​Is There a Best Stimulation Protocol in OI/IUI Cycles?

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​Is There a Best Stimulation Protocol in OI/IUI Cycles?

  1. 1. Is There a Best Stimulation Protocol in OI/IUI Cycles? Sandro Esteves, M.D., Ph.D. Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL ASPIRE III, Istanbul, September 2013
  2. 2. Esteves, 2 Is There a Best Stimulation Protocol in OI/IUI Cycles? Review this Lecture at: http://www.androfert.com.br/review ASPIREIII,Istanbul September2013
  3. 3. Esteves, 3 Level Type of evidence 1a Meta-analysis of randomized trials 1b At least one randomized trial 2a Well-designed controlled study without randomization 2b At least one other type of well-designed quasi- experimental study 3 Well-designed non-experimental studies (comparative and correlation studies, case series) 4 Expert committee reports or opinions or clinical experience of respected authorities Adapted from Sackett et al. Oxford Centre for EBM Levels of Evidence (2009) Level of Evidence  OI and IUI population  Grade A recommendation
  4. 4. Esteves, 4 Top Problems Concerning Ovarian Stimulation in OI/IUI and How to Solve Them What is in it for me?
  5. 5. Esteves, 5 Do We Need to Individualize the Protocol per Patient?
  6. 6. Esteves, 6 Singleton live birth at term Maximize Beneficial Effects 1Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; 2Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356; 3Aboulghar. Fertil Steril. 2012;97:523-6. Multiple Pregnancy2 10-40% Cycle Cancellation1 2-8% Risk of OHSS OHSS3 Severe 2% Moderate 3-6% Minimize Complications and Risks
  7. 7.  Age, BMI, Race  Genetic profile  Cause  Duration  Health  Nutrition Esteves, 7
  8. 8. Reproductive Hormones Report - GCC Countries (Feb 2011) Bologna criteria: Ferraretti et al. Hum Reprod 2011. Esteves, 8 Up to 68% Infertile Patients (WHO II) with PCO in Clinical Practice Up to 45% Patients Aged ≥35 have Poor Response to Stimulation
  9. 9. Esteves, 9 La Marca et al, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097; Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700 Reflect No. Pre-antral and Small Antral Follicles (≤4-8mm) Low inter and intra-cycle variation AMHAFC 2D-TVUS at early follicular phase 2-10 mm (mean diameter) Reflect No. AF at a given time that can be stimulated by medication Relatively low inter-cycle variation
  10. 10. Esteves, 10 Evidence Level 1a Biomarkers
  11. 11. 1Nardo et al. Fertil Steril 2009; 2Checa et al. Fertil Steril 2010 Esteves, 11 AMH (ng/mL) AFC False Result Risk OHSS1,2 >3.5 >16 ~15% pmol/L X1000/140 Level 2a
  12. 12. Esteves, 12 Individualized approaches maximize treatment beneficial effects and minimize complications and risks. Biomarkers, AMH and AFC, are useful to predict ovarian response and to define an individualized stimulation.
  13. 13. Esteves, 13 Clomiphene Citrate for How Many Cycles and How?
  14. 14. Pituitary GnRH FSH/LH estrogen Hypothalamus Ovary ClomipheneCitrate Esteves, 14 Similar to estrogen Extended binding depletes ER levels1 Ovulatory women Increase GnRH pulse frequency2 PCOS Increase GnRH amplitude3 1Clark & Markaverich. Pharmacol Ther 1982;15:467; 2Kerin JF et al. J Clin Endocrinol Metab 1985;61:265; 3Kettel et al. Fertil Steril 1993;59:532; 4Ibrahim et al. Arch Gynecol Obstet. 2012;286:1581; 5Annapurna et al. Int J Fertil Womens Med 1997;42:215. Negative Effect on Endometrium4 and Cervical Mucus5
  15. 15. ClomipheneCitrate Esteves, 15 How to Use? Dose: 50 mg/d for 5 days UltrasoundMenses Start day CC 2 3 4 5 76 8 9 10 11 12 131 Adapted form the ASRM Practice Committee. Fertil Steril 2003;5:1302–8 Ultrasound
  16. 16. Points to ConsiderClomipheneCitrate Esteves, 16 PCOS: >75% of anovulatory infertility ~25% CC-resistant (mainly obese & hyperandrogenic) ~15% who ovulate have thin endometrium/poor mucus Ultrasound monitoring 1. Dose can be adjusted, if necessary, in subsequent cycles. 2. Allows endometrial evaluation. In IUI, endometrial appearance/thickness more important than follicle size for hCG administration 3. Assessment for the risk of OHSS.
