1. Physiopathology and diagnosis of PCOS Ertan SARIDOĞAN Consultant in Reproductive Medicine and Minimal Access Surgery University College London Hospitals

2. Polycystic ovary syndrome Most common endocrinopathy Affects 6-10% Key features –Hyperandrogenism/hyperandrogenaemia –Oligo/anovulation –Polycystic ovaries

3. Key physiopathological features Androgen excess LH hypersecretion Insulin resistance Adrenal hypothesis

4. Ovarian dysfunction and hyperandrogenism Dysregulation of P450c17α activity –Increased androstenedione and 17-OHP rise to GnRHa stimulation in PCOS women –P450c17α and 3-ßHSD activities increased in vitro cultured theca cells

6. LH hypersecretion and PCOS Increased GnRH pulse amplitude and/or frequency – secondary to reduced steroid negative feedback Increased LH responsiveness to GnRH LH hypersecretion Ovarian hyperandrogenism

7. Hyperinsulinaemia and PCOS Insulin enhances LH stimulated androgen production –Via binding to its own receptor –Via binding to insulin like growth factor 1 receptor –Stimulates 17α hydroxylase activity in theca cells Decreases SHBG synthesis by the liver, increasing free androgens Supresses IGF-BP synthesis, increasing IGF-1 bioactivity

8. Mechanisms of excessive androgen secretion in PCOS, Homburg 2008

9. Mechanisms of abnormal ovarian morphology Homburg 2008

10. Mathematical modelling of follicle maturation in PCOS Franks 2008

11. Long term implications Subfertility –Anovulation Diabetes mellitus –Insulin resistance –Obesity Cardiovascular morbidity –Dyslipidemia –Atherosclerosis Endometrial cancer –Chronic unopposed oestrogen

12. Diagnosis

13. Bethesda Criteria, 1990

14. Rotterdam Criteria, 2003

15. The Rotterdam ESHRE/ASRM Criteria 2003 Oligo- and/or anovulation Clinical and/or biochemical signs of hyperandrogenism Polycystic ovaries and exclusion of other causes (congenital adrenal hyperplasias, androgen secreting tumours, Cushing’s syndrome) 2 out of 3 of the above criteria

16. Oligo-anovulation Amenorrhoea Oligomenorrhoea Meno-metrorrhagia

17. Hyperandrogenism Hirsutism –Less prevalent in East Asians/Adolescents –Relatively subjective –Standardised scoring systems rarely used Acne Androgenic alopecia

19. Ferriman-Gallway Score

20. Androgenic alopecia

21. Hyperandrogenaemia Laboratory methods variable and may be inaccurate Normative ranges not well established Free Testosterone and FAI

22. Ultrasound diagnosis of PCO 12 or more follicles 2-9 mm Ovarian volume > 10 ml –(0.5 x length x width x thickness) Early follicular phase (Day 3-5) or after withdrawal bleeding

25. Possible phenotypes of PCOS

26. Conclusions Etiology and pathogenesis of PCOS remains elusive Hyperandrogenism, insulin resistance, hypothalamic-pituitary-ovarian dysfunction contribute Different mechanisms may be involved in different individuals Diagnosis can usually be made on the basis of history, clinical examination and ultrasound assessment