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Optimizing the Management of the Poor Responder

In this lecture, Dr. Kaylen Silverberg discusses the management and treatment alternatives for poor responders in assisted reproductive technology (ART) patients. The talk covers definitions, pathophysiology, ovarian reserve testing, and novel approaches. Learn how to effectively optimize management for this patient population.

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Optimizing the Management of the Poor Responder

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  1. Optimizing the Management of the Poor Responder Kaylen Silverberg, M.D. Texas Fertility Center Austin, Texas San Antonio, Texas

  2. 2 Choices • Donor Oocytes • Break, eat, visit, enjoy weather • Listen to lecture • Argue, get grumpy, be depressed... • Until we conclude with Donor Oocytes 

  3. Agenda • Definitions • Pathophysiology • Ovarian Reserve Testing • Treatment Alternatives • Novel Approaches

  4. Who Is the Poor Responder?

  5. Background Poor Responder • 10-24% of all ART patients • Diminished ovarian reserve • Advanced age, Ovarian surgery, Idiopathic Definitions • # mature follicles, retrieved oocytes • Peak E2 levels • Antral follicle counts • Day 3 FSH, E2, AMH levels • Repetitive premature LH surges • Over 20 published definitions (and climbing…)

  6. Bologna Criteria for Poor Responders • At least 2 of the following criteria: • Advanced maternal age (≥ 40 yo) or “any other risk factor for poor ovarian response” • Poor prior response to stimulation (≤ 3 oocytes when receiving at least 150 IU gonadotropin) • Abnormal ovarian reserve testing (AFC < 7, AMH < 1.1 ng/mL) ESHRE 2011

  7. Poor Responder: Pathophysiology • Declining oocyte quality • Oocyte chromosomal degeneration (dissociated chromatids) a • 23.7% < 34 yo • 52% 35-39 yo • 95.8% >40 yo • Mitochondrial DNA deletions increase with patient age b a Lim et al. Fertil Steril 1997;68:265 b Keefe et al. Fertil Steril 1995;6:577

  8. Hormonal Tests of Ovarian Reserve • Day 3 FSH Levels • Day 3 Estradiol Levels • Inhibin B Levels • AMH • Clomiphene Challenge Testing

  9. Day 3 FSH Levels Toner et al. Fertil Steril 1991 (n=1478) • Indirect measure of ovarian reserve • Pregnancy/delivery rates fall as FSH rises • Begins to rise 5-6 years before menopause onset • Predictive value supported by many other investigators • Elevated D3 FSH portends poor response, but many • poor responders have normal D3 FSH levels

  10. Day 3 Estradiol Levels Author # Pts D3 E2 Cxl(%) Preg(%) • Proposed mechanism involves negative hypothalamic feedback on FSH, leading to false negative FSH levels • Most studies suggest no incremental value over • Day 3 FSH alone (ASRM Practice Committee, 2015)

  11. Basal FSH & E2 Variability Hansen et al Hum Reprod 1996;11:486

  12. Predictors of Ovarian Reserve Laszlo et al. Fertil Steril 2002;77:328

  13. AMH as a Predictor of Ovarian Reserve Retro analysis of 2 multicenter RCTs comparing AMH to AFC n=519 and 686 Reviewed long GnRH-A and GnRH-ant cycles AMH more strongly correlated with oocyte yield (r=0.56 vs. 0.28; agonist), (r=0.55 vs. 0.33; antagonist) Nelson SM, et al; FertilSteril 2015;103:923

  14. Clomiphene Citrate Challenge Testing (CCCT) • Basal (D3) FSH, E2 • CC 100 mg cycle days 5-9 • Day 10 FSH, E2 • Abnormal: “Elevated” Day 3 or Day 10 FSH • Tanbo (1992): • < 12: 32% cxl rate, 10% preg rate • > 12: 85% cxl rate, 0% preg rate • Loumaye (1990): • < 26: 1% cxl rate, 28% preg rate • > 26: 25% cxl rate, 0% pregrate • Better test than basal FSH (ASRM Practice Committee, 2015)

  15. Sonographic Evaluation of Ovarian Reserve • Antral follicle counts • Ovarian volume (not recommended by ASRM, 2015) • Doppler imaging techniques

