Evolution of ovarian stimulation for ART - towards an individualized approach

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Evolution of ovarian stimulation for ART - towards an individualized approach

  1. 1. “Meet the Expert” - May 2012The Evolution of Ovarian Stimulation for ART Sandro Esteves, MD, PhD Director, ANDROFERT Center for Male Reproduction Campinas, BRAZIL
  2. 2. 1. Historical perspective of gonadotropins development. 2. Primary factors affecting IVF success and ovarian response to stimulation. 3. Taking advantage of new products and clinical strategies to individualize COS.Esteves, 2
  3. 3. www.slideshare.net/sandroesteves
  4. 4. UN Census Estimates, 2008
  5. 5. Central Paradigm Maximize Minimize beneficial effects complications of treatment and risks High-quality Cycle cancellation, oocyte yield OHSS, multiple pregnancyEsteves, 7 Fauser et al., 2008
  6. 6. Milestones in the development of gonadotrophins 2001 2008 1940 1962 Full recombinant First First hCG 1993 2000 Purified u-hMG gonadotropin r-hLH+r-FSH extracted from First highly purified First r-hLH (Pergonal®) and u- portfolio available combined human urine FSH-only product launched hCG (Profasi®) (Pergoveris®) launched (Luveris®) become available (Metrodin HP®) 1949 1980s 1995 2001 2002 First hMG extracted First FSH-only First r-hFSH First r-hCG First filled-by-mass from urine pools product launched launched launched product launched (Metrodin®) (GONAL-f®) (Ovidrel®/Ovitrelle) (GONAL-f® FbM) Milestones in the development of r-hFSH 1980 1983 1985 1988 1992 α-subunit β-subunit β-FSH gene cloned and Human FSH expressed First pregnancy sequenced sequenced expressed in fibroblasts in Chinese hamster ovary with r-hFSH (CHO) cells Bassett et al. Reprod Biomed Online 2005;10:169–177; Lunenfeld. Hum Reprod Update 2004;10:453–467. Bosch. Expert Opin. Biol. Ther. 2010;10:1001-1009.Esteves, 8
  7. 7. 1. Demand increased
  8. 8. From urinary to recombinant 2. Safety - Impurities in Urinary-derived Drugs Impossibility to trace donor 30% of impurities per source vial with Quality cannot be checked duringhMG HP (different proteins transportation identified) varying Decontamination may denature from batch to batch proteins Cross‐contamination cannot be avoided Many of the protein contaminants are active and have unknown effects Suboptimal testing for consistency and purity Protein FSH van de Weijer et al. Reprod Biomed Online 2003;7:547–557 impurities Kuwabara Y et al, J Reprod Med 2009; 54:459–466
  9. 9. Culture media Bioreactor Harvest Cell attachment and proliferation Concentration of r-hFSH production and supernatant secretion Chromatographic Collection of cell purification culture supernatant steps medium containing Ultrasterile filtration r-hFSH Characterization In-process QC and full QC of bulk r-hFSHEsteves, 11
  10. 10. 2. Safety - Impurities in Urinary-derived Drugs Impurities cannot be associated with a better or worse outcome but certainly are not needed for COH Molecular u-hMG HP (5 batches) r-hFSH weight (follitropin markers alfa)Esteves, 12 Merck Serono data on file
  11. 11. Typical Cycle (long protocol): Daily SC GnRH-a: x21 HMG/FSH: x10-15 hCG: x1 Progesterone: x14 Blood tests: x4-7 Number of sticks: 36-57
  12. 12. Purity Mean specific Injected (FSH FSH activity protein content) (IU/mg protein) per 75 IU (mcg) hMG < 5% ~100 ~750 hMG-HP < 70% 2000–2500 ~33 r-hFSH Follitropin beta – 7000–10,000 8.1 Follitropin alfa > 99% 13,645 6.1Esteves, 14 Bassett et al. Reprod Biomed Online 2005;10:169–177.
  13. 13. Conventional FbM: Novel Bioassay analitycal method High Protein content by Rat ovary mass weight variability gain Minimal batch-to- batch variability (1.6%)1,2 Urinary gonadotropins Follitropin beta Follitropin alfa 1. Bassett et al. Reprod Biomed Online 2005;10:169–177; 2. Driebergen et al.Esteves, 15 Curr Med Res Opin 2003;19:41–46.
