Management of Poor Responders

Sandro C. Esteves, MD, PhD Director, ANDROFERT

Andrology & Human Reproduction Clinic Campinas, BRAZIL

Management of Poor Responders

ISAR 2014, Ahmedabad INDIA

http://www.androfert.com.br/review

Management of Poor Responders

ANDROFERT androfert.com.br

ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 FEBRUARY

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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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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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LBR by No. Oocytes and Age



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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 responder2 0.82 76% 86% 0.88

*Beckman-Couter generation II assay; 1>20 oocytes retrieved; 2≤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. #O-51: ASRM 2013



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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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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



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*Growth Hormone (4 IU/d) + iCOS

Alternatives for Poor Responders

* Occasionally


ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 FEBRUARY ANDROFERT

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 NC or HRT

36-37h

CC 25 mg/d

Minimal Stimulation

Dr. J. Voget



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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%)

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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Best care in the IVF lab



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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%



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Adapted from Ubaldi, et al. Hum Reprod, 2010

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



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•  D2 vs D3 vs D5 •  D6 (or frozen-thawed blastocyst) if TE biopsy

D2 ET gives the best results in cycles with conventional COS



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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

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 elements 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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Health & Medicine

Management of Poor Responders