1. Polycystic Ovarian Syndrome Christina C Ding Consultant in Obstetrics and gynaecology Subspecialist in Reproductive Medicine and Surgery

2. Overview Definition (and Prevalence)- much debated Diagnostic Criteria update Management update: General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

3. Definition -PCOS Why is reaching consensus difficult? Problems with the lack of unified definition? New criteria in 2003

4. Definition- PCOS Challenges in reaching a consensus Heterogeneity in symptom and sign For an individual, these may change over time PCO can exist without clinical signs of the syndrome, which may become expressed overtime

5. Range of presenting complaints Menstrual irregularities (unopposed E 2 ) Anolulatory Infertility Hyperandrogenism (Acne/Hirsutism/Alopecia) Obesity Metabolic Risks (DM, H/T, CVD) Asymptomatic – incidental Scan finding of PCO

6. Definition Problems without a consensual definition Progress in Clinical Research hampered Inconsistencies and poor delivery of clinical care

7. Definition Revised 2003 Rotterdam diagnostic criteria Two out of three Oligo / Anovulation Hyperandrogenism: clinical or biochemical USS Features – >12 follicles of 2-9 mm in diameter, or – ovarian volume >10 cm 3 in one or both ovaries Excluding: thyroid dysfunction, congenital adrenal hyperplasia, hyperprolactinaemia, androgen-secreting tumours and Cushing syndrome

8. Prevalence NIH criteria 1990 – 6-7% Rotterdam consensus 2003 – 20-25% UK Caucasian – 52% UK South Asian immigrant

9. Wt. increase Insulin receptor disorder Insulin increase Free estradiol increase High LH Low FSH Free testosterone increase Androstenandione increase SHBG decrease atresia Theca (IGF-I) Endometrial cancer Testosterone increase Estrone increase hirsutism IGFBP-I **** decrease IGFBP*** insulin like growth factor binding protein

10. Clinical Challenges Menstrual irregularities (unopposed E 2 ) Anolulatory Infertility Hyperandrogenism (Acne/Hirsutism/Alopecia) Obesity Metabolic Risks (DM, H/T, CVD)

11. Management Update General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

12. Management Update General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

13. Life Style Changes The best diet and exercise regimens are unknown, but caloric restriction and increased physical activity are recommended. RCOG guideline

15. Management Update General: – Life style changes – insulin sensitising agent – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

16. Metformin Not licensed outside DM treatment Safe (not established in pregnancy) Short term benefits (Wt. loss, OI, hirsutism) No long term benefits

17. Management Update General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

18. Cancer risks Endometrial Cancer – Risk is 3.1 x higher(95% C I 1.1- 7.3) Coulam et al, 1983 (1270 chronic anovulation pt) Breast Cancer – No significant increased risks Pierpoint et al., 1998; Coulam et al., 1983; Anderson et al., 1997 Ovarian Cancer – No significant increased risks Pierpoint et al., 1998

19. Long term risks : CVD PCOS metabolic abnormalities suggesting increased cardiovascular risk ObservationReference Triglycerides↑, HDL↓ Rajkhowa et al. (1997); Orio et al. (2004) C-reactive protein↑ Taponen et al. (2004); Boulman et al. (2004) Homocysteine↑ Carmina et al. (2005) Leucocytes↑ Orio et al. (2005) Fibrinolytic activity↓ Yildiz et al. (2002) Metabolic syndrome↑ Apridonidze et al. (2005) The ESHRE Capri Workshop Group, ‘Hormones and cardiovascular health in women’, Human Reproduction Update, 2006

20. Long term risks: DM,H/T Follow-up studies of PCOS AuthorsPatients Intermediate outcomes CVD outcomes Dahlgren et al. (1992) 33 followed for 22–31 years More diabetes and hypertension Pierpoint et al. (1998) 786 diagnosed between 1930 -79 SMR 0.9 (95% CI: 0.7, 1.2) Wild et al. (2000) 240 PCOS diagnosed before 1979 More cerebral disease and diabetes Similar CHD mortality Elting et al. (2001) 346 followed for 2–32 years More diabetes and hypertension SMR, Standardized Mortality Ratio The ESHRE Capri Workshop Group, ‘Hormones and cardiovascular health in women’, Human Reproduction Update, 2006

