PCOS What s new in Diagnosis & Treatment?

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Abigayle Goodwin
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1 PCOS What s new in Diagnosis & Treatment? Roy Homburg Maccabi Medical Services and Barzilai Medical Centre, Ashkelon, Israel. Antalya, October, 2009

2 PCOS diagnosis NIH criteria - Hyperandrogenism PCOS Chronic anovulation

3 The Rotterdam ESHRE/ASRM Consensus Group Revised 2003 Diagnostic Criteria for PCOS 2 out of 3 criteria required Oligo- and/or anovulation i.e. oligomenorrhoea or amenorrhoea Hyperandrogenism - clinical and/or biochemical Polycystic ovaries Exclusion of other aetiologies Hum Reprod 2004; 19: Fertil Steril, 2004; 81:

4 1 PCOS Hyperandrogenemia PCO Oligo/anovulation (WHO 2 type)

5 ESHRE/ASRM 2003 consensus broader than NIH 1990 consensus - Increases population base by ~ 20% - Includes more women of normal weight Belosi et al Human Reprod 2006; 21: Concern about negative labelling of women with milder phenotype and uncertainty of health risk - Greater heterogeneity limits finding the unifying diagnostic test or gene. Azziz, JCEM 2006; 91: 781

6 Rotterdam additions Oligo/anovulation + Hyperandrogenism + PCO + + n=165 vs Controls (n=284) LH, insulin, waist circumference, dyslipidemia FSH, SHBG Norman et al, 1995; Dewailly et al 2006 Clearly distinguishable from controls. Welt et al, 2006 Part of the spectrum of PCOS Barber et al, 2007

7 Rotterdam additions Oligo/anovulation + Hyperandrogenism + PCO + + n=165 vs O/A+PCO + HA (n=839) No difference in I, SHBG, gonadotrophins, similar phenotypic features. Milder endocrine & metabolic features Norman et al, 1995; Welt et al, 2006; Dewailly et al 2006 Part of the spectrum of PCOS Barber et al, 2007

8 Rotterdam additions Oligo/anovulation + Hyperandrogenism + PCO + + n=50 vs PCO + HA n=204 Insulin lower in ovulatory, otherwise, very similar Norman et al, 1995, Welt et al, 2006 Milder metabolic abnormalities Dewailly et al 2006 Less IR & HA but have dyslipidemia and elevated risk markers in 38% vs 45% In ovulators: A & I, 17OHP response to GnRHa all raised Carmina et al, 2005; Chang, 2000

9 Polycystic ovaries alone Behave exactly like full-blown PCOS when stimulated. AMH a possible new marker for PCO.

10 Rotterdam criteria: Recognize the broad spectrum of the syndrome Acknowledges that clinical & biochemical features may vary in time. Arguments against:

11 Clomiphene citrate

12 Clomiphene questions? Give hcg at mid-cycle?? Monitor CC cycles with ultrasound?? Is CC still the best first-line treatment?

13 ? Give hcg in CC cycles? Agrawal & Buyalos, 1995 Routine addition of hcg at mid-cycle does not improve conception rates

14 Should we monitor clomiphene cycles with ultrasound? Konig, Homburg et al, ESHRE, cycles of CC Group 1: N=105, with U/S monitoring + hcg Group 2: N=150, no U/S monitoring, no hcg

15 Should we monitor clomiphene cycles with ultrasound? Konig, Homburg et al, ESHRE, 2009 With U/S + hcg No U/S or hcg 48% Cumulative conception rate 34.7% 35.6% Deliveries 26.7% 0 Multiple pregnancies 1

16 Anti-estrogen effect on endometrium Endometrial thinning in 15-50% (Gonen &Casper, 1990;Dickey et al, 1993) Causes ER downregulation and depletion. Suppresses pinopode formation (Creus et al, 2003) No pregnancies when endometrial thickness at midcycle < 7mm Not dose related and recurs in repeat cycles (Homburg et al, 1999)

17 Clomiphene Homburg, Hum Reprod, 2005 n = 5268 patients Ovulation (73%) Pregnancies (36%) Miscarriage (20.4%) Multiple pregnancy rate - 10%

18 Twin pregnancy rate with clomiphene Konig, Homburg et al, ESHRE, pregnancies achieved with clomiphene 1 twin pregnancy only!!

