A Life of PCOS Roy Homburg Barzili Medical

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

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

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. Polly Sistik o/e Obese – BMI 31. 5 Abdo circ. 92 cm Acne face and back Mild hirsutism

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

symptoms OBESITY hormones ultrasound INSULIN after Dewailly, 2003

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

symptoms OBESITY hormones ultrasound WEIGHT LOSS INSULIN after Dewailly, 2003

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

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

72%

Polly Sistik – age 25 • Married. • Trying to conceive for 6 months. • 4 periods in the last year. • Examinations • Treatment

Multiple Choice • • Weight loss Clomiphene citrate (CC) Aromatase inhibitors Insulin lowering medications • Low dose FSH • Laparoscopic ovarian drilling • IVF/IVM

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

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

Should we monitor clomiphene cycles with ultrasound? With U/S + h. CG No U/S or h. CG n 105 150 Cumulative pregnancy rate 48% 34. 7% Deliveries 35. 6% 26. 7% Multiple pregnancies 0 1 Konig, Homburg et al, ESHRE, 2009

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

Clomiphene Citrate Treatment CC ER ER E 2 FSH Day 5

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 < 7 mm • Not dose related and recurs in repeat cycles (Homburg et al, 1999)

Aromatase Inhibitor Treatment: Day 3 -7 of Cycle ER ER E 2 FSH AI 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 ER E 2 FSH Day 5 E 2 FSH Day 10 Casper & Mitwally

Aromatase Inhibitor Treatment ER ER E 2 FSH AI Day 5 Day 10 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 • 911 newborns in 5 centers CC Letrozole Pregnancies 397 Congenital 19 (4. 8%) malformations Major malformations 12 (3%) Total cardiac anomalies 1. 8% 514 14 (2. 7%) 6 (1. 2%) 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)

Metformin for ovulation induction?

Live birth rates CC 22. 5% Metformin 7. 2% CC+metformin 26. 8% Legro et al, NEJM, 2007 15. 4% 7. 9% 21. 1% Zain et al, Fertil Steril, 2009

Insulin-sensitising drugs for women with PCOS, oligo/amenorrhea and subfertility • Tang 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.

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

CONVENTIONAL REGIMEN WITH GONADOTROPHINS 75 75 75 5 DAYS 5

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

Low dose rec-FSH 100 -150 IU 50 -75 IU 75 -112. 5 IU 14 7 Days 7

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

Low-dose FSH • 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.

Duration of Initial Dose: 14 or 7 Days? N=50, 107 cycles 14 days 7 days FSH required - Amps - Days 22 17. 4 17 13 1 large follicle/cycle 74% 60% E 2 (pmol/L) 1659 Pregnancies 10 (40%) OHSS 0 Multiple pregnancies 0 2072 14 (56%) 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 h. CG within 14 days Homburg & Howles, 1999

Factors affecting outcome of LOD for PCOS CCR: 54% after 12 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

Maternal PCOS in pregnancy Increased prevalence of: • • Early pregnancy loss Gestational diabetes Pregnancy induced hypertension SGA babies

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

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

Sleep Disorders in 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

PCOS - Late sequelae Hyperinsulinemia / hyperandrogenism / obesity • Diabetes mellitus x 7 • Hypertension x 4 • Low HDL/high LDL *All are risk factors for cardiovascular disease and CVA

Polly Gone