
 Incomplete oocyte denudation
 Laser-assisted ICSI
 Standardization of lab environment and
culture conditions
 Oocyte/embryo banking with vitrification
 Blastocyst culture for TE biopsy
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43. 4. TAILORING EMBRYO
TRANSFER…
• D2 vs D3 vs D5
• D6 ( or Frozen thawed blastocyst ) if TE biopsy.
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45. Thank you
…