This document discusses management strategies for poor responders undergoing assisted reproductive technology. It begins by defining poor responders according to the Bologna criteria. It then reviews biomarkers for predicting poor response, finding AMH and AFC to be similarly accurate. The document outlines an individualized approach to controlled ovarian stimulation for poor responders, discussing adjuvant therapies like growth hormone and testosterone. It reviews evidence that recombinant FSH preparations retrieve more oocytes than urinary FSH or HMG. GnRH antagonists may shorten stimulation duration slightly. LH supplementation, specifically recombinant LH added to FSH, may modestly improve pregnancy rates.

1. Sandro C. Esteves, MD, PhD
Director, ANDROFERT
Andrology & Human Reproduction Clinic
Campinas, BRAZIL
Management of Poor
Responders
Al Azhar Conference, Cairo EGYPT

2. http://www.androfert.com.br/review
Management of Poor
Responders
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3. Definition of Poor Responders
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
1+3 only: Expected poor responder
Definitions
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4. 0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 30 35 40
Livebirthrate(%)
Oocyte number
Observed live birth rate Predicted live birth rate
Sunkara et al. Hum. Reprod., 2011
450,135 IVF cycles
Number of Oocytes and LBR
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5. LBR by No. Oocytes and Age
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6. Impaired Oocyte Quality
Reduced Fertilization Rate
Reduced Embryo Quality
Increased Miscarriage Rates
Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002
Poor Responders and ART Outcome
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7. Identify
patients
at risk Individualize
COS Best care in
the IVF lab Tailor embryo
transfer
Management of Poor Responders
Outline
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8. Identification of
patients at risk
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9. Older patients
High FSH/small ovaries
Previous poor response
Risk factors (ovarian surgery, etc.)
Easily
Recognized
Fiedler & Ezcurra Reprod Biol and Endocrinol 2012;
Humaidan et al. Fertil Steril. 2010.
BIOMARKERS of
Ovarian Response
Decreased Ovary Sensitivity
Who is who in ART
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10. No. pre-antral and small
antral follicles (≤4-8mm)
AMHAFC
Broekmans et al. Fertil Steril 2010; Scheffer et al. Hum Reprod 2003.
..
2D-TVUS early follicular phase
2-10 mm (mean diameter)
No. AF at a given time that can
be stimulated by medication
La Marca et al. Hum Reprod 2009;
Fleming et al. Fertil Steril 2012;
.
..
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11. Which one is best, AMH of AFC?
Evidence
Level
1a
FSH: Cut-off point >11 IU/L*
Sensitivity = 10%-30% (ñfalse-negatives)
Specificity = 83%-100%
AMH: Cut-off points <0.5-1.1 ng/mL
Sensitivity >75% (ê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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12. Population Cut-off Sensitivity Specificity Accuracy
AMH*
ng/mL
Poor
responder1
0.82 76% 86% 0.88
*Beckman-Couter generation II assay; 1≤4 oocytes retrieved
AMH in Poor
Responders
In a group of 131 women
undergoing conventional COS
after pituitary down-regulation
for IVF:
Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (3; Suppl): S16
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13. Key Points (1)
Identifying Patients at Risk
Biomarkers such as AMH and AFC helpful to
identify “expected” poor responders
Similar accuracy to determine who is at risk of POR
Clinical utility need to be validated with own data
Opportunity to offer an individualized COS
iCOS includes the combination of factors such as patient
phenotype, biomarkers and stimulation protocol
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14. Individualization of
controlled ovarian
stimulation
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15. Adjuvant Therapy
Increase FSH Drive
GnRH Antagonists
LH Supplementation
Minimal/Mild Stimulation
Reduced
ovarian
paracrine
activity
Hurwitz & Santoro
2004
Androgen
secretory
capacity
reduced
• Piltonen et al.,
2003
Decreased
numbers of
functional
LH receptors
• Vihko et al. 1996
Reduced LH
bioactivity
• Mitchell et al. 1995;
Marama et al 1984
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16. Growth Hormone in Poor
Responders
GH and IGF-1 levels in follicular fluid (FF)
Higher in successful IVF attempts1
Decrease with ageing2
Lower in poor responders2
GH administration increases IGF-1 levels3
IGF-1 enhances LH-mediated androgen production within the
thecal compartment as well as FSH-mediated aromatization in GC
(beneficial effect on steroidogenesis)4
E2 levels in FF increased by GH therapy (beneficial effect on oocyte
quality)1
1Mendoza 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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17. Testosterone in Poor Responders
Increased No. small preantral/antral follicles and granulosa/
theca cell proliferation by androgen treatment in primates1
PCOS-like morphological/functional changes by exposure to
extraovarian androgens (e.g., congenital adrenal hyperplasia,
androgen-producing tumors, transsexuals)2
Basal T level related to No. large follicles on hCG day and
pregnancy outcome in poor responders3
Up-regulation of FSH receptor density by androgens (increased
ovarian sensibility to FSH)1
1Weil et al. J Clin Endocrinol Metab 1999; 2Hugues & Durnerin. Reprod Biomed Online 2005;
3Frattarelli & Peterson. Fertil Steril 2004.
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18. Intervention Meta-analyses
Effect on
Pregnancy
Growth Hormone
Kyrou et al, 20091
Kolibianakis et al, 20092
Duffy et al, 20103
Higher LBR1,2,3
Higher PR2
Higher CPR3
Testosterone Bosdou et al, 2012
Higher LBR
Higher CPR
Kolibianakis et al, Hum Reprod Update 2009,15:613-22; Kyrou et al, Fertil Steril 2009;91: 749–66; Duffy et al,
Cochrane Database Syst Rev 2010;1:CD000099; Bosdou JK et al, Hum Reprod Update 2012;8:127-45;
Evidence
Level
1a Adjuvant Therapy in Poor
Responders
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19. Pregnancy
rates
Cycle
cancellation
Number
oocytes
retrieved
RCT
Manzi et al, 1994
Klinkert et al, 2004
Berkkanoglu & Ozgur, 2010
Manzi DL et al. Fertil Steril. 1994; Klinkert ER et al. Hum Reprod. 2005;
Berkkanoglu & Ozgur Fertil Steril. 2010.
Increasing FSH Dose
Evidence
Level
1b
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…is not associated with
better IVF outcome

