1. PCOS Dr. Mridula A Benjamin Dept of Obs and Gyn RIPAS Hospital, Brunei

2. Introduction Heterogenous problem Commonest hormonal disturbance Ovarian expression of metabolic syndrome Long term consequences - strategies to screen Stein Leventhal syndrome

3. ASRM/ ESHRE Rotterdam: May 2003 Two of three: Oligomenorrhoea & or anovulation Hyperandrogenism; Clinical/biochemical PCO on USG; 12 or more, 2-9mm,10cm 3 Single PCO The follicle distribution & increase in stromal echogenecity & volume should be omitted Chronic anovulation & hyperandrogenism in absence of other endocrine disorders January issue of Fertility & Sterility J, 2004

4. Ultrasound Polycystic ovaries –Bilateral –Multiple cysts –Cyst diam <2-9mm –Stroma increased Multicystic ovaries –Bilateral –Multiple cysts –Cyst diam > 6-10 mm –Stroma not increased

8. Gross appearance of ovaries Enlarged bilaterally and have a smooth thickened avascular capsule On cut section, subcapsular follicles in various stages of atresia are seen Microscopically luteinizing theca cells are seen

11.  The best biochemical markers of hyperandrogenism are free testosterone levels or free androgen index Not all patients with PCOS have elevated circulating androgen levels  Routine measurement of androstenedione cannot be recommended  DHEAS is raised in small fraction of patient with PCOS levels

12.  LH levels are elevated in 60% women with PCOS LH/FSH ratios can be elevated in up to 95% of women with PCOS if women with recent ovulation are excluded  LH levels are not necessary for clinical diagnosis of PCOS  Implications?? High miscarriage / low fertility  The chances of ovulation or pregnancy rates using CC or HMG are unaffected

13. PCOS should be excluded from other disorders in which hirsutism and menstrual irregularities are prominent Congenital adrenal hyperplasia Cushing's syndrome Androgen-secreting tumors In oligo/anovulation: E2 & FSH to exclude hypogonadotrophic hypogonadism (central origin of ovarian dysfunction)

14. Thyroid disorders in PCOS patients are not more common than in other young women, and TSH is unnecessary In hyperandrogenic females: Prolactin

15. Metabolic syndrome 3 of the following 1. Waist circumference >88cm 2. Triglycerides >150 mg/dl 3. HDL <50 mg/dl 4. Blood pressure > 130/85 5. Fasting Blood glucose 110-126 &/or 2-h glucose 140-199 mg/dl

16. Prevalence PCO on ultrasound - 20%-33% Oligomenorrhea - 4 – 21 % Oligomenorrhea + hyperandrogenism - 3.5 – 9 %

17. Pathogenesis (etiology?) Hypersecretion of adrenal androgens? Hypersecretion of ovarian androgens? A genetic disorder with an autosomal dominant mode of inheritance? A multifactorial genetic disorder?

18. Cholesterol Pregnenolone Progesterone 17 OH-Pregnenolone 17 OH-Progesterone DHEA Androstenandion 17-20 Lyase 17 hydroxylase Theca cell Estrone estradiol Granulosa cell FSH LH OVARIAN STEROIDOGENESIS T

19. Obesity Insulin Free testosterone SHBG IGF-1 5-alfa reductase activity is stimulated IGF*** insulin like growth factor

20. Obesity and insulin resistance Diminished biological response to insulin In both obese and non obese In 40% More in obese and oligomenorrhoeic Euglycaemia at expense of hyperinsulinaemia Obesity more of central -35-60%

21. 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

22. Presentation Amenorrhea- Oligomenorrhea Infertility Hirsutism Obesity Acne Vulgaris Asymptomatic

24. Laboratory studies Increased androgen levels in blood (testosterone and androstendione) Increased LH, exaggerated surge Increased fasting insulin Increased prolactin Increased estradiol and estrone levels Decreased SHBG levels

25. Long term risks in PCOS Definite Type 2 diabetes(15%), IGT( 18-20%) Dyslipidemia (Hypercholesterolemia with diminished HDL2 and increased LDL) Endometrial cancer (OR 3.1 95% CI 1.1 -7.3)

26. Possible Hypertension Cardiovascular disease Gestational diabetes mellitus Pregnancy-induced hypertension Ovarian cancer Unlikely Breast cancer Long term consequences

27. Management Symptom oriented Diet & exercise Wt. loss Improves both symptoms & endocrine profile BMI >30kg/ m 2 Keep CHO content down, avoid fatty food Obesity clinics

28. Contd Menstrual irregularities OCP- Yasmin, Dianette ET >10mm(oligo), >15mm(amen)-Withdrawal bleed Fails - Endometrial sampling

29. STEPWISE APPROACH FOR OVULATION INDUCTION IN PCOS (ACOG,2