Management of Poor Responders

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  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2014 FEBRUARY ANDROFERT androfert.com.br
  • 6. LBR by No. Oocytes and Age ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2014 FEBRUARY ANDROFERT androfert.com.br
  • 7. Management of Poor Responders Outline Identify patients at risk Individualize COS Best care in the IVF lab Tailor embryo transfer ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2014 FEBRUARY ANDROFERT androfert.com.br
  • 8. Identification of patients at risk ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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. ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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. .. ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2014 FEBRUARY ANDROFERT androfert.com.br
  • 14. Individualization of controlled ovarian stimulation ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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. ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2014 FEBRUARY ANDROFERT androfert.com.br
  • 17. Which gonadotropin preparations offer the highest oocyte yield? ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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. ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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. ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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   ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 FEBRUARY Dr. J. Voget ANDROFERT androfert.com.br
  • 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%) ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2014 FEBRUARY ANDROFERT androfert.com.br
  • 28. Best care in the IVF lab ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2014 FEBRUARY ANDROFERT androfert.com.br
  • 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2014 FEBRUARY ANDROFERT androfert.com.br
  • 30. Air Quality Control and GMP 2,315 patients; 14,660 embryos On average, an extra top-quality embryo for transfer or cryopreservation ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2014 FEBRUARY ANDROFERT androfert.com.br
  • 31. 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2014 FEBRUARY II warming ANDROFERT androfert.com.br
  • 32. 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) ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2014 FEBRUARY ANDROFERT androfert.com.br
  • 33. Tailoring embryo transfer •  D2 vs D3 vs D5 •  D6 (or frozen-thawed blastocyst) if TE biopsy ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2014 FEBRUARY ANDROFERT androfert.com.br
  • 34. 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2014 FEBRUARY ANDROFERT androfert.com.br
  • 35. 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2014 FEBRUARY ANDROFERT androfert.com.br
  • 36. 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 ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2014 FEBRUARY ANDROFERT androfert.com.br
  • 37. Management of Poor Responders Conclusions Tailor embryo transfer Best care in the IVF lab Individualize COS Identify patients at risk ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2014 FEBRUARY ANDROFERT androfert.com.br
  • 38. obrigado Thank You