  14. 14. u-FSH HP r-hFSH FbM Horse Pituitary r-hFSH u-FSH PMSG FSH u-hMG Safety, Quality, Consistency and Patient Convenience 1930s 1950 1980 1995 2003 Intramuscular administration sc Injector pens sc, subcutaneous; FbM, filled by Mass; HP, highly-purifiedEsteves, 16
  15. 15. Advantages of Novel Products For clinicians: Manufactured to the highest standards of quality and consistency; Delivers a guaranteed dose. For patients: Best convenience; Improve satisfaction & treatment compliance.Esteves, 18
  16. 16. 2. Primary factors affecting IVF success and ovarian response to stimulation.Esteves, 19
  17. 17. Female Age Negative Duration of infertility Predictors Basal FSH Type of infertility All reflecting Indication ovarian reserve Fertilization method Number of oocytes retrieved Positive Number of embryos transferred Predictor Embryo quality van Loendersloot et al.Esteves, 20 Hum Reprod Update 2010; 16: 577–589.
  18. 18. Ovarian Response toGonadotropin Stimulation  Demographics and anthropometrics (Age, BMI, Race)  Genetics profile  Cause of Infertility  Years of Infertility  Health status  Nutritional status
  19. 19. Chronological vs Biological Ageing 20 FSH IU/L <3 15 Live births (%) 3–5.9 6–8.9 10 9–11.9 5 ≥12 (n = 1019) 0 20–24 25–29 30–34 35–39 40–44 45–49 Age (years)Esteves, 22 Akande et al. Hum Reprod 2002;17:2003–2008.
  20. 20. = remaining population of primordial and resting follicles Anti-Mullerian Hormone levels are correlated with the number of follicles at gonadotropin independent stage.Esteves, 23 La Marca et al. Hum Reprod 2009.
  21. 21. Antral Follicle Count (AFC) Mean number of oocytes retreived 25 20 15 r=0.64 10 p<0.001 Number of antral follicles present in the 5 ovaries at a given time 0 that can be stimulated 0 5 10 15 20 25 into dominant follicle Number of antral follicles growth by exogenous Hansen KR, et al. Fertil Steril gonadotropins. 2003;80:577–83 Devroey et al. Hum Reprod Update 2009; Broekmans et al. Fertil Steril 2009.Esteves, 24
  22. 22. AMH = AFC >Inhibin B >FSH >Age Excessive Response Predictor Poor Response PredictorEsteves, 25 Broer et al. Fertil Steril, 2009; Broer et al. Hum Reprod Update 2011.
  23. 23. AMH and AFC – Operational Purposes Response to Anti- Antral False Ovarian Mullerian Follicle Positive Stimulation Hormone Count Rate (ng/mL) Risk of Excessive Response (≥15 ≥ 3.5 > 15 oocytes or OHSS) ~15% Risk of Poor Response < 1.1 <5 (≤ 4 oocytes)* *Bologna criteria: Ferraretti et al. Hum Reprod 2011; Broer et al. Hum Reprod Update 2011; Nelson et al. Hum Reprod. 2009;Esteves, 26 Broer et al. Fertil Steril. 2009; Hendricks et al. Fertil Steril 2007.
