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? Is CC still the best first-line treatment?

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

Should we give hCG in CC cycles? NO Maybe Yes 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 Favoured hCG but no significant difference Brown et al, 2009, Cochrane review

Should we monitor clomiphene cycles with ultrasound? No U/S or hCG With U/S + hCG 150 105 n 34.7% 48% Cumulative pregnancy rate 26.7% 35.6% Deliveries 1 Multiple pregnancies Konig, Homburg et al, ESHRE, 2009

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

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

Aromatase Inhibitor Treatment: Day 3-7 of Cycle ER ER ER ER E2 FSH AI Figure 1. Administration of an aromatase inhibitor (AI) from days 3 to 7 results in suppression of ovarian estradiol secretion and reduction in estrogen negative feedback at the pituitary and mediobasal hypothalamus. Increased FSH secretion from the anterior pituitary results in stimulation of multiple ovarian follicle growth. Later in the follicular phase, the effect of the AI is reduced and estradiol levels increase as a result of follicular growth. Because AIs do not affect estrogen receptors (ER) centrally, the increased estradiol levels result in normal negative feedback on FSH secretion and follicles less than dominant follicle size undergo atresia, with resultant monofollicular ovulation in most cases. Casper & Mitwally

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

Clomiphene Citrate Treatment CC CC ER E2 FSH Day 5 ER ER ER ER ER ER E2 FSH Figure 2. Administration of clomiphene citrate (CC) from days 3 to 7 results in estrogen receptor (ER) depletion at the level of the pituitary and mediobasal hypothalamus. As a result, estrogen negative feedback centrally is interrupted and FSH secretion increases from the anterior pituitary leading to multiple follicular growth. By the late follicular phase, because of the long tissue retention of CC, there continues to be ER depletion centrally and increased estradiol secretion from the ovary is not capable of normal negative feedback on FSH. The result is multiple dominant follicle growth and multiple ovulation. Day 10 Casper & Mitwally

Aromatase Inhibitor Treatment ER ER E2 FSH Day 10 ER ER ER ER ER E2 FSH AI Figure 1. Administration of an aromatase inhibitor (AI) from days 3 to 7 results in suppression of ovarian estradiol secretion and reduction in estrogen negative feedback at the pituitary and mediobasal hypothalamus. Increased FSH secretion from the anterior pituitary results in stimulation of multiple ovarian follicle growth. Later in the follicular phase, the effect of the AI is reduced and estradiol levels increase as a result of follicular growth. Because AIs do not affect estrogen receptors (ER) centrally, the increased estradiol levels result in normal negative feedback on FSH secretion and follicles less than dominant follicle size undergo atresia, with resultant monofollicular ovulation in most cases. Day 5 Casper & Mitwally

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

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, Fertil Steril, 2008

Letrozole vs CC CC Letrozole Pregnancies 397 514 911 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

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, eds Allahbadia, Agrawal)

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

Conventional Regimen With Gonadotropins 75 75 75 5 5 5 5 Days

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

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

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

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

50 IU starting dose; increments of 25 or 50 IU Incremental Dose Rise 50 IU starting dose; increments of 25 or 50 IU n=158 1 8 15 22 29 35 150 IU daily 100 IU daily 125 IU daily 75 IU daily 7 days 50 IU daily Start day 3 of menses 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

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

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

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

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

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

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

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

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 days Homburg & Howles, 1999

Comparison of Results: CC vs FSH – 100 Women 34 25 Single live births 2 3 Twins BUT……. Low-dose FSH has only been given to clomiphene failures! Homburg, Hum Reprod, 2005; Homburg & Howles, HR Update, 1999

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

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

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

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

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

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

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

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

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

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