  17. 17. 50 mg/d 100 mg/d 150 mg/d OvulationOvulation 2 – 3 cycles with the same dose Ovulation No Ovulation No Ovulation No Ovulation No pregnancySuboptimal Endometrium (thickness <7mm) Injectable Gonadotropins ClomipheneCitrate Esteves, 17 Hypogonadotropic Hypogonadism Adapted from the ASRM Practice Committee. Fertil Steril 2003;5:1302–8 How Many Cycles and How?
  18. 18. Esteves, 18 How to Use Injectable Gonadotropins and What to Expect?
  19. 19. Esteves, 19 Low Dose Step-up StimulationGonadotropins Starting dose: 37.5 - 50 IU (rec-hFSH) Step-up (by 37.5 IU) if no follicles >10mm after 7 days Step-up every 7 days until dominant follicle appear hCG ≥18mm and endometrium ≥7mm 2 3 4 5 76 8 9 10 11 12 131 Ultrasound Menses Start day 14 15
  20. 20. Gonadotropins N = 968 Cycles >70% ovulatory cycles >85% monofollicular development Threshold to produce a dominant follicle: 37.5 to 75 IU (~75%) Average stimulation duration: 15 days CPR after 6 cycles: ~60% No OHSS; ~10-15% cancellation (multifollicular development) Low Dose Step-up Stimulation in PCO Esteves, 20
  21. 21. Points to Consider Esteves, 21 Gonadotropins Be patient! It may take 10 days or more for a dominant follicle to appear during the first treatment cycle with low-dose gonadotropin. TVUS scan before starting: if endometrium thickness >8 mm, we use progestin (medroxyprogesterone acetate, 5-10 mg/d) to induce a withdrawal bleed.
  22. 22. Esteves, 22 Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 Gonadotropins No. Studies No. Participants Odds-ratio Pregnancy 7 556 OR: 1.76 (95% CI: 1.16 to 2.66) Miscarriage 4 120 OR: 1.2 (95% CI: 0.67 to 1.9) Multiple Pregnancy 4 120 OR: 0.73 (95% CI: 0.32 to 1.67) OHSS 2 200 OR: 4.44 (95% CI: 0.48 to 41.25) Level 1a
  23. 23. Esteves, 23 Conventional vs Low Dose Step-up Stimulation in IUI Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 2 RCT; n= 297 >75 IU/day 50-75 IU/day Odds-ratio OHSS 13% 2.7% 5.52 (95% CI: 1.85-16.52) Pregnancy 31.1% 28.2% 1.15 (95% CI: 0.69-1.92) Level 1aGonadotropins
  24. 24. Esteves, 24 Injectable gonadotropins when… 3 CC ovulatory cycles but no pregnancy Suboptimal endometrium thickness (< 7mm) after CC-OI No response with CC 150 mg/d WHO I (hypo-hypo) anovulation Yields higher PR than CC without increased risks. Low-dose (37.5 to 50 IU) step-up (every 7d) stimulation is the best protocol.
  25. 25. Recombinant or Urinary Gonadotropins?
