Polycystic Ovarian Syndrome

1. Polycystic Ovarian Syndrome John Miell University Hospital Lewisham Kings College Hospital

2. A heterogenous condition (or many conditions)

3. Stein-Leventhal Syndrome(1935) • Menstrual Irregularity • Hirsutism, Acne, Alopecia • Obesity • Stein I and Leventhal M (1935) Amenorrhoea associated with bilateral polycystic ovaries. Am J Obst Gyn 29:181

4. Hyperinsulinism, glucose intolerance and hyperandrogenism • Achard C and Thiers J (1921): Le virilisme pilaire et son association a l’insufficiance glycolytique (diabetes des femmes a barb) • Bulletin of the Academy of National Medicine

5. Features of PCOS • Clinical: • Menstrual abnormalities • Anovulatory subfertility • Hirsutes, acne, alopecia • Weight gain • ?recurrent miscarriage

6. Features of PCOS • Endocrine: • Elevated androgen • Elevated LH • Elevated estrogen and prolactin • Elevated androstenedione • Decreased SHBG

7. Biochemistry not reliable • LH elevated in 40% • Serum testosterone not always elevated • In a study of 1741 women with PCOS confirmed on clinical features and USS only 28.9% had elevated testosterone

8. Features of PCOS • Metabolic: • Insulin resistance • Impaired GT and T2 DM • Lipid abnormalities • Cardiovascular risks • Neoplastic risk (?)

9. PCOS-Definition • Ovulatory dysfunction and clinical features of hyperandrogenism • Polycystic ovaries plus one or more of the clinical features

10. Revised Diagnostic criteria for PCOS • 1999: • Chronic anovulation • Clinical/biochemical signs of hyperandrogenism and exclusion of other pathologies* • 2003: 2/3 of • Oligo and/or anovulation • Clinical/biochemical signs of hyperandrogenism • Polycystic ovaries

11. USS appearance of PCO

12. PCOS Definition Two out of the following • Oligo/anovulation • Clinical or Biochemical hyperandrogenism • PCO Rotterdam consensus meeting 2003

13. Cause of PCOS 1 • Unknown - but probably a vicious cycle with a number of entry points: • Defect in insulin action and secretion - hyperinsulinemia and insulin resistance • Neuroendocrine defect - high LH pulse frequency and amplitude • Defect of androgen synthesis - enhanced ovarian androgen production • Defect in cortisol metabolism - enhanced adrenal androgen production

14. Cause of PCOS 2 • Insulin resistance -Hyperinsulinaemia -Increased ovarian androgen -inhibits SHBG production in liver -increased free Testosterone -inhibits IGFBP-1 production -more free IGF-I • Weight gain -hyperinsulinaemia

15. Mechanism of hyperinsulinemia • Insulin resistance: Obese PCOS>obese>lean PCOS>Lean • Pancreatic Beta cell secretory dysfunction • Decreased hepatic clearance of insulin • Abnormal insulin signalling - • serine vs tyrosine phosphorylation • serine phosphorylation inhibits receptor TK activity and accentuates P450c17 activity

16. Ovarian steroid biosynthesis

17. Pathways leading to androgen excess in PCOS

18. Increased cortisol metabolism • Increased adrenal androgen production may occur secondary to alteration in cortisol metabolism • Increased 5alphaR or reduced 11betaHSD may lead to reduced cortisol • This leads to increased ACTH (to maintain normal cortisol levels) at the expense of excess adrenal androgen stimulation

19. Increased cortisol metabolism 5alpha reductase mediates conversion of testosterone to 5 alpha Dihydrotestosterone and cortisol to 5alpha dihydrocortisol

20. Genetics of PCOS • High correlation between twin pairs for hyperinsulnemia and hyperandrogenism (monogenic trait, 2 alleles, autosomal locus) • Prospective study of 1st degree relatives of women with PCOS – 46% affected – half have hyperandrogenemia with regular cycles, half have PCOS • Association between PCOS and polymorphism at INS VNTR • No difference in polymorphisms at CYP17 (encoding P450c17a) • No real luck looking at follistatin or CYP11a (coding P450scc) • ?type I IGF receptor/insulin receptor

21. Long term consequences of PCOS • Increased risk of diabetes • Increased risk of cardiovascular disease • Increased risk of carcinoma

22. Increased risk of diabetes • Insulin resistance and beta cell dysfunction precede Type2 DM • Up to 40% of PCOS have IGT or T2DM (vs 10.3% in normal population studies) • Legor et al (1999): 31.1% IGT (vs 7.8% in age, weight, race matched controls) and 7.5% frank diabetes (vs 1.0%). Lean PCOS – 10.3% IGT, 1.5% frank T2DM.

