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Ovulation Induction for PCOS

Ovulation Induction for PCOS. Roy Homburg Barzilai Medical Center, Ashkelon, Israel and Homerton University Hospital, London. Clomiphene Questions. Spelling – clomiphene or clomifene? Give hCG at mid-cycle? Monitor CC cycles with ultrasound? When to stop?

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Ovulation Induction for PCOS

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  1. Ovulation Induction for PCOS Roy Homburg Barzilai Medical Center, Ashkelon, Israel and Homerton University Hospital, London

  2. Clomiphene Questions • Spelling – clomiphene or clomifene? • Give hCG at mid-cycle? • Monitor CC cycles with ultrasound? • When to stop? • Is CC still the best first-line treatment?

  3. Clomiphene n = 5268 Ovulation – 3858 (73%) Pregnancies – 1909 (36%) Miscarriage – 20% Multiple pregnancy rate – 10% Single live-birth rate – 25% Homburg, Hum Reprod, 2005

  4. Should we give hCG in CC cycles? Agarwal & Buyalos, 1995 No improvement in conception rates Deaton et al, 1997 No difference Viahos et al, 2005 hCG may be beneficial Kosmas et al, 2007 Meta-analysis FavouredhCG but nosignificant difference Brown et al, 2009, Cochrane review No difference NO NO Maybe Yes NO

  5. Should we monitor clomiphene cycles with ultrasound? Konig, Homburg et al, ESHRE, 2009

  6. Stopping… No ovulation with 150 mg/day 6 ovulatory cycles fail to yield a pregnancy Endometrial thickness <7 mm at ovulation Clomiphene Citrate

  7. Ovulation but no conception Anti-estrogen effects - Cervical mucus - Endometrium High LH Reasons for Clomiphene Failure • Failure to ovulate • FAI • BMI • LH • Insulin

  8. Aromatase Inhibitor Treatment: Day 3-7 of Cycle ER ER ER ER E2 FSH AI Casper & Mitwally

  9. Aromatase Inhibitors:Theoretical Advantages • Do not block estrogen receptors • No detrimental effect on endometrium or cervical mucus • Negative feedback mechanism not turned off—less chance of multiple follicular development

  10. ER ER E2 FSH Day 5 Clomiphene Citrate Treatment CC CC ER ER ER ER ER ER E2 FSH Day 10 Casper & Mitwally

  11. ER ER E2 FSH Day 10 Aromatase Inhibitor Treatment ER ER ER ER ER ER E2 FSH AI Day 5 Casper & Mitwally

  12. Aromatase InhibitorQuestions • Do they work? • Better than CC for first-line treatment? • Safety?

  13. Aromatase Inhibitors vs CC • Meta-analysis, 4 RCTs • Clear superiority of aromatase inhibitors in pregnancy rates (OR 2.0) and deliveries (OR 2.4) Polyzos et al, FertilSteril, 2008

  14. Letrozolevs CC • 911 newborns in 5 centers CC Letrozole Pregnancies 397 514 Congenital 19 (4.8%) 14 (2.7%) malformations Major malformations 12 (3%) 6 (1.2%) Total cardiac anomalies 1.8%0.2% Tulandi et al, 2006

  15. Aromatase Inhibitors • Letrozole 2.5-10 mg/day, n=1102 • Pregnancies 368 (33.4%) • Miscarriages 99 (26.9%) • Twins 2 (0.5%) • Fetal anomalies 1 (0.2%) Aghssa et al, 2007 (PCOS, edsAllahbadia, Agrawal)

  16. Gonadotropin Treatment: Why Is PCOS Different? Greater sensitivity to gonadotropin stimulation Therefore, multiple (“explosive”) follicular development

  17. Conventional Regimen With Gonadotropins 75 75 75 5 5 5 5 Days

  18. Results of Conventional Therapy:14 Series, 1966-1984, WHO I & II Conceived 46% (16-78) Multiple preg. 34% (22-50) Miscarriages 23% (12-30) Severe OHSS 4.6% (1.3-9.4) Hamilton-Fairley & Franks, 1990

  19. Problems With Conventional Gonadotropin Therapy for PCOS • Multiple follicle development - Multiple pregnancies - OHSS

  20. Low-Dose rFSH 100-150 IU 75-112.5 IU 50-75 IU 14 7 7 Days

  21. Low-Dose Gonadotropins:Summary of Results Patients - 1040, Cycles 2472 Updated from Homburg & Howles, 1999

  22. Start day 3 of menses 150 IU daily 125 IU daily 7 days 100 IU daily 7 days 75 IU daily 50 IU daily 7 days 7 days 7 days 1 8 15 22 29 35 Incremental DoseRise 50 IU starting dose; increments of 25 or 50 IU n=158 250 IU daily 200 IU daily 150 IU daily 7 days 100 IU daily 7 days 7 days 50 IU daily 7 days 7 days 1 8 15 22 29 36 Days of treatment FSH increments: Only allowed when no follicle 12 mm hCG: 1 follicle 18 mm Cancellation: 3 follicles 15 mm Leader et al, 2006