21. Long term risks : obstetric Meta –analysis of 15 studies involving 720 women presenting with PCOS and 4505 controls Higher risks of Gestational DM (OR 2.94; 95% CI: 1.70–5.08) Pregnancy-induced H/T (OR 3.67; 95% CI: 1.98–6.81) Preterm birth (OR 1.75; 95% CI: 1.16–2.62) Perinatal mortality (OR 3.07; 95% CI: 1.03–9.21) Hum. Reprod. Update 2006, A meta-analysis of pregnancy outcomes in women with PCOS

22. Psychological: Quality of Life Symptoms such as acne, hirsutism, irregular menses, amenorrhoea, obesity and subfertility are a major source of psychological morbidity and can negatively affect quality of life (QoL). Systematic review: PCOS has a significant negative impact on a woman’s health-related quality of life Health-related quality of life measurement in women with polycystic ovary syndrome: a systematic review. Jones et al, Human Reproduction Update (2008)

23. Management Update General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

24. Management Update General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

25. Antiobesity Drug Orlistat (Xenical) – gastric/pancreatic Lipase inhibitor Sibutramine (Reductile) – SNRI – Withdrawn since Jan 2010 due to increased heart attack and stroke risks

26. Bariatric Surgery Two groups: malabsorptive & restrictive procedures Malabsorptive procedures induce decreased absorption of nutrients by shortening the functional length of the small intestine. The created short- bowel syndrome leads to a negative energy balance and weight loss. Restrictive operations reduce the storage capacity of the stomach and as a result early satiety arises, leading to a decreased caloric intake.

27. Figure 1 Bariatric procedures. (a) Jejunoileal bypass; (b) biliopancreatic diversion; (c) biliopancreatic diversion with duodenal switch; (d) vertical banded gastroplasty; (e) laparoscopic adjustable gastric band; and (f) Roux-en-Y gastric bypass.

28. Bariatric Surgery Benefits – Average weight loss 20–40 kg – Recovery from type 2 diabetes in 76.8% Risks – Mortality: early (<30/7) 0.1-2% – Morbidity: VTE (0.4-3.1%) Infection Anastomotic leak / stenosis (20-30%)

29. Management Update General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

30. Hyperandrogenism Acne Hirsutism Male pattern hair loss – Sign of severe androgen excess (virilization)

31. Hirsutism 5-10% women of child bearing age – 70% PCOS – 23% idiopathic – 4.3% CAH – 0.2% A S tumour (ovarian or adrenal) Hx: sudden onset, rapid virilization Ix: testosterone, free testosterone. – If [testosterone] > 5nmol/L => [DHEA-S] & [androstenedione] to exclude an adrenal or ovarian tumour

32. Hirsutism - treatment options Systemic (over 3-6 months) COCP: less androgenic progesterone: cyproterone acetate Diannette, drospirenone Yasmin Antiandrogens (uncommonly used) – Spironolactone (Aldactone), an aldosterone antagonist – Cyproterone acetate – Flutamide is a pure nonsteroidal antiandrogen that acts as an androgen receptor blocker. – Finasteride is a potent inhibitor of the type 2 isoenzyme of 5-á-reductase, which blocks the conversion of testosterone to 5-á-dihydrotestosterone Corticosteroids : late onset CAH Topical – Eflornithine cream (Vaniqa) Cosmetic Direct Hair Removal: plucking, waxing, electrolysis, laser removal

33. Management Update General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

34. Ovulation Induction: stepwise approach (RCOG) 1. Weight loss: If BMI >30 K/m 2 2. Clomiphene citrate 3. CC + Metformin 4. Low dose FSH injection 5. Ovarian drilling 6. IVF

35. Laparoscopic ovarian drilling Diathermy or laser Clomid resistant anovulatory PCOS Benefits Ovulation rate >70% Pregnancy rates >50% Similar pregnancy and miscarriage rates to Gonadotrophins No increase in multiple pregnancies and reduces ovarian hyperstimulation. Risks Risk of loss of ovarian tissue and thus reducing the ovarian reserve Risk of surgery ?Adhesions

36. Ovarian drilling

37. Management Update General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities

38. Mx of a/oligomenorrhea Progesterone induced Bleeding – 3 monthly – Reduce risks of E hyperplasia and E carcinoma

39. Overview Definition (and Prevalence)- much debated Diagnostic Criteria update Management update: General: – Life style changes – insulin sensitising agents – Prevention of long term health risks (CVD, Cancers, Psychological) Specific: symptomatic control – Obesity Mx – Antiobesity drugs, Bariatric surgery – Hyperandrogenism Tx – Infertility: Anoulatory cycles – Menstrual irregularities