  24. 24.  Tailoring gonadotropin dose using recombinant FSH fbM pre-filled ready-to- use pen devices.  Exploring the flexibility of GnRH antagonist protocols.  Improving success in IVF by identifying the subgroups of patients who benefit from LH supplementation.Esteves, 27
  25. 25. Reproductive Biology and Endocrinology 2009; 7:111. Unselected group of NG down-regulated women (n=865) Group A (hMG; N=299) Group B (HP-hMG; N=330) Group C (r-hFSH; N=236) Day Day 1 Day 6 of hCG Cycle day 21 Gonadotropin rFSH/hMG Individualized dose 112.5-450 UI Vaginal progesterone Agonist (nasal spray): Nafarelin acetate (400 mcg/day; fixed) mensesEsteves, 28 Day 2-5 of menses
  26. 26. Outcome Measure HMG HP-hMG r-hFSH P- n=299 N=330 n=236 valueTotal gonadotropin dose (IU) 2,685 2,903 2,268 <0.01Retrieved oocytes (N) 10.9 10.7 10.8 NSMII oocytes (N) 8.9 8.9 8.7 NS2PN fertilization rate (%) 72 72 71 NSImplantation rate (%) 24 27 23 NSLive birth rate per cycle (%) 24.4 32.4 30.1 NSModerate/severe OHSS(%) 2.3 1.8 1.3 NS Esteves et al, Reprod Biol Endocrinol. 2009; 7:111
  27. 27. Total Dose per Live Birth (IU)* To achieve a 10,000 live birth, 52.2% 9,690 21-52% more 7,000 21.6% 7,739 HP-hMG and 6,324* hMG was 3,000 required 0 compared with r-hFSH HP-hMG hMG r-hFSH * Mean total dose per cycle/Live birth rate (≤35 years)
  28. 28. % Cycles with “Step-down”during ovarian stimulation 53.4* *P<0.01 18.7 20.3 HMG HP-HMG rec-hFSH (fbm)
  29. 29. Evidence-based truth: Scientific truth: Rec-hFSH is more Rec-hFSH is potent purer ↑ 3.1 oocytes (Bosch, 2008) Non urine- extracted product ↑ 1.8 oocytes (MERIT, 2006) Recombinant technology ↑ 2.8 oocytes (Hompes, 2007)Esteves, 32
  30. 30. Batch variability Batch variability +20%, -25% ± 2%IU Risk of OHSS270 16.5 mcg225 (225 IU)170 Poor response Bioassay Filled by Mass Urinary and Follitropin beta Folitropin alfa (Gonal-f)
  31. 31. • Incidence of62% Infertility (WHO II) • Infertile Patients with PCOS67% (WHO II) • Prevalence of Patients with PCOS41% in Clinical Practice Treatment Management of Infertility GCC Countries (IPSOS May 2008) Yeko et al. Fertil Steril 2004; Keck et al. RBM Online 2005.
  32. 32. CONSORT = CONsistency in r-hFSH Starting dOses for Individualized tReatmenT: ART results Individualized dosing in Clinical pregnancy rates/cycle increments of 37.5 IU of started 60% Folitropin alfa possible by FbM technology 50% 50.0% 40% Use of algorithm of 30% 35.3% patients characteristics 31.3% ● 31.1% basal FSH 20% ● body mass index (BMI) 20.0% ● age 10% ● antral follicle count 0% 75 IU 112.5 IU 150 IU 187.5 IU 225 IU Age (28-32) Oocytes retrieved (8-12)Esteves, 35 Olivennes F, et al. The CONSORT study. Reprod Biomed Online. 2009;18:95–204.
  33. 33. 1. Rec-hFSH fbM is purer, safer and more potent than urinary gonadotropins. 2. Lower starting doses and step- up/step-down (by 37.5 UI) COS is advisable.Esteves, 36
  34. 34.  Exploring the flexibility of GnRH antagonist protocols.Esteves, 37
  35. 35. 1 2 3pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 Activation of the Antagonistic Regulation of Regulation of receptor GnRH receptor effect receptor affinity biological activity
  36. 36. Prevent Can be OHSS by integrated in GnRH-a No flare spontaneousGnRH antagonist and OI cycles Antagonist effect with No hormonal protocol administration possible cyst withdrawal formation Gonadotropin administration Shorter Can exclude duration of early stimulation pregnancy Flare up Pituitary effect suppression Gonadotropin administration Long GnRH agonist Longer Agonist administration protocol treatment Pre-treatment cycle Treatment cycle
  37. 37. Probability of Live Birth N studies 45 22 Included IUI Yes No cycles N patients 7511 3176 Primary outcome OPR or LBR LBR Odds-ratio 0.86 0.86 (95% CI: 0.69-1.08) (95% CI: 0.72-1.02) 1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750.Esteves, 40 2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
  38. 38. Duration of OS and Risk of OHSS Duration of OS -1.13 days -1.54 days (-1.83; -0.44) (-2.42; -0.66; p=.0006) Oocytes retrieved -- -1.19 (-1.82; -0.56) Risk of severe 0.43* 0.61 OHSS (95% CI 0.33-0.57) (0.42; 0.89; p=.01) 1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750.Esteves, 41 2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
  39. 39. POOR RESPONDERS 14 RCT (1127 patients); Pu et al. 2011 Duration of Oocytes Cycle CPR stimulation retrieved cancellation -1.9 days -0.17 1.01 1.23 (-3.6; -0.12) (-2.42; -0.66) (0.71; 1.42) (0.92, 1.66) PCOS RCT; 220 patients; Lainas et al. 2010 Days of Oocytes Grades II + III CPR (%) stimulation retrieved; N OHSS (%) 10 vs 12 27 vs 28 44 vs 65 50.9 vs 47.3 (P<.001) (P=0.22) (P=0.006) (P=0.68)Esteves, 42 Lainas et al. Hum Reprod. 2010;25:683; Pu D et al. Hum Reprod. 2011; 26: 2742.
