1. 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

2. 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?

3. 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 ( B.C)

4. 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

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

6. 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

7. 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

8. 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

9. 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

10. 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

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

12. 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

13. 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

14. 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 Jan 20;(1):CD

15. 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 May 23.

16. Metformin in ART
In obese patients

17. 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 May 27.

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

19. 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 Jan-Feb;15(1):57-68.

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

21. 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 Jan;24(1):219-25 ,

22. 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 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 Jul;26(7)

23. 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?

24. 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

25. 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.

26. 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.

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

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

30. Sex steroid synthesis

31. PCOS and IVF
High risk of OHSS

32. 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

33. 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 May 11;15:CD001750

34. 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

35. 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

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

38. Thank you