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

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Presentation on theme: "Ovulation Induction for PCOS Roy Homburg Barzilai Medical Center, Ashkelon, Israel Barzilai Medical Center, Ashkelon, Israel and Homerton University Hospital,"— Presentation transcript:

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

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

3 Clomiphene n = 5268 n = 5268 Ovulation – 3858 (73%) Ovulation – 3858 (73%) Pregnancies – 1909 (36%) Pregnancies – 1909 (36%) Miscarriage – 20% Miscarriage – 20% Multiple pregnancy rate – 10% Multiple pregnancy rate – 10% Single live-birth rate – 25% 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 No improvement in conception rates Deaton et al, 1997 No difference No difference Viahos et al, 2005 hCG may be beneficial hCG may be beneficial Kosmas et al, 2007 Meta-analysis Favoured hCG but no significant difference Favoured hCG but no significant difference Brown et al, 2009, Cochrane review No difference No difference NO Maybe Yes NO

5 Should we monitor clomiphene cycles with ultrasound? Konig, Homburg et al, ESHRE, 2009 No U/S or hCG With U/S + hCG n 34.7%48% Cumulative pregnancy rate 26.7%35.6%Deliveries 10 Multiple pregnancies

6 Clomiphene Citrate Clomiphene Citrate Stopping… No ovulation with 150 mg/dayNo ovulation with 150 mg/day 6 ovulatory cycles fail to yield a pregnancy6 ovulatory cycles fail to yield a pregnancy Endometrial thickness <7 mm at ovulationEndometrial thickness <7 mm at ovulation

7 Reasons for Clomiphene Failure Reasons for Clomiphene Failure Ovulation but no conception Anti-estrogen effects - Cervical mucus - Endometrium High LH Failure to ovulate FAIFAI BMIBMI LHLH InsulinInsulin Failure to ovulate FAIFAI BMIBMI LHLH InsulinInsulin

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

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

10 ERERE2 FSH Day 5 Clomiphene Citrate Treatment ER ER Day 10 FSH E2 CC CC ER ER ER ER Casper & Mitwally

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

12 Aromatase Inhibitor Questions Do they work?Do they work? Better than CC for first-line treatment?Better than CC for first-line treatment? Safety?Safety?

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

14 Letrozole vs CC 911 newborns in 5 centers911 newborns in 5 centers CC Letrozole Pregnancies 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 mg/day, n=1102Letrozole mg/day, n=1102 Pregnancies 368 (33.4%)Pregnancies 368 (33.4%) –Miscarriages 99 (26.9%) –Twins 2 (0.5%) –Fetal anomalies 1 (0.2%) Aghssa et al, 2007 (PCOS, eds Allahbadia, Agrawal)

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

17 Conventional Regimen With Gonadotropins 555 Days

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

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

20 Low-Dose rFSH IU IU IU 1477 Days

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

22 Incremental Dose Rise 50 IU starting dose; increments of 25 or 50 IU n= IU daily 100 IU daily 125 IU daily 75 IU daily 7 days 50 IU daily 7 days Start day 3 of menses menses Days of treatment IU daily 150 IU daily 7 days 200 IU daily 7 days 100 IU daily 7 days 50 IU daily 7 days 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 Leader et al, 2006 Higher cancellation rate with 50 IU increments Duration and pregnancy rate - same

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

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

26 Low-Dose rFSH in Vietnamese Women With PCOS N=183, PCOS, CC failure, normal or low BMIN=183, PCOS, CC failure, normal or low BMI 25 IU 50 IU 75 IU Days Days Puregon 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% – 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 FSH required - Amps Days large follicle/cycle 74% 60% E2 (pmol/L) Pregnancies 10 (40%) 14 (56%) OHSS 0 0 Multiple pregnancies 0 2/14 N=50, 107 cycles Homburg, 1999

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

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 hCG within 14 daysWith a starting dose of 75 IU FSH, unchanged for a minimum of 14 days, 90% will get to the criteria for hCG within 14 days Homburg & Howles, 1999

31 Comparison of Results: CC vs FSH – 100 Women BUT……. Low-dose FSH has only been given to Low-dose FSH has only been given to clomiphene failures! clomiphene failures! Homburg, Hum Reprod, 2005; Homburg & Howles, HR Update, 1999 FSHCC 3425 Single live births 23Twins

32 If we started with FSH…. Starting with CCrFSH Singleton live births2550 Multiples33 Projection/100 women

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

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

35 RandomizedN=302 AllocatedN=143 AllocatedN=159 Drop-outsN=20 AnalyzedN=132AnalyzedN=123 CC FSH Per-protocol Drop-outsN=27

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 in subsequent cycles FSH (Puregon) FSH (Puregon) 50 IU 100 IU 75 IU hCG – when at least 1 follicle >17 mm.

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

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

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

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

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

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