  16. Antral Follicle Counts • 2-5 mm antral follicles • Typically measured on Day 2 or 3 • Correlates with Day 3 FSH, amount of gonadotropin used, peak E2 level, # oocytes, and pregnancy rates a • Better predictor of ovarian response than patient age, D3 FSH level b, or inhibin B level c,d • Normal responders typically have > 10 antral follicles vs. < 5 for poor responders b,e a Chang et al. Fertil Steril 1998;69:505 b Beckers, et al. Hum Reprod 2000;15:43 c Fauser Fertil Steril 2000;74:629 d Laszlo et al. Fertil Steril 2002;77:328 e Beckers, et al. Fertil Steril 2002;78:291

  17. Poor Responder: Treatment Alternatives • High Dose Gonadotropin • Priming (OCPs, Estrogen, Testosterone) • Clomiphene Citrate plus High Dose hMG • Letrozole • Reduction/Elimination of GnRH-A • Addition of LH • GnRH-antagonists • Growth Hormone, GH-RH • Estrogen/Progesterone pretreatment • Recombinant Gonadotropins vs. combo protocols • “Flare” protocols • Micro-dose Lupron Flare • DHEA, CoQ10

  18. High Dose Gonadotropin Therapy

  19. High Dose hMG Plus Clomiphene • Blankstein (1989) • N=18, CC100 + hMG(75-150) • Increased peak E2, improved follicular development • 10/18 to retrieval (0/18 in prior cycle) • Pantos (1990) • N=271, CC 100 + hMG (150-225) • Data difficult to interpret as patients received different doses of hMG • No improvement in stimulation or pregnancy rate • Benadiva (1995) • N=93, previously failed gonadotropins alone • No improvement in cxl rate, peak E2, stimulation length • Increased implantation rate and live birth rate • Cycle cxl rates of 25-30% due to LH surge

  20. Poor Responders: Letrozole • N=147, OCP/hMG150/FSH225 • Antagonist at 14mm Garcia-Velasco et al. Fertil Steril 2005;84:82

  21. Poor Responders: Letrozole • P,R;N=70, OCP/rFSH 450 ± Letrozole 5mg • Antagonist “flexible” dosing Ozmen, et al RBM online. 2009;19:478-85

  22. Adjunctive GnRH-agonists Advantages • Lower cancellation rates • Prevents LH surge • Higher peak E2 levels • Greater number of retrieved oocytes • Higher pregnancy rates Disadvantages • Longer stimulations • Direct ovarian suppression • More exogenous gonadotropin required

  23. “Stop” GnRH-a Protocol • Administer luteal GnRH-a until onset of menses • High dose gonadotropin therapy Faber: • 12.5% cxl rate • Over half of the patients produced > 10 oocytes, and had 3 embryos for transfer • Clinical pregnancy rate 32.5% per transfer Dirnfield: • No benefit Wang: • 13.5% cxl rate • Clinical pregnancy rate 20.5% per transfer Faber, et al. Fertil Steril 1998;69:826 Dirnfield et al. Fertil Steril 1999;72:406 Wang et al. J Asst Reprod Genet 2002;19:1

  24. LH Supplementation Barrenetxea, et al. FertilSteril 2008;89:546-53 • P, R Controlled trial (n=84) • rFSH, rLH • Basal FSH ≥10, ≥40yo, 1st IVF cycle • No differences: • OPR, implantation rate • # days of gonadotropin, E2 level, # follicles, # oocytes, # embryos/ET

  25. Addition of Exogenous r-LH • Meta analysis of 3 studies • No increase in pregnancy rates (OR 1.3, CI 0.8-2.11) • No differences: • # oocytes retrieved • Dose of FSH • Duration of stimulation • Cycle cxl rate Fan et al. GynecolEndocrinol. 2013;29:278-84

  26. GnRH Antagonists • Directly, quickly suppress pituitary FSH, LH production • Lessen duration of direct ovarian suppressive effect • Daily dose (0.25mg) vs single dose (3 mg) – equally effective a,b,c • Optimal size for antagonist initiation?? • 12-13 mm • 14-15 mm or larger?? a,b Olivennes et al Hum Reprod 1998;13:2411, RBM Online 6;4:432, 2003 c Albano et al Fertil Steril 1997;67:917

