Polycystic ovarian syndrome – an update Dr. Eeson Sinthamoney MD(Malaysia), MRCOG(London), DFFP(UK) Fellowship in Reproductive Medicine (Singapore/UK) Consultant Obstetrician, Gynaecologist and Fertility Specialist Pantai Hospital Kuala Lumpur

Is polycystic ovary syndrome (PCOS) an ancient disorder? Or is it a disorder of recent development, the consequence of rising metabolic stress in an increasingly obese society? And if it is ancient, why has it persisted despite its reproductive disadvantage?

From the ancient scripts….. “But those women whose menstruation is less than three days or is meagre, are robust, with a healthy complexion and a masculine appearance, yet they are not concerned about bearing children nor do they become pregnant” Diseases of women 1.6 – Hippocrates (460-377B.C)

An ancient disorder? Observations suggest PCOS is an ancient disorder, arising from ancestral gene variants selected and maintained over the past 10,000 years Such ancient genes likely transmitted trans-generationally through offspring conceived between fertile carrier males and sub-fertile affected females; The reduced fecundity of affected women potentially would have been offset, at least in part, by their greater sturdiness and improved energy utilization, a rearing advantage for their children and kin, and a reduction in the risk of maternal mortality

Is anything new? PCO versus PCOS Is metformin useful? Role of ovarian diathermy / drilling Is weight loss useful? Fertility treatment and OHSS risk

Revised diagnostic criteria for PCOS 1999 criteria (both 1 and 2) 1. Chronic anovulation 2. Clinical and/or biochemical signs of hyperandrogenism, and exclusion of other aetiologies Revised 2003 criteria (2 out of 3) 1. Oligo- and/or anovulation 2. Clinical and/or biochemical signs of hyperandrogenism 3. Polycystic ovaries and exclusion of other aetiologies (congenital adrenal hyperplasias, androgen-secreting tumours, Cushing's syndrome) PCO ,IR

Pathophysiology of PCOS Insulin interferes with follicular development and may affect LH sec Pathophysiology of PCOS IGF – 1 and II – important regulators of ovarian follicular maturation and steroidogenesis Prolonged exp. to androgens causes foll. suppression and stromal hypertrophy

PCO versus PCOS Up to 23% of normal volunteer women meet the sonographic criteria for polycystic ovaries Ovarian morphological changes considered a sign and not a disease Diagnosis of disease based on criteria However: Metabolic similarities including degree of IR Significantly increased risk of OHSS in IVF

Insulin resistance Although not included in diagnostic criteria, IR is regarded as a major / pivotal pathophysiological feature 40-70% of women with PCOS have IR Defined as reduced glucose response to a given amount of insulin Common in obese and non-obese PCOS Obese PCOS more IR than non-obese PCOS Indications that IR in PCOS independent of obesity

Measuring IR No standard definition and assessment A unique defect in insulin action and secretion Possible mechanisms: Peripheral target tissue resistance Decreased hepatic clearance Increased pancreatic sensitivity The pathophysiology of polycystic ovary syndrome. Tsilchorozidou T et al. Clinical Endocrinology (2004)60,1-17

Metformin Does metformin (or other insulin sensitizing agents) improve clinical features – hirsuitism and acne? reproductive outcomes – OI, ART? Does metformin help with weight loss?

Improves insulin sensitivity Metformin Reduces hepatic glucose production Stimulates glycolysis in liver Increases peripheral glucose uptake by the liver, skeletal muscle and adipose tissue Reduces lipolysis in adipose tissue Inhibits intestinal glucose absorption Improves insulin sensitivity

Metformin Menstrual irregularity: Improves menstrual cyclicity in normal weight and over-weight PCOS patients Hirsuitism: metformin improves hirsuitism in normal weight PCOS patients In obese patients – long term (2 years) therapy may be helpful Hirsutism and acne in polycystic ovary syndrome. Archer JS et al. Best practice and research clinical obstetrics and gynaecology 18(5) 2004

Metformin in ovulation induction Metformin is beneficial in improving clinical pregnancy rates and ovulation rates No evidence it improves live birth rates (either alone, in comparison or combination with CC) Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Tang T et al. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003053.

Metformin in ART In Non-obese PCOS patient (BMI < 28) undergoing IVF/ICSI, metformin treatment (2000mg/day) for  12 weeks prior to and during long protocol Significantly increased pregnancy and LBRs compared to placebo Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind, multi-centre study. Kjøtrød SB et al. Hum Reprod. 2011 May 23.

Metformin in ART In obese patients

Metformin in ART In women with PCO morphology but no other features of PCOS Appears to be no benefit of metformin co-treatment before and during IVF in women with PCO without any other features of PCOS Do women with ovaries of polycystic morphology without any other features of PCOS benefit from short-term metformin co-treatment during IVF? A double-blind, placebo-controlled, randomized trial. Swanton A, et al. Hum Reprod. 2011 May 27.