23. Increased risk of diabetes • Gestational diabetes is very common in PCOS (? Role for Metformin in pregnancy).

24. PCOS and cardiovascular disease • The metabolic syndrome: • Impaired glucose tolerance • Type 2 DM • Abdominal obesity • Adverse lipid profiles

25. PCOS and cardiovascular disease • The metabolic syndrome • Diagnosis based on 3/5 of: • Fasting Triglycerides >1.7 mmol/L • HDL – C < 1.3 mmol/L • BP > 135/85 • FBG > 6 mmol/L • Waist circumference > 88cms

26. PCOS and cardiovascular disease • Angiography reveals increased incidence in coronary artery disease in women with • Hirsutism (Wild et 1990) • USS evidence of PCO (Birdsall et al 1997)

27. PCOS and cardiovascular disease • Follow up of women who have had wedge resection 7.4 fold increase in risk of MI

28. PCOS and cardiovascular disease • 30 year follow up of 786 women fulfilling reasonable diagnostic criteria for PCOS ( Pierpoint et al 1998, Wild et al, 2000) • Increase in mortality/morbidity from diabetes and increased risk of non-fatal cerebrovascular disease. • No increase in deaths from heart disease • mean BMI was 27 kg/m2 • No increase in prevalence of T2DM in this study • ? Protective effects of unopposed estrogen and increased levels of VEGF

29. PCOS and cardiovascular risk factors • Dyslipidemia – secondary to: • Elevated androgens, body fat distribution and hyperinsulinemia • Raised triglycerides • Marginal elevation of LDL • Reduced HDL • Raised small dense LDL-III • Increased hepatic lipase activity • Elevated plasminogen activator inhibitor, PAI-1 • ?Consequence of androgens or hyperinsulinemia.

30. PCOS prevention of long term consequences • Advise to modify risk factors Lose weight – diet/exercise Stop smoking Insulin sensitisation (?) • Screen for diabetes

31. Increased risk of cancer (??) • No powerful well controlled studies using accurately defined diagnostic criteria • Possibly no overall increased risk of cancer in practice (Venn et al, Lancet, 1999)

32. Increased risk of cancer (??) • Endometrial cancer • Theoretical risk of amenorrhoea and unopposed estrogen • Mayo clinic – 3X increased risk of endometrial cancer in women with anovulation without hypoestrogenemia (prob PCOS – Coulam, ObsGyn, 1983) • BUT – no good studies, poordiagnostic criteria, retrospective analyses etc.

33. Increased risk of cancer (??) • Breast cancer • Theoretical risk of amenorrhoea and unopposed estrogen • PCOS protective against Breast cancer in a self reported historical study (Odd ratio 0.52 (0.32-0.87 – Gammon 1991) • No significant excess deaths from Breast cancer in a large group of PCOS (Pierpoint, J Clin Epidemiol, 1998)

34. Increased risk of cancer (??) • Ovarian cancer • The jury is out • 2 studies suggest an increased risk - possibly both subject to recall bias • 3 studies suggest no increased risk

35. Treatment • Depends on Symptoms

36. Clinical Presentation • Oligo/amenorrhoea • Subfertility • Obesity • Acne • Hirsutism

37. Exercise and weight loss • Improves insulin sensitivity • Reduces serum testosterone • Improves menstrual regularity • Induces regular ovulation

38. Visceral fat • Responsible for the adverse effects of obesity • Strong correlation with insulin resistance

39. Obesity and PCOS • Waist circumference is better guide to metabolic risk factors than is waist:hip ratio or BMI • waist ideally should be < 87cm ( and possibly <79cm) • Exercise is more important than diet in reducing visceral fat and correcting metabolic abnormalities

40. Oligo/amenorrhoeaRisk of endometrial pathology • Combined oral contraceptive • Cyclical progestagen OR • Annual TVS assessment of endometrium

41. Treatment of Hirsutism • Shaving, Electrolysis or waxing • Ornithine decarboxylase inhibitors • COC • Cyproterone acetate • Spironolactone • Flutamide and Finasteride • Metformin

42. Hirsutism • Oestrogen suppresses ovarian testosterone Increases SHBG • Cyproterone acetate (progestogen) Androgen antagonist Suppresses LH

43. Oral contraceptive • Ethinyl oestradiol 35mcg Cyproterone Acetate 2mg • Ethinyl Oestradiol 30 or 50mcg Desogestrel 150mcg Equally effective in treatment of Hirsutism Porcile & Gallardo 1991 Ethinyl oestradiol +drosperinone

44. Reverse sequential Regime • Dianette Plus Cyproterone acetate 50-100mg day 1-10 of pill packet Earlier improvement in hirsutism Barth et al 1991

46. Metformin • Reduces insulin resistance • 1000mg -1500mg daily • reduces serum insulin • reduces serum testosterone • Improves lipid profile • Improves menstrual irregularity • Improves fertility

47. Metformin & Clomiphene • 61 women with BMI>28 • Received Metformin 500mg tds or placebo

48. Metformin and clomiphene • Metfomin 34% ovulated • Placebo 4% ovulated • Metformin + clomiphene 90% ovulated • Placebo + Clomiphene 8% ovulated

49. PCOS - conclusions • Insulin resistance, hyperandrogenism, unusual gonadotrophin dynamics • Familial though no stron evidence of candidate gene identity • Links with obesity, cardiovascular disease, DM and maybe endometrial cancer • Needs lifestyle modification which remains the mainstay of treatment • Metformin has been a revelation

50. Surgical or medical treatment of PCOS And/or