The document discusses management strategies for poor responders undergoing assisted reproductive technology. It begins by defining poor responders according to the Bologna criteria and shows how live birth rates decrease significantly with fewer oocytes retrieved. It then outlines an approach to managing poor responders that includes identifying at-risk patients using biomarkers like AMH, individualizing controlled ovarian stimulation protocols, optimizing lab procedures, and tailoring embryo transfer. Specific strategies discussed include using gonadotropins like recombinant FSH, adding LH supplementation, antagonist protocols, and minimal stimulation approaches.

1. ISAR 2014, Ahmedabad INDIA
Management of Poor
Responders
Sandro C. Esteves, MD, PhD
Director, ANDROFERT
Andrology & Human Reproduction Clinic
Campinas, BRAZIL

2. Management of Poor
Responders
http://www.androfert.com.br/review
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3. DefinitionDefinitions
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
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4. Number of Oocytes and LBR
Live birth rate (%)
Observed live birth rate
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
Predicted live birth rate
450,135 IVF cycles
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 20 25 30 35 40
Oocyte number
Sunkara et al. Hum. Reprod., 2011
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5. Poor Responders and ART Outcome
Impaired Oocyte Quality
Reduced Fertilization Rate
Reduced Embryo Quality
Increased Miscarriage Rates
Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002
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6. LBR by No. Oocytes and Age
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7. Management of Poor Responders
Outline
Identify
patients
at risk
Individualize
COS
Best care in
the IVF lab
Tailor embryo
transfer
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8. Identification of
patients at risk
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9. Who is Who in ART
Older patients
High FSH/small ovaries
Previous poor response
Risk factors (ovarian surgery, etc.)
Easily
Recognized
Decreased Ovary Sensitivity
BIOMARKERS of
Ovarian Response
Fiedler & Ezcurra Reprod Biol and Endocrinol 2012;
Humaidan et al. Fertil Steril. 2010.
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10. AFC AMH
No. pre-antral and small
antral follicles (≤4-8mm)
La Marca et al. Hum Reprod 2009;
Fleming et al. Fertil Steril 2012;
.
..
2D-TVUS early follicular phase
2-10 mm (mean diameter)
No. AF at a given time that can
be stimulated by medication
Broekmans et al. Fertil Steril 2010; Scheffer et al. Hum Reprod 2003.
..
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11. Evidence
Level
1a
Which one is best, AMH of AFC?
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. AMH in Poor
Responders
In a group of 131 women
undergoing conventional COS
after pituitary down-regulation
for IVF:
Population
AMH* Poor
2
ng/mL responder
Cut-off
Sensitivity
Specificity
Accuracy
0.82
76%
86%
0.88
*Beckman-Couter generation II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved
Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
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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
Androgen
secretory
capacity
reduced
Decreased
numbers of
functional
LH receptors
Reduced LH
bioactivity
Hurwitz & Santoro
2004
• Piltonen et al.,
2003
• Vihko et al. 1996
• Mitchell et al. 1995;
Marama et al 1984
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16. Evidence
Level
1b
Increasing FSH Dose
RCT
Number
oocytes
retrieved
Manzi et al, 1994
Klinkert et al, 2004
Berkkanoglu & Ozgur, 2010
Cycle
Pregnancy
cancellation
rates
…is not associated with
better IVF outcome
Manzi DL et al. Fertil Steril. 1994; Klinkert ER et al. Hum Reprod. 2005;
Berkkanoglu & Ozgur Fertil Steril. 2010.
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17. Which gonadotropin preparations
offer the highest oocyte yield?
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18. Evidence
Level
1a & 1b
Studies comparing oocyte yield
with different gonadotropins
Higher with
rec-FSH vs.
hMG, HP-hMG,
and uFSH
↑ 1.5 oocytes (GnRH antagonist cycles)
Devroey et al., 2012
↑ 2.1 oocytes (16 RCT; different protocols)
Lehert et al., 2010
↑ 3.1 oocytes (GnRH antagonist cycles)
Bosch et al., 2008
↑ 2.8 oocytes (GnRH agonist cycles)
Hompes et al., 2008
↑ 1.8 oocytes (GnRH agonist cycles)
MERIT Study, 2006
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19. Evidence
Level
1a
GnRH Antagonists
Duration of
stimulation
(MD)
Pu et al.
14 RCT
(N=1,127)
Xiao et al.