Metformin and infertility - summary For OI In IVF/ICSI (non-obese patients) In IVF/ICSI (obese patients) In women with PCO appearance only

Metformin and weight loss Treatment with metformin showed a statistically significant decrease in BMI compared with placebo Some indication of greater effect with high-dose metformin (>1500 mg/day) and longer duration of therapy (>8 weeks). A structured lifestyle modification programme to achieve weight loss should still be the first line treatment in obese women with or without PCOS. Adequately powered RCTs are required. Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese: systematic review and meta-analysis. Nieuwenhuis-Ruifrok AE et al. Hum Reprod Update. 2009 Jan-Feb;15(1):57-68.

Ovarian drilling Number of punctures? Mechanism of action? Laparoscopic versus newer options?

LOD – first line? When compared to CC as a method of OI in PCOS, LOD is not superior to CC Therefore, what is the role if any of LOD? Randomized controlled trial comparing laparoscopic ovarian diathermy with clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary syndrome. Amer SA. Hum Reprod. 2009 Jan;24(1):219-25 ,

LOD – in ‘CC resistant’ patients When compared to Gn for OI, pregnancy rates are comparable Avoids risk of OHSS and multiple pregnancy More cost effective (?) and better tolerated Improves ovarian response to CC in at least 1/3 of CC resistant patients Long term – increases chances of second pregnancy Side effects – no evidence Ovarian drilling for surgical treatment of polycystic ovarian syndrome: a comprehensive review. Fernandez H et al. Reprod Biomed Online. 2011 Jun;22(6) Long-term outcomes in women with polycystic ovary syndrome initially randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotrophins. Nahuis MJ et al. Hum Reprod. 2011 Jul;26(7)

Obesity in PCOS 40-60% of women with PCOS are overweight or obese 40-70% have insulin resistance Widespread variability in degree of adiposity by geographical location and ethinicity Spain: 20%, China: 43%, US: 69% What is best method to manage?

Obesity in PCOS In morbidly obese women with PCOS – sustained weight loss and complete resolution of all features defining PCOS, including hirsuitism, hyperandrogenism, menstrual irregularity, anovulation, IR and metabolic abnormalilities The higher the weight loss, the greater the benefit achieved NHI advocates when BMI 35-40kg/m2

Obesity in PCOS – weight loss Studies demonstrate fairly uniform improvements in many key features of PCOS with modest weight loss (5% to 15%) Improvements in biochemical hyperandrogenism, menstrual cyclicity, ovulation, and fasting insulin and glucose as well as glucose tolerance.

Obesity in PCOS – exercise Studies examining the effects of exercise in PCOS suggest that exercise improves reproductive hormones, menstrual cyclicity or ovulation and metabolic features. Remaining research questions -optimal amount, type, duration, and mechanisms of action of exercise.

Key features Lifestyle modification is first form of therapy ↓500-1000 kcal/day 7-10% weight loss over 6-12 months Alternative dietary options? Structure and support Exercise important  >30mins/day

Letrozole versus CC Letrozole is as effective as CC for OI in patients with PCOS

Sex steroid synthesis

PCOS and IVF High risk of OHSS

Strategies to prevent OHSS Cycle cancellation Coasting IV albumin at OR Antagonist cycles versus agonist (long protocol) GnRH agonist trigger in antagonist cycle Natural cycle IVM Dopamine agonist GnRH antagonist in agonist cycles (antogonist rescue protocol) Dual trigger

Antagonist cycles versus Agonist cycles The use of antagonist compared with long GnRH agonist protocols are associated with a large reduction in OHSS and there was no evidence of a difference in live birth rates Al-Inany HG et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2011 May 11;15:CD001750

GnRH agonist trigger in antagonist cycle In fresh autologous cycles, the moderate and severe OHSS incidence was significantly lower in the GnRH agonists group compared to the the hcg group but was also less effective than hcg in terms of live birth rate and on-going pregnancy rates. Therefore, not recommended for routine use as final oocyte maturation trigger in fresh cycles except in high risk women, after counselling Youssef MA et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev. 2011, Jan 19;(1):CD008046

Dopamine agonists for prevention of OHSS Significantly reduces the chances of developing OHSS in IVF and ICSI cycles No difference in live birth rate, on-going pregnancy rate, clinical pregnancy rate or miscarriage rate NNT = 9 Acts by reversing VEGFR-2 dependent increased vascular permeability Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ ICSI treatment cycles? A systematic review and meta-analysis. Mohamed A.F.M. Youssef et al. Human Reproduction Update, Vol.16, No.5 pp. 459–466, 2010

Summary Metformin for clinical features, weight loss and fertility Drilling Managing obesity in PCOS Preventing OHSS

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