Management of poor responders
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Transcript of Management of poor responders
Sandro C. Esteves, MD, PhD Director, ANDROFERT
Andrology & Human Reproduction Clinic Campinas, BRAZIL
Management of Poor Responders
Al Azhar Conference, Cairo EGYPT
http://www.androfert.com.br/review
Management of Poor Responders
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 APRIL
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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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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
Live
birt
h ra
te (%
)
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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LBR by No. Oocytes and Age
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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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Identify patients at risk Individualize
COS Best care in the IVF lab Tailor embryo
transfer
Management of Poor Responders Outline
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Identification of patients at risk
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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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No. pre-antral and small antral follicles (≤4-8mm)
AMH
AF
C
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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Which one is best, AMH of AFC? Evidence
Level 1a
FSH: Cut-off point >11 IU/L* Sensitivity = 10%-30% (ñfalse-negatives) Specificity = 83%-100%
AMH: Cut-off points <0.5-1.1 ng/mL Sensitivity >75% (êfalse-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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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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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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Individualization of controlled ovarian
stimulation
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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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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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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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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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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
Which gonadotropin preparations offer the highest oocyte yield?
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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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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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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-hFSHCPR
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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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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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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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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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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2 3 4 5 7 6 8 9 10 11 12 13 1
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 ANDROFERT
androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2014 APRIL
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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
ANDROFERT androfert.com.br
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Best care in the IVF lab
ANDROFERT androfert.com.br
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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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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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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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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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Tailoring embryo transfer
• D2 vs D3 vs D5 • D6 (or frozen-thawed blastocyst) if TE biopsy
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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
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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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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Management of Poor Responders Conclusions
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Best care in the IVF lab
Identify patients at risk
Individualize COS
Tailor embryo transfer
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