19 Aromatase Inhibitor Treatment - day 3-7 of cycle ER ER ER FSH E2 AI Day 5 Casper & Mitwally

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

21 Aromatase inhibitors Aghssa et al, 2007 (PCOS, eds Allahbadia,Agrawal) Letrozole mg/day, n=1102 Pregnancies 368 (33.4%) miscarriages 99 (27.3%) twins 2 (0.5%) fetal anomalies 1 (0.2%)

22 Metformin + Letrozole or + CC Sohrabvand et al, 2006 N=59 given metformin for 6-8 weeks Letrozole 2.5mg CC 100mg

23 Metformin + Letrozole or + CC 40 Full-term pregnancies in letrozole - metformin group vs clomiphene citrate - metformin group 34.5 % % 0 Letrozole group Clomiphene citrate group Sohrabvand et al, 2006

24 Letrozole induction of ovulation in women with CC resistant PCOS (Elnashar et al, 2006) Ovulation- 24/44 cases (54.6%) Clinical pregnancy- 6/44 cases (25%of ovulators)

25 Resistance to CC 100mg Begum et al, 2008 N=64 PCOS resistant to 100mg CC Letrozole 7.5mg CC 150mg

26 Resistance to CC 100mg Letrozole CC 150mg Ovulation 20 (62.5%) 12 (37.50%) E2 dhcg (pg/ml) Endometrial thickness on dhcg mm 9.03 mm Pregnancies 13 (40.6%) 6 (18.75%) Begum et al, 2008

27 Treatment scheme for anovulatory PCOS Clomiphene citrate mg/day for 5 days Ovulation x6 No ovulation on 150mg/day No pregnancy Low-dose FSH

28 Clomifene or low-dose FSH for the first-line treatment of anovulatory PCOS. A randomized, prospective, study The COFFI group (10 centres in 7 countries)

29 A.Martinez R.Rueda-Saenz M-L.Hendriks T.Konig CB.Lambalk P.Hompes T.D Hooghe M.Welkenhuysen A.Balen T.Child R.Anderson M.Rajkhowa M.Davis M.Brincat

30 Clomifene Homburg, Hum Reprod, 2005 n = 5268 patients Ovulation (73%) Pregnancies (36%) Miscarriage - 20% Multiple pregnancy rate - 10% Single live-birth rate 25%

31 Low dose gonadotrophins IU IU IU Days

32 Low Dose Gonadotropins Summary of Results Patients - 841, Cycles 1556 Pregnancies 320 (40%) Fecundity/cycle 20% Uniovulation 70% OHSS 0.14% Multiple pregs. 5.7% Updated from Homburg & Howles, 1999

33 Comparison of results CC vs FSH 100 women CC FSH 25 Single live births 34 3 Twins 2 BUT. Low dose FSH has only been given to clomiphene failures!

34 If we started with FSH. Starting with CC rec-fsh Singleton live births Multiples 3 3 Projection / 100 women

35 CC or low-dose FSH for first-line treatment? Treatment-naïve PCOS Randomization CC Low-dose FSH 3 cycles

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

37 Power calculation Assuming an absolute difference of 15% in pregnancy rates in favour of FSH, 80% power and P<0.05, 150 subjects needed in each arm.

38 CC Randomized N=268 FSH Allocated N=130 Allocated N=138 Drop-outs N=18 Drop-outs N=24 Analysed N=112 Per-protocol Analysed N=114

39 Results CC FSH P Patients per protocol Cycles Pregnancies 46 (41%) 64 (56%) 0.02 Miscarriage rates 15% 12.5% Multiple pregnancies 0 2 (3%)

40 Results CC FSH P Pregnancies/cycle 16% 26% Live births 40 (35.7%) 56 (49%) 0.03

41 Cumulative conception rates 80% 70% 60% 50% 40% 30% 20% 10% 0% Cycle CC FSH After 3 cycles - CC 48%, FSH 72%

42 Cumulative live-birth rates 70% 60% 50% 40% 30% CC FSH 20% 10% 0% Cycle After 3 cycles - CC 42%, FSH 62%

43 Of pregnancies achieved.. With CC 46 With FSH 64 (P=0.02) Cycle % 54.6% (P=0.003) Cycle % 90% (P=0.005)

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

45 CC vs low-dose FSH as firstline therapy for PCOS Lopez et al, 2004 Single centre RCT Subjects, CC 38, FSH - 38 Cycles, CC 104, FSH 91 Pregnancy rates RR 1.78 ( ) Live birth rates RR 1.83 ( ) in favour of FSH

46 Summary Clear superiority of low-dose FSH over CC for first line treatment of anovulatory PCOS. Absolute difference - of 24% in CCR over 3 cycles. of 10% in pregnancy rates/cycle. of 20% in cumulative live birth rates. More than x2 chance of conception in 1 st cycle. Shorter treatment to pregnancy time.

47 Conclusions Differences in cost and convenience may limit the choice of low-dose FSH as firstline treatment. But. This study provides real-life results to enable judgment of this option, according to individual countries and circumstances.

Richard S. Legro, M.D., Penn State College of Medicine, Dept of Ob/Gyn, Hershey, PA, USA

What have we learned from Multi-Clinical Trials in PCOS: Focus on Infertility Richard S. Legro, M.D., Penn State College of Medicine, Dept of Ob/Gyn, Hershey, PA, USA Disclosures Consultant: Euroscreen,