20. Which gonadotropin preparations
offer the highest oocyte yield?
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21. Studies comparing oocyte yield
with different gonadotropins
Evidence
Level
1a & 1b
↑ 1.5 oocytes (GnRH antagonist cycles)
Devroey et al., 2012
↑ 3.1 oocytes (GnRH antagonist cycles)
Bosch et al., 2008
↑ 1.8 oocytes (GnRH agonist cycles)
MERIT Study, 2006
↑ 2.8 oocytes (GnRH agonist cycles)
Hompes et al., 2008
↑ 2.1 oocytes (16 RCT; different protocols)
Lehert et al., 2010
Higher with
rec-FSH vs.
hMG, HP-hMG,
and uFSH
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22. Duration of
stimulation
(MD)
No. Oocytes
retrieved
(MD)
Cancellation
(OR)
CPR
(OR)
Pu et al.
14 RCT
(N=1,127)
-1.9 days
(-3.6; -0.12)
-0.17
(-0.69; 0.34)
1.01
(0.71; 1.42)
1.23
(0.92, 1.66)
Xiao et al.
12 RCT
(N=1,332)
-0.48 days
(-0.68; -0.17)
-0.34
(-0.54; -0.13)
1.34
(0.86; 2.11)
0.79
(0.54; 1.14)
-0.54*
(-0.9; -0.1)
1.08
(0.75; 1.57)
1.33
(0.88; 2.01)
MD = mean difference; OR = odds ratio; *flare protocol
Pu D et al. Hum Reprod. 2011; Xiao J et al Fertil Steril 2013
GnRH Antagonists
Evidence
Level
1a
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23. LH Supplementation
Regimen Outcome Effect on Pregnancy
Mochtar et al, 2007
3 RCT (N=310)
r-hFSH+rLH
vs.
r-hFSH *
OPR OR: 1.85
(95% CI: 1.10; 3.11)
Bosdou et al, 2012
7 RCT (N= 603)
r-hFSH+rLH
vs.
r-hFSH*
CPR
LBR (only 1 RCT)
RD: +6%,
(95% CI: -0.3; +13.0)
RD: +19%
(95% CI: +1.0; +36.0%)
Hill et al, 2012
7 RCT (N=902)
Age ≥35 yo.
r-hFSH+rLH
vs.
r-hFSH
CPR OR: 1.37
(95% CI: 1.03; 1.83)
Fan et al. 2013
3 RCT (N=458)
r-hFSH+rLH
vs.
r-hFSH*
OPR OR: 1.30
(95% CI: 0.80; 2.11)
*long GnRH-a protocol; OR=odds-ratio; RD=risk difference
Mochtar et al. Cochrane Database 2007;
Bosdou et al, Hum Reprod Update 2012; Hill et al. Fertil Steril 2012; Fan et al. Gynecol Endocrinol 2013.
Evidence
Level
1a
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24. 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
Rationale of LH supplementation
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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25. Individualized vs. Conventional COS
in Expected Poor Responders (N=118)
72.0
3.5
45.0
20.0
46.6
4.8
23.3
26.8
0
20
40
60
80
Observed Poor
Response (%)
Oocytes retrieved
(N)
Cancellation (%) Pregnancy/cycle
(%)
cCOS (Long GnRH with recFSH)
iCOS (GnRH Antag. with rFSH+rLH)
Expected poor response: AMH<0.82 ng/dL; Observed poor response <5 oocytes retrieved;
Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (Suppl.): S16.
*p<0.05
*
*
*
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26. Recombinant FSH/LH (2:1 or 3:1 ratio) from stimulation D1
Follitropin alfa + Lutropin alfa (150:75 IU); fixed
Follitropin alfa (150-225 IU) + Lutropin alfa (75-150 IU)
Total dose: 225-375 IU
GnRH antagonist (flexible protocol): mean diameter 13mm
LH trigger with rec-hCG (mean diameter 17-18 mm)
2
3
4
5
7
6
8
9
10
11
1
Menses
12
Our Preferred Stimulation Regimen
in Poor Responders
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27. 2-3 attempts
with <4 oocytes
retrieved and no
pregnancy
Failed iCOS
Minimal/Mild
COS
Oocyte
Donation
*Growth Hormone (4 IU/d) + iCOS