  40. 40. Individualized Treatment with AMH AMH + antagonists in hyper-responders AMH category (ng/mL) >2.1 GnRH analogue + r-hFSH 150UI Agonist Antagonist Oocytes (n) 14 (10-19) 10 (8.5-13.5) Severe OHSS 20 (13.9%) 0 (0%)* Cancellation 4 (2.7%) 1 (2.9%) CPR per transfer 40.1% 63.6%* *P < 0.01 Adapted from Nelson SM et al . Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009; 24(4): 867-75.Esteves, 43
  41. 41.  GnRH-a triggering (0.2-1.5 mg): antagonist protocol;  Reduced if not eliminated risk for OHSS;  In specific high risk patients for OHSS and egg donation programs should become the choice  Challenge is to rescue luteal phase insufficiency;  Modified luteal support improved delivery rate: hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses; recLH; intense progesterone + estradiol; combined Delivery rates: 18% risk difference favoring hCG (before) X 6% risk (after modified luteal support)Esteves, 44 Humaidan et al. Hum Reprod Update 2011.
  42. 42. 1. GnRH antagonists improve COS flexibility. 2. Duration of stimulation is decreased by 1-2 days (gonadotropin total dose by 10-20%). 3. Use of GnRH antagonists in COS reduces (or eliminate) the risk of severe OHSS.Esteves, 45
  43. 43. OHSS: Three Levels of Protection 1st Level: Antagonist rather than Agonists. 2nd Level: In patients on antagonist protocol at risk of OHSS, replace hCG with GnRH-a for oocyte maturation trigger. 3rd Level: In patients with early OHSS onset, use of GnRH-ant luteal phase.Esteves, 46
  44. 44. r-hFSH r-hFSH+hMG hMG Cycles with GnRH 2009 Antagonists 60% 15% 52% 1999 2009 39% 9%Esteves, 47 Data supplied by REDLARA and ICMART
  45. 45. Esteves, 48
  46. 46. • Mild Stimulation (low dose rec-hFSH + GnRH ant.): Promotion of Steroidogenesis • 5 oocytes (TCs) early FP retrieved; • IR = 31% • Adequate estrogen production • Uterine/endometrial changes • Conventional Stimulation : Stimulation of final Follicular Maturation (GCs) late FP • 10 oocytes retrieved; • IR = 29% Verberg et al.Esteves, 49 Alviggi et al.Hum Reprod Update 2009; 15: 5–12. Reprod Biomed Online 2006;12:221.
  47. 47. • Suppression of GC proliferation High • • Mild Stimulation Follicular atresia (non-dominant follicles) dose rec-hFSH + (low • Premature luteinization GnRH ant.): • Oocyte development compromised • 5 oocytes CEILING retrieved; Normal • IR = 31% • Normal androgen and estrogen biosynthesis • Normal follicular growth and development • Normal oocyte maturation THRESHOLD • Conventional Stimulation : Low • Insufficient androgen (and estrogen) synthesis • 10 oocytes • Follicular growth and maturation impaired retrieved; • Inadequate endometrial proliferation • IR = 29% Verberg et al.Esteves, 50 Balasch J, Fábreques F. Curr Opin Obstet Gynecol 2009; 15: 5–12. Hum Reprod Update 2002, 14:265.
  48. 48. • Mild Stimulation Normal (low dose rec-hFSH + • ~80% normogonadotropic women undergoing ART1-3 GnRH ant.): • 5 oocytes retrieved; • IR = 31% • 15-20% of NG women have less sensitive ovaries • Older patients (≥35 years)4 Low • Poor responders5 • Conventional • Slow/Hypo-responders6 Stimulation : • Deeply suppressed endogenous LH (endometriosis)7 • 10 oocytes retrieved; • IR = 29% 1. Alviggi et al. Reprod Biomed Online 2006;12:221; 2. Tarlatzis et al. Hum Reprod 2006;21:90; 3. Esteves et al. Reprod Biol Endocrinol 2009;7:111; 4. Marrs et al. Reprod Biomed Online 2004;8:175 Verberg et al. 5. Mochtar MH, Cochrane Database, 2007; 6. Alviggi, et al. RBMOnline 2009.Esteves, 51 7. DeHum Reprod Update 2009;2004;60:637; Placido et al. Clin Endocrinol (Oxf) 15: 5–12.