  27. Agonist vs Antagonist: Data • Cochrane review (2002) 1 • 5 studies • Lower delivery rates with antagonist 0.79 (CI 0.63-0.99) • 5% absolute treatment effect, so for every 20 couples treated, there will be one more pregnancy with agonist • Cochrane review (2006) 2 • 27 studies • Significantly lower pregnancy/delivery rates with antagonist (p<0.05) 1 Al-Inany et al, Hum Reprod. 2002;17:874 2 Al-Inany et al, Cochrane Database Syst Rev. 2006;19:3

  28. Oral Contraceptive Pre-Treatment Potential Advantages • Prevents rescue of corpus luteum from previous cycle • Blocks cyst development • Synchronized follicular cohort development • Allows better scheduling of cycles • Decreases gonadotropin requirements?? • Lower cancellation rates • Greater number of retrieved oocytes • Higher pregnancy rates Potential Disadvantages • Longer stimulations, higher gonadotropin doses in poor responders • Residual ovarian suppression • Exacerbated ovarian suppression when combined with GnRH-a

  29. Oral Contraceptive Pretreatment Gelety, TJ: ASRM abstract 010, 1997

  30. Are OCPs suppressive? No: • Kolibianakis Hum Rep 2006 • RCT antag w/w/o OCP • No diff • Barmat F&S 2005 • RCT, OCP/Antag vs LPL • No diff in IR, PR, # embryos • Gasia-Velasco F&S 2011 • RCT, OCP/Antag vs LPL • No diff in IR, PR, LBR • Lower E, Less days stim Yes: • Griesinger F&S 2005 • Meta- analysis/ OCP vs No OCP • Lower PR, increased drug requirement (CI crossed 1) • BendicksonClin Exp 2006 • OCP vs No OCP • Increased drug requirement • No diff in PR • Cochrane Review, 2010: • OCP vs no OCP • Increase drug requirement • Lower PR

  31. Luteal Estrogen Hill, et al. Fertil Steril 2009; 91:739-43

  32. Luteal Estrogen Priming: Meta Analysis Reynolds, et al. Hum Reprod 2013 • 2260 studies evaluated; 8 included • 468 women exposed to luteal estrogen • 621 controls • Lower risk of cycle cxl (RR 0.6, CI 0.45-0.78) • Improved pregnancy rate (RR1.33, CI 1.02-1.72)

  33. Luteal Testosterone • Used in the luteal phase to increase responsiveness to FSH/HMG • More eggs, better quality • Bosdou Hum Repo Update 2012 • 11% increase in LBR • Kim F&S 2011 • Transdermal T Gel • RCT: 21 days • Higher IR, PR • Fewer days less drug better quality embryos • Fabrigues Hum Rep 2009 • Improved response to FSH • Massin Hum Rep 2006 • No difference

  34. Comparative Trials

  35. Recombinant FSH vs. Urinary FSH: Clinical Efficacy • In randomized prospective statistically powered clinical studies, significantly more oocytes were retrieved and less medication required with r-FSH than with u-FSH. (Bergh 97; Frydman 98; Schats et al 2000) • Pregnancy rates significantly improved • FIVNAT 1999: data from 37,211 cycles • Clinical pregnancy rates achieved with r-FSH were statistically higher than those achieved with urinary FSH (Daya et al 1999) • Meta Analysis: 12 randomized controlled trials (2875 cases, Daya, 1999)

  36. Micro Dose Lupron Flare: • Higher E2 levels, more mature oocytes, no spont. LH surges, 90% with improved outcome, 9% preg rate (n=34) 1 • Higher E2 levels, more mature oocytes, fewer cxl cycles, no LH surges , 50% preg rate – used growth hormone as well (n=32) 2 • Higher E2 levels, fewer cxl cycles, more patients to embryo transfer, 35% preg rate (n=34) 3 1Scott RT, Navot D FertilSteril 1994;61:880 2 Schoolcraft W, Schlenker T, et al FertilSteril 1997;67:93 3 Surrey E, et al. FertilSteril 1998;69:419

  37. Materials and Methods • Prospective, sequential trial of LLL and ULDLF protocols • n=53 (1997-1998) • IVF • LLL • LA 0.5 mg (OCP overlap or LH timing) • 0.25 mg with FSH initiation • hCG 10,000 IU; 2 follicles > 18 mm Silverberg & Vaughn, ASRM, 1998

