Management of poor responders

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Management of poor responders

  1. 1. Sandro C. Esteves, MD, PhD Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL Management of Poor Responders Al Azhar Conference, Cairo EGYPT
  2. 2. 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 APRIL ANDROFERT
  3. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2014 APRIL ANDROFERT
  4. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2014 APRIL ANDROFERT
  5. 5. LBR by No. Oocytes and Age ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2014 APRIL ANDROFERT
  6. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2014 APRIL ANDROFERT
  7. 7. Identify patients at risk Individualize COS Best care in the IVF lab Tailor embryo transfer Management of Poor Responders Outline ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2014 APRIL ANDROFERT
  8. 8. Identification of patients at risk ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2014 APRIL ANDROFERT
  9. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2014 APRIL ANDROFERT
  10. 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; . .. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2014 APRIL ANDROFERT
  11. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2014 APRIL ANDROFERT
  12. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2014 APRIL ANDROFERT
  13. 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 androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2014 APRIL ANDROFERT
  14. 14. Individualization of controlled ovarian stimulation ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2014 APRIL ANDROFERT
  15. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2014 APRIL ANDROFERT
  16. 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. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2014 APRIL ANDROFERT
  17. 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. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2014 APRIL ANDROFERT
  18. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2014 APRIL ANDROFERT
  19. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2014 FEBRUARY ANDROFERT …is not associated with better IVF outcome
  20. 20. Which gonadotropin preparations offer the highest oocyte yield? ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2014 APRIL ANDROFERT
  21. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2014 APRIL ANDROFERT
  22. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2014 APRIL ANDROFERT
  23. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2014 APRIL ANDROFERT
  24. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2014 APRIL ANDROFERT
  25. 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 * * * ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2014 APRIL ANDROFERT
  26. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2014 APRIL ANDROFERT
  27. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2014 APRIL ANDROFERT
  28. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2014 APRIL ANDROFERT
  29. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2014 APRIL ANDROFERT
  30. 30. Best care in the IVF lab ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2014 APRIL ANDROFERT
  31. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2014 APRIL ANDROFERT
  32. 32. On average, an extra top-quality embryo for transfer or cryopreservation Air Quality Control and GMP 2,315 patients; 14,660 embryos ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2014 APRIL ANDROFERT
  33. 33. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2014 APRIL ANDROFERT
  34. 34. 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) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2014 APRIL ANDROFERT
  35. 35. Tailoring embryo transfer •  D2 vs D3 vs D5 •  D6 (or frozen-thawed blastocyst) if TE biopsy ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2014 APRIL ANDROFERT
  36. 36. D2 ET gives the best results in cycles with conventional COS ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2014 FEBRUARY ANDROFERT 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
  37. 37. 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   ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2014 APRIL ANDROFERT
  38. 38. 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 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2014 APRIL ANDROFERT
  39. 39. Management of Poor Responders Conclusions ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2014 FEBRUARY ANDROFERT Best care in the IVF lab Identify patients at risk Individualize COS Tailor embryo transfer
  40. 40. ThankYou obrigado

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