Alternatives for Poor Responders
* Occasionally
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28. 2 3 4 5 76 8 9 10 11 12 131
Letrozole 2.5-5.0 mg/d
Rec-hFSH 150 IU GnRH agonist (SC injection)
Oocyte pick-up
Modified from New Hope Fertility Center (Dr. J. Zhang)
- Ibuprofen 600 mg on day of GnRH-a
- If LH raise: early OCP
- Vitrification for oocyte/embryo banking
- Blastocyst ET in natural or artificial FET cycle
36-37h
CC 25 mg/d
Minimal Stimulation
Dr. J. Voget
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29. Key Points (2)
Individualization of COS
iCOS with recFSH + recLH supplementation
(GnRH antag. protocol) may elicit good
results in some poor responders
Minimal stimulation protocols an alternative to
highly-compliant patients and may reduce
treatment burden
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30. Best care in the IVF lab
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31. 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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33. On average, an extra top-quality
embryo for transfer or cryopreservation
Air Quality Control and GMP
2,315 patients; 14,660 embryos
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34. Oocyte banking with vitrification
increases LBR
0%
10%
20%
30%
40%
50%
60%
70%
fresh I warming II warming
≤34 yr
35-37 yr
38-40 yr
41-43 yr
+ 35,5%
+
16,6%
+
29,5%
+
43,0%
Adapted from Ubaldi, et al. Hum Reprod, 2010
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35. TE biopsy and aCGH yields higher
implantation rates
<34 yr 34-35 yr 36-37 yr 38-39 yr 40-41 yr 42-43 yr
44.4%
31.7%
27.2%
24.4%
17.6%
10.5%
72.1% 71.4%
65.2%
62.4% 60.0% 60.0%
implantation rate without PGS
implantation rate with PGS
Courtesy of F. Ubaldi, (Data from GENERA Jan 2012- Nov 2013)
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36. Tailoring embryo
transfer
• D2 vs D3 vs D5
• D6 (or frozen-thawed blastocyst) if TE biopsy
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37. D2 ET gives the best results in cycles
with conventional COS
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D2 D3 P-value RD
Mean No. transferred
embryos ± SD
2.0 ± 0.8 1.7 ±
0.8 0.003
+0.30
(95% CI: +0.11; +0.49)
Cancelled cycles (%) 4.3 10.8 0.04
OPR per ET (%) 29.0 18.3 0.03
OPR per OCP (%) 27.7 16.2 0.02
+11.4
(95% CI +1.6; +21.0)
Bahceci M et al, Fertil Steril 2006
1 RCT (n=281) in IVF-ET
Long or short GnRH agonist/recFSH protocol

38. Blastocyst ET gives the best results
in cycles with minimal stimulation
Kato, et al. Reprod Biol Endocrinol 2012
N
=
10,401
fresh
or
frozen
single
ET
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39. Key Points (3)
Best lab care and tailored ET
Great care to avoid jeopardizing the already
compromised gametes
Vitrification program, blastocyst culture and TE
biopsy-aCGH are useful to optimize outcome
Tailored ET according to stimulation protocol
and treatment strategy may increase PRs
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40. Management of Poor Responders
Conclusions
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Best care in the IVF lab
Identify patients at risk
Individualize COS
Tailor embryo transfer

41. ThankYou
obrigado