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

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  • 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. 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. 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. Esteves, 4 Top Problems Concerning Ovarian Stimulation in OI/IUI and How to Solve Them What is in it for me?
  • 5. Esteves, 5 Do We Need to Individualize the Protocol per Patient?
  • 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.  Age, BMI, Race  Genetic profile  Cause  Duration  Health  Nutrition Esteves, 7
  • 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. 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. Esteves, 10 Evidence Level 1a Biomarkers
  • 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. 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. Esteves, 13 Clomiphene Citrate for How Many Cycles and How?
  • 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. 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. 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. 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. Esteves, 18 How to Use Injectable Gonadotropins and What to Expect?
  • 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. 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. 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. 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. 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. 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. Recombinant or Urinary Gonadotropins?
  • 26. Esteves, 26 Up to 70% impurities
  • 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. 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. 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. ; 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. 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. 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. 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. 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. 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. Do We Need to give LH in OI/IUI Cycles?
  • 37. Steroidogenesis Steroidogenesis and Final Follicular Maturation Alviggi et al. Reprod Biomed Online 2006;12:221.
  • 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. 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. 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. 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. 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. 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. 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. *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. 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. 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. 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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