  49. 49. Women with Less Sensitive Ovaries Poor Responders* Hypo/Slow Responders At least 2 of the following: Normal markers of ovarian reserve; Advanced maternal age (≥40 years) Hypo-responders: Previous POR (≤3 oocytes with a d1-d7: normal initial follicullar recruitment conventional stimulation protocol) using fixed starting dose of FSH; d7- d10: plateau on follicullar growth Abnormal ovarian reserve test (AFC<5; despite continuing same FSH dosage AMH <1.1) Slow responders: Or: High doses of FSH (>3,000UI) to promote 2 episodes of POR after maximal follicular growth; stimulation May indicate genetic polymorphisms of LH and/or FSH receptor *Bologna criteria: Ferraretti et al. Hum Reprod 2011; Alviggi, et al. RBM Online 2009; De Placido et al. Hum Reprod. 2004; 20: 390-6;Esteves, 52 Ferraretti et al. Fertil Steril. 2004; 82: 1521-6.
  50. 50. LH • Theca cells Consider increasing LH drive LH • Granulosa cells Increasing FSH drive of limited FSH value There is a potential role for r-hLH in women with less sensitive ovariesEsteves, 53
  51. 51. Rec-hLH for older women (≥35 years) Comparison of Clinical Pregnancy RatesEsteves, 54 Hill MJ et al. Fertil Steril 2012; 97: 1108-4.
  52. 52. Rec-hLH for Poor Responders Cochrane review 2007:Esteves, 55 Poor-responders using r-hFSH vs r-hLH + r-hFSH (Ongoing PR)
  53. 53. Deeply Suppressed Endogenous LH RCT 260 pts; “Steady” response on D8 (E2 <180pg/mL; >6 follicles <10mm) Mean No. oocytes retrieved IR (%) OPR (%) 40 32 22 18 14 10 9 11 6 FSH step-up (+150 UI) LH supplementation Normal Responders (+150 UI)Esteves, 56 De Placido et al. Hum Reprod. 2004; 20: 390-6.
  54. 54. LH for Slow/Hypo Responders RCT 180 pts; follicular stagnation d7-d10 Mean No. oocytes retrieved IR (%) LBR (%) 41 37 35 37 22 14 11 11 8 rec-hFSH step-up rec-hLH Control supplementationEsteves, 57 Ferraretti et al. Fertil Steril. 2004; 82: 1521-6.
  55. 55. 1. LH supplementation to COS increase IVF success in patients subgroups: i. Advanced female age (≥35 years) ii. Poor responders iii. Slow/Hypo-responders iv. Profound LH suppression after down- regulation (endometriosis pts.) 2. 75-150 UI/day is sufficient. 3. Take advantage of rec-hLH fbM.Esteves, 58
  56. 56. The Evolution of Ovarian Stimulation for ART 1. Using markers of ovarian reserve (AMH; AFC) 2. Using better drugs (rec-gonadotropins FbM) 3. Mild stimulation (PCOS) 4. Flexibility of antagonist protocols 5. LH supplementation 6. Integrate strategies to maximize beneficial effects of treatment and minimize risks and complications.Esteves, 59
  57. 57. Up to 65% of couples dropout from IVF without achieving pregnancy before they complete 3 cycles ReasonsPsychological burden 49%-26% Oocyte retrieval 52%Prognosis 40%-23% Embryo transfer 29%Cost of treatment 23%-0% Injections 29%Relationship/divorce 15%-9% Physical pain 20%Physical burden 7-6% Blood tests 14% 1. Olivius K t al, Fertil Steril 2004;81:258; 2. Land JA et al, Fertil Steril 1997; 68:278; 3. Schroder AK, et al, RBM Online 2004; 5:600; 4. Osmanangaoglu K et al, Hum Reprod 2002; 17:2655; 5. Rajkhowa M et al, Hum Reprod 2006; 21:358; 6. Brandes M et al, Hum Reprod 2009; 24:3127; 7. Hammarberg K et al, Hum Reprod 2001; 16:374.
  58. 58. Color-coded for differentiation The New Family of PensTM: • same injection device design for all gonadotropins; • first & only pre-filled, ready-to-use family of pens for fertility treatment.Esteves, 61
  59. 59. Consider a change...Esteves, 62

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