  38. Materials & Methods • ULDLF • 21 days OCPs • 3 days later, LA 40 µg BID • 2 days later, FSH 225-300 IU BID • hCG 10,000 IU; 2 follicles >18 mm • TVA 36 h post hCG • D3 embryo transfer • Progesterone in oil 25 mg IM; D2 start Silverberg & Vaughn, ASRM, 1998

  39. Materials & Methods • 4 analyses • separate (n=112 cycles) • completed both LLL & ULDLF (n=48) • failed LLL/ completed ULDLF (n=35) • failed ULDLF/ completed LLL (n=2) • Statistical Analysis • t test • paired t test Silverberg & Vaughn, ASRM, 1998

  40. Overall Results • 53 poor responders • 59 LLL cycles • 53 ULDLF cycles • Cycle Cancellation Rates • LLL 22/59 (37.3%) • ULDLF 6/53 (11.3%) (p<0.05) • No spontaneous LH surges Silverberg & Vaughn, ASRM, 1998

  41. Overall Results 18/42 22/59 % 13/42 9/30 6/53 3/30 * p < 0.05 Silverberg & Vaughn, ASRM, 1998

  42. Results: Direct Comparisons LLLULDLFP # cycles 24 24 # with ET 21 21 Stim (days) 11.0 (1.5) 10.8 (2.2) 0.8 Gonadotropin (IU) 4953 (1447) 6183 (1769) 0.01 E2 peak (pg/mL) 1160 (507) 1390 (803) 0.2 # oocytes retrieved 6.1 (2.5) 6.7 (3.7) 0.5 # oocytes fertilized 4.0 (2.0) 4.6 (2.6) 0.4 # embryos trans 3.5 (1.5) 3.6 (1.3) 0.8 Silverberg & Vaughn, ASRM, 1998

  43. Results: Direct Comparisons 3/5 11/21 % 9/21 5/21 2/11 2/21 * p < 0.001 Silverberg & Vaughn, ASRM, 1998

  44. ULDLF Results: Previous LLL Failures 21/35 % 12/35 8/35 Silverberg & Vaughn, ASRM, 1998

  45. Summary • Poor responders do poorly • Comparing LLL and ULDLF: • No differences in stimulation parameters • No differences in # embryos transferred • Yet significantly higher Preg/Deliv rates • Evaluating LLL Failures • 60% TVA, 23% Delivered • Poor responders who fail LLL have excellent outcome with ULDLF • Poor responders who complete LLL have higher delivery rate with ULDLF • ULDLF represents a better option for poor responders than does the LLL protocol

  46. Modified Micro-Dose Flare vs. GnRH Antagonist Akman et al. Hum Reprod 2001;16:868

  47. Poor Responders: Agonist vs Antagonist • Conflicting Data: • P,R n=534; higher OPR with microdose flare vs. Antagonist/Letrozole 1 • P,R; higher OPR with antagonist 2 • Meta analysis of 6 trials • No differences in cycle cxl, # oocytes, pregnancy rate 3 1 Schoolcraft et al. Fertil Steril. 2007 2 Lainas et al. Hum Reprod. 2008 3 Franco et al. Reprod Biomed Online. 2006;13:618

  48. CC/low dose FSH/Antagonist vs.Agonist/high dose FSH • RCT, n=695 • Group A(n=355) • Shorter stim, lower total FSH dose • Lower peak E2 • Group B (n=340) • Lower cxl rate • More oocytes, more mature ooc, more embryos • No diffs: • Implantation rate, ongoing (12 week) IUP Revelli A, et al. J Assist Reprod Genet 2014;31:809

  49. Modified Natural Cycle Kedem, et al. FertilSteril 2014;101:1624-8 Cohort study (n=111) All patients had previous failed conventional IVF cycle within 3 months with ≤ 3 oocytes on ≥ 300 IU/day FSH GnRH-ant and 150-225 IU hMG started once largest follicle ≥ 13 mm Live birth rate < 1%

  50. Growth Hormone • IGF-1 augments response of rat granulosa cells to FSH in vitro • GH increases IGF-1 production • GH appears to sensitize ovary to exogenous gonadotropins • Unanswered Questions: • Optimal Dosage? • Are physiologic doses adequate? • Only effective in GH deficient individuals? Adashi E, et al. Endocrin Rev 1985;6:400

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