  26. 26. Esteves, 26 Up to 70% impurities
  27. 27. Bassett et al. Reprod Biomed Online 2005;10:169–177. Purity (protein content) Mean specific activity (IU/mg protein) LH activity (IU/vial) Injected protein per 75 IU (mcg) hMG < 5% ~100 75 ~750 hMG-HP < 70% 2,000–2,500 75 ~33 rec-hFSH* > 99% 13,645 0 6.1 Esteves, 27 RecombinantvsUrinary *Follitropin alfa
  28. 28. Esteves, 28 Level 1a Matorras et al. Fertil Steril. 2011;95(6):1937-42 3 RCT; “equal dose group” Higher PR with rec-hFSH (16.4% vs 12.3%) RR: 1.39 (95% CI: 1.00-1.96) Meta-analysis Rec-hFSH vs HP-uFSH in IUI 6 RCT; (N=713 pts; 1,581 cycles) Similar PR: 14.5% vs 14.9% with rec-FSH dose 50% lower (RR: 0.970; 95% CI: 0.68-1.37) Recombinantvs Urinary
  29. 29. Esteves, 29 68% 25% Folitropin alfa prefilled ready-to- use pen Needle-free reconstitution, conventional syringe Easy of use 58% Dosing mechanism 43% Less chance of error 26% Reasons Weiss N. RBMonline 2007;15:31-7 Level 2a • Allowed injections at home • Improved pts. satisfaction (QOL)
  30. 30. ; Bassett et al. Reprod Biomed Online 2005;10:169–177; Driebergen et al. Curr Med Res Opin 2003;19:41–46. Steelman-Pohley Bioassay High variability Rat ovary weight gain Esteves, 30 Gonadotropin injected sc 1x 3days Sacrifice day 4 and collect Ovaries Ovaries are weighed and data processed UrinaryProducts
  31. 31. Bassett et al. Reprod Biomed Online 2005;10:169–177; Driebergen et al. Curr Med Res Opin 2003;19:41–46. FbM: Novel analitycal method Protein content in solution by mass 1.6% batch-to-batch variability Follitropin alfa Esteves, 31 Size Exclusion High Performance Liquid Chromatography (SE- HPLC) 37.5 62.5 50 RecombinantProducts
  32. 32. hCG for Triggering Ovulation Urinary lyophilized vials (5,000-10,000 IU) IM Recombinant choriogonadotropin alfa pre-filled syringes (250 mcg ≅ 6,750 IU) SC Recommended Dose: 5,000 IU (or 250 mcg rec-hCG) ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; Tsoumpou et al. Reprod Biomed Online. 2009;19:52-8 Recombinantvs Urinary
  33. 33. Esteves, 33 When: 19–30 mm (~25 mm)1 2D TVUS Mean Diameter of Dominant Follicle Size 23-28 mm (988 IUIs with CC & Letrozole)2 ≥16 mm (620 IUIs with gonadotropins)3 hCG for Triggering Ovulation 1ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; 2Palatnik et al, Fertil Steril 2012;97:1089–94; 3da Silva et al. Eur J Obstet Gynecol Reprod Biol. 2012;164:156-60.
  34. 34. Clinical Efficacy LH Surge RCT N Odds-ratio Live birth 6 1,019 OR: 1.04 (95% CI 0.79 to 1.37) Miscarriage 7 1,106 OR: 0.69 (95% CI: 0.41 to 1.18) Severe OHSS 3 549 OR: 1.49 (95% CI: 0.54 to 4.1) Side Effects 3 374 OR: 0.39 (95% CI: 0.25 to 0.61) Level 1a Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719.Esteves, 34 Recombinantvs Urinary
  35. 35. Esteves, 35 Better safety, purity and potency with recombinants. Similar PRs using 50% less dose with rec-hFSH; Higher PR with the same dosage. SC self-injection and individualized stimulation using small dose adjustments with Pen injectors. Better tolerability with rec-hCG.
  36. 36. Do We Need to give LH in OI/IUI Cycles?
  37. 37. Steroidogenesis Steroidogenesis and Final Follicular Maturation Alviggi et al. Reprod Biomed Online 2006;12:221.