  23. P=0.009 P=0.009 Higher cancellation rate with 50 IU increments Duration and pregnancy rate - same Leader et al, 2006

  24. Only Minimal Dose Increment Needed • Incremental dose rise of 8.3 IU each week • N=25, PCOS, CC failures, 69 cycles 64.6 IU 58.3 IU 50 IU 7 14 21 Days Orvieto & Homburg, 2008

  25. Only Minimal Dose Increment Needed • Treatment days – 10.8 ± 4.3 • Total dose of FSH (IU) – 622 ± 286 • Cycle cancellation – 1/69 • 1 follicle only >16 mm – 82.6% • Clinical pregnancies – 20/25 (29% of cycles) • Live births – 16/25 patients • Twins – 1 • OHSS – 0 Orvieto & Homburg, 2008

  26. Low-Dose rFSH in Vietnamese Women With PCOS • N=183, PCOS, CC failure, normal or low BMI 75 IU Puregon 50 IU 25 IU 14 5 5 Days Lan et al, RBM Online, 2009

  27. Low-Dose rFSH in Vietnamese Women With PCOS Duration 15.9 (± 4.8) days Total FSH dose 484 (± 257) IU Ovulation rate 97% Mono-ovulation 62% Pregnancy – Clinical 35.5% – Ongoing 34% Multiple pregnancy 0 Mild OHSS 1 Lan et al, RBM Online, 2009

  28. Duration of Initial Dose: 14 or 7 Days? 14 days 7 days N=50, 107 cycles FSH required - Amps 22 17 - Days 17.4 13 1 large follicle/cycle 74% 60% E2 (pmol/L) 1659 2072 Pregnancies 10 (40%) 14 (56%) OHSS 0 0 Multiple pregnancies 0 2/14 Homburg, 1999

  29. Extended Study Multiple pregnancies 14 days 0/10 7 days 6/29 Homburg, 1999

  30. How long does it take? • With a starting dose of 75 IU FSH, unchanged for a minimum of 14 days, 90% will get to the criteria for hCGwithin 14 days Homburg & Howles, 1999

  31. Comparison of Results:CC vs FSH – 100 Women BUT……. Low-dose FSH has only been given to clomiphene failures! Homburg, Hum Reprod, 2005; Homburg & Howles, HR Update, 1999

  32. If we started with FSH…. Starting with CC rFSH Singleton live births 25 50 Multiples 3 3 Projection/100 women

  33. CC or low-dose FSH for first-line treatment? Treatment-naive PCOS Randomization CC Low-dose FSH 3 cycles Homburg et al, Hum Reprod, In press

  34. M-L. Hendriks T. Konig CB. Lambalk P. Hompes A. Martinez R. Rueda-Saenz T. D’Hooghe M. Welkenhuysen R. Anderson M. Rajkhowa A. Balen T. Child M. Davis M. Brincat

  35. Randomized N=302 FSH CC Allocated N=143 Allocated N=159 Drop-outs N=20 Drop-outs N=27 Analyzed N=123 Analyzed N=132 Per-protocol

  36. CC or low-dose FSH for first-line treatment? • CC • 1st cycle, 50 mg/day • If no ovulation, dose increased by 50 mg • in subsequent cycles 100 IU • FSH (Puregon) 75 IU 50 IU 1 7 14 21 hCG – when at least 1 follicle >17 mm.

  37. Results CC FSH P Patients per protocol 123 132 Cycles 310 288 Pregnancies 54 (44%) 76 (58%) 0.03 Miscarriage rates 5 (9%) 7 (9%) Multiple pregnancies 0 2 (3%) Pregnancies/cycle 17% 26% 0.008 Live births 49 (39%) 69 (52%) 0.04 Homburg et al, Hum Reprod, In press

  38. Cumulative Live-Birth Rates Cycles 1 2 3 After 3 cycles - CC 36%, FSH 47% (P=0.03)

  39. Summary • Clear superiority of low-dose FSH over CC for first-line treatment of anovulatory PCOS • ×2 chance of clinical pregnancy in 1st cycle • 30% vs 14.6% (P=0.003) • After 2nd cycle, 50.7% vs 32.5% (P=0.003) • Shorter treatment to pregnancy time Homburg et al, Hum Reprod, In press

  40. Can low-dose FSH replace CC? CC FSH + Ease of administration + Cost = Monitoring = Treatment - pregnancy time + Chances for pregnancy + Single live birth +

  41. Conclusions • Differences in cost and convenience may limit the choice of low-dose FSH as first-line treatment But…. • This study provides “real-life” results to enable judgment of this option, according to individual countries and circumstances

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