12 RCT
(N=1,332)
No. Oocytes
retrieved
(MD)
Cancellation
(OR)
-1.9 days
(-3.6; -0.12)
-0.17
(-0.69; 0.34)
1.01
1.23
(0.71; 1.42) (0.92, 1.66)
-0.34
(-0.54; -0.13)
1.34
0.79
(0.86; 2.11) (0.54; 1.14)
-0.48 days
(-0.68; -0.17)
-0.54*
(-0.9; -0.1)
CPR
(OR)
1.08
1.33
(0.75; 1.57) (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
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20. Evidence
Level
1a
LH Supplementation
Outcome
Effect on Pregnancy
Mochtar et al, 2007
3 RCT (N=310)
Regimen
r-hFSH+rLH
vs.
r-hFSH *
OPR
OR: 1.85
Bosdou et al, 2012
7 RCT (N= 603)
r-hFSH+rLH
vs.
r-hFSH*
CPR
(95% CI: -0.3; +13.0)
LBR (only 1 RCT)
RD: +19%
Hill et al, 2012
7 RCT (N=902)
CPR
Age ≥35 yo.
r-hFSH+rLH
vs.
r-hFSH
Fan et al. 2013
3 RCT (N=458)
r-hFSH+rLH
vs.
r-hFSH*
OPR
(95% CI: 1.10; 3.11)
RD: +6%,
(95% CI: +1.0; +36.0%)
OR: 1.37
(95% CI: 1.03; 1.83)
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.
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21. 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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22. Individualized vs. Conventional COS
in Expected Poor Responders (N=118)
80
60
72.0
*
cCOS (Long GnRH with recFSH)
iCOS (GnRH Antag. with rFSH+rLH)
46.6
45.0
40
*p<0.05
20
3.5
*
23.3
20.0
26.8
*
4.8
0
Observed Poor Oocytes retrieved Cancellation (%) Pregnancy/cycle
Response (%)
(N)
(%)
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.
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23. Our Preferred Stimulation Regimen
in Poor Responders
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)
1
2
3
4
5
6
7
8
9
10
11
12
Menses
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24. Alternatives for Poor Responders
Failed iCOS
Oocyte
Donation
2-3 attempts
with <4 oocytes
retrieved and no
pregnancy
Minimal/Mild
COS
*Growth Hormone (4 IU/d) + iCOS
* Occasionally
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25. Minimal Stimulation
Letrozole 2.5-5.0 mg/d
CC 25 mg/d
36-37h
1
2
3
4
5
6
7
8
9
10
11
12
13
Oocyte pick-up
Rec-hFSH 150 IU
GnRH agonist (SC injection)
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 NC or HRT
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26. Minimal/Mild vs Conventional
Stimulation
Zarek & Muasher, 2011 (55 pts.; retrospective)
q Lower No. oocytes (2.4 vs 3.8); similar
CPR (38% vs 33%)
Yoo et al, 2011 (285 pts.; retrospective)
q Lower No. oocytes (1.5 vs 1.9); similar
CPR (6.7% vs 11.5%)
Klinkert et al, 2005 (52 pts.; RCT)
q Similar No. oocytes (3) and CPR (4% vs 12%)
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27. 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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28. Best care in the IVF lab
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29. 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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31. Air Quality Control and GMP
2,315 patients; 14,660 embryos
On average, an extra top-quality
embryo for transfer or cryopreservation
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32. Oocyte banking with vitrification
increases LBR
70%
+ 35,5%
60%
+
16,6%
50%
+
29,5%
40%
+
43,0%
30%
≤34 yr
35-37 yr
38-40 yr
41-43 yr
20%
10%
Adapted from Ubaldi, et al. Hum Reprod, 2010
0%
fresh
I warming
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II warming
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33. TE biopsy and aCGH yields higher
implantation rates
72.1%
71.4%
implantation rate without PGS
implantation rate with PGS
65.2%
62.4% 60.0% 60.0%
44.4%
31.7%
27.2%
24.4%
17.6%
10.5%
<34 yr 34-35 yr 36-37 yr 38-39 yr 40-41 yr 42-43 yr
Courtesy of F. Ubaldi, (Data from GENERA Jan 2012- Nov 2013)
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34. Tailoring embryo
transfer
• D2 vs D3 vs D5
• D6 (or frozen-thawed blastocyst) if TE biopsy
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35. D2 ET gives the best results in cycles
with conventional COS
1 RCT (n=281) in IVF-ET
Long or short GnRH agonist/recFSH protocol
D2
D3
P
RD
Mean number of
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
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36. Blastocyst ET gives the best results
in cycles with minimal stimulation
N
=
10,401
fresh
or
frozen
single
ET
Kato, et al. Reprod Biol Endocrinol 2012
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37. 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 elements to
optimize outcome
Tailored ET according to stimulation protocol
and treatment strategy may increase PRs
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38. Management of Poor Responders
Conclusions
Tailor embryo transfer
Best care in the IVF lab
Individualize COS
Identify patients at risk
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39. obrigado
Thank You