  38. 38. Balasch J, Fábreques F. Curr Opin Obstet Gynecol 2002, 14:265.Esteves, 38 • Normal androgen and estrogen biosynthesis • Normal follicular growth and development • Normal oocyte maturation Normal • Suppression of GC proliferation • Follicular atresia (non-dominant follicles) • Premature luteinization • Oocyte development compromised High • Insufficient androgen (and estrogen) synthesis • Follicular maturation impaired • Inadequate endometrial proliferation Low
  39. 39. WHO group I (LH levels <1.2 UI/L) Level 1b Esteves, 39 LHinOI/IUI Similar follicular development HMG vs FSH + rec-hLH; Higher cumulative PR after 3 cycles in FSH + rec-hLH (56% vs 23%; p=0.01) Carone et al., 2012 Higher follicular development pts. receiving LH (67% vs 20%; p=0.02) Shoham et al., 2008
  40. 40. Level 1b Esteves, 40 Clomiphene-resistant Fewer intermediate-sized follicles and OHSS in LH-supl. vs FSH group; similar ovulation rate. Plateau, 2006 Previous Excessive Response Higher monofollicular development in LH group (32% vs 13%; p=0.04). Hughes et al., 2005 IUI Higher monofollicular development in LH group w/o intermediate-size (42% vs 11%; p=0.03); Lower cycle cancellation due to risk of OHSS (-7% difference). Segnella et al., 2011 WHO group IILHinOI/IUI
  41. 41. Esteves, 41 • ~80% normogonadotropic women undergoing Ovarian Stimulation1,2 Normal • 15-20% of NG women have less sensitive ovaries • Older patients (≥35 years)3 • Poor responders4 • Slow/Hypo-responders5 • Deeply suppressed endogenous LH levels (hypo-hypo; endometriosis treated with GnRH-a)6 Low 1Tarlatzis et al. Hum Reprod 2006;21:90; 2Esteves et al. Reprod Biol Endocrinol 2009;7:111; 3Marrs et al. Reprod Biomed Online 2004;8:175;4Mochtar MH, Cochrane Database, 2007; 5Alviggi, et al. RBMOnline 2009; 6De Placido et al. Clin Endocrinol (Oxf) 2004;60:637 LHinOI/IUI
  42. 42. Reduced ovarian paracrine activity Hurwitz & Santoro 2004 LH receptor poly- morphisms Alviggi et al., 2006 Androgen secretory capacity reduced • Piltonen et al., 2003 Decreased numbers of functional LH receptors • Vihko et al. 1996 Reduced LH bioactivity while imnuno- reactivity unchanged • Mitchell et al. 1995; Marama et al 1984 Action of LH at the follicular level increases androgen production for its later aromatization to estrogens; May restore the follicular milieu with positive impact on oocyte quality. LHinOI/IUI
  43. 43. Mochtar et al, 2007 3 RCT (N=310) r-hFSH+rLH vs. r-hFSH alone* OPR OR 1.85 (95% CI: 1.10; 3.11) Bosdou et al, 2012 7 RCT (N= 603) r-hFSH+rLH vs. r-hFSH alone* 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) r-hFSH+rLH vs. r-hFSH alone CPR OR 1.37 (95% CI: 1.03; 1.83) *long GnRH-a protocol; OR=odds-ratio; RD=risk difference Mochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al, Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4.Esteves, 43
  44. 44. Esteves, 44 PCOS w/previous excessive response Add 75 IU LH activity from D1 (min. 7 days) Hypo-hypo Add 75 IU LH activity from D1 Poor responders 1:1 or 2:1 FSH/LH ratio from stimulation D1 Add 75 IU LH activity starting on D6 2 3 4 5 76 8 9 10 11 12 131 Ultrasound Menses 14 15 LHinOI/IUI
  45. 45. *derives from hCG Beta unit Carboxyl terminal segment Longer in hCG; higher receptor affinity Absent in LH and present in hCG (Longer Half-life) Purity (LH content) hCG content (IU/vial) LH activity (IU/vial) Specific activity (LH/mg protein) >99% 0 75 22,000 IU 3% ~70 75* ≥ 60 IU Adapted from ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20.Esteves, 45 Rec-hLH hMG-HP*
  46. 46. HMG: lower expression of LH/hCG receptor and other genes involved in steroids biosynthesis in GC Down-regulation due to constant ligand exposure of receptors to hCG Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. Biol Reprod 2004; 70:861-866; Grondal ML et al. Fertil Steril 2009; 91: 1820-1830. Esteves, 46 Level 2a
  47. 47. Esteves, 47 Mandatory in anovulation WHO I (~75 IU). WHO II CC-resistent and hyper-responders Higher monofollicular growth and Lower cancellation Diminished Ovarian Reserve May restore follicular millieu and optimize oocyte quality LH activity is different in HMG and rec-hLH May influence oocyte and corpus luteum competence.
  48. 48. Esteves, 48 Yes, we should individualize the stimulation protocol. CC can be your first line, but move to gonadotropins after 3 ovulatory cycles. Low dose step-up when using gonadotropins. Better safety and pt. tolerability Higher purity, potency and efficacy with recombinants. LH supplementation has a role in selected patients.

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