1. A Life of PCOS Roy Homburg Barzili Medical Centre, Ashkelon and Maccabi Medical Services, Israel Homerton Fertility Centre, London

2. PCOS – A typical case history A life in 25 minutes of ……….. Polly Sistik

3. Age 16, schoolgirl. c/o irregular periods, acne, hirsutism. All symptoms started age 13.5 when had first period, since then 3-4 periods/year. o/e Obese – BMI 31.5 Abdo circ. 92cm Acne face and back Mild hirsutism

4. PCOS revised diagnostic criteria ~ 2003 Rotterdam consensus ~ 2 out of 3 criteria required Oligo- and/or anovulation Hyperandrogenism (clinical and/or Hyperandrogenism (clinical and/or biochemical) biochemical) Polycystic ovaries Polycystic ovaries Exclusion of other aetiologies Exclusion of other aetiologies

5. ultra- sound hormones symptoms OBESITY INSULIN after Dewailly, 2003

8. Treatment aims & options Life-style changesLife-style changes Anti-androgens / OC pill Anti-androgens / OC pill ? metformin? metformin Cure acne and hirsutism Regulate menstruation

9. ultra- sound hormones symptoms OBESITY INSULIN WEIGHT LOSS after Dewailly, 2003

11. HIRSUTISM/ACNE TREATMENT - Cyproterone acetate + ethinyl estradiol - Cyproterone acetate + ethinyl estradiol - Drosperinone + ethinyl estradiol - Drosperinone + ethinyl estradiol - Contraceptive pills Cosmetic treatment - Cosmetic treatment Metformin not recommended as first line treatment - Metformin not recommended as first line treatment

12. Polly Sistik – age 24 Engaged to be married.Engaged to be married. BMI now 28BMI now 28 Amenorrhea for the last 6 months.Amenorrhea for the last 6 months. Wants to know her chances of conceiving.Wants to know her chances of conceiving.

13. 72%

14. Polly Sistik – age 25 Married.Married. Trying to conceive for 6 months.Trying to conceive for 6 months. 4 periods in the last year.4 periods in the last year. ExaminationsExaminations TreatmentTreatment

15. Multiple Choice Weight lossWeight loss Clomiphene citrate (CC)Clomiphene citrate (CC) Aromatase inhibitorsAromatase inhibitors Insulin lowering medicationsInsulin lowering medications Low dose FSHLow dose FSH Laparoscopic ovarian drillingLaparoscopic ovarian drilling IVF/IVMIVF/IVM

16. Clomiphene Homburg, Hum Reprod, 2005 n = 5268 patients n = 5268 patients Ovulation - 3858 (73%) Ovulation - 3858 (73%) Pregnancies - 1909 (36%) Pregnancies - 1909 (36%) Miscarriage - 827 (20%) Miscarriage - 827 (20%) Multiple pregnancy rate- 8% Multiple pregnancy rate- 8% Single live-birth rate – 25% Single live-birth rate – 25%

17. 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

18. Should we monitor clomiphene cycles with ultrasound? Konig, Homburg et al, ESHRE, 2009 No U/S or hCG With U/S + hCG 150105n 34.7%48% Cumulative pregnancy rate 26.7%35.6%Deliveries 10 Multiple pregnancies

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

20. Clomiphene Citrate Treatment ER ER E2 FSH Day 5 CCER ER

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

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

23. 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

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

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

26. 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?

27. 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

28. Letrozole vs CC 911 newborns in 5 centers911 newborns in 5 centers CC Letrozole Pregnancies 397514 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

29. Aromatase Inhibitors Letrozole 2.5-10 mg/day, n=1102Letrozole 2.5-10 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)

30. Metformin for ovulation induction?

31. Live birth rates CC Metformin CC+metformin 22.5% 7.2% 26.8% Legro et al, NEJM, 2007 Legro et al, NEJM, 2007 15.4% 7.9% 21.1% Zain et al, Fertil Steril, 2009 Zain et al, Fertil Steril, 2009

32. Insulin-sensitising drugs for women with PCOS, oligo/amenorrhea and subfertility Tang et al. Cochrane Database, 2009Tang et al. Cochrane Database, 2009 There is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited.

33. Maitake mushroom Chen JT et al, J Altern Complement Med, 2010 Maitake mushroom extract improves insulin resistance.Maitake mushroom extract improves insulin resistance. Capable of inducing ovulation in PCOS (77%)Capable of inducing ovulation in PCOS (77%) 6/8 CC resistant ovulated with CC+Maitake6/8 CC resistant ovulated with CC+Maitake

34. CONVENTIONAL REGIMEN WITH GONADOTROPHINS 555 DAYS 75 75 75 5

35. Results of Conventional Therapy 14 series, 1966-1984, WHO I & II Hamilton-Fairley & Franks, 1990

36. Low dose rec-FSH 75-112.5 IU 50-75 IU 100-150 IU 1477 Days

37. Low dose gonadotropins Summary of results Patients - 841, Cycles 1556 Updated from Homburg & Howles, 1999

38. Low-dose FSH Only a low-dose protocol should be used for ovulation induction in PCOS.Only a low-dose protocol should be used for ovulation induction in PCOS. Small starting and incremental dose increases recommended with no dose change for 14 days.Small starting and incremental dose increases recommended with no dose change for 14 days.

39. Duration of Initial Dose: 14 or 7 Days? 14 days 7 days 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 N=50, 107 cycles Homburg, 1999

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

41. 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

45. Factors affecting outcome of LOD for PCOS CCR: 54% after 12 months 75% after 30 months 75% after 30 months CC and low-dose FSH may be added if no ovulation after 3 months One-off treatment with low multiple pregnancy rate and no OHSS Best if < 3 years infertility, thin and high LH

46. Maternal PCOS in pregnancy Increased prevalence of: Early pregnancy lossEarly pregnancy loss Gestational diabetesGestational diabetes Pregnancy induced hypertensionPregnancy induced hypertension SGA babiesSGA babies

47. Polly Sistik – age 44 Happy mother with 2 kids.Happy mother with 2 kids. The futureThe future

48. Effect of aging on PCOS Women with PCOS gain regular menstrual cycles when aging Menstrual cycle restored in those with a smaller follicle count Elting et al, 2000, 2003

49. Sleep Disorders in PCOS PCOS n=53, controls n=452 Risk of Sleep Apnea in PCOS Odds Ratio 29 (95% CI 5-294) Adjusted for differences in BMI Vgontzas et al, JCEM, 2001

50. PCOS - Late sequelae Hyperinsulinemia / hyperandrogenism / obesity Diabetes mellitus x7Diabetes mellitus x7 Hypertension x4Hypertension x4 Low HDL/high LDLLow HDL/high LDL *All are risk factors for cardiovascular disease and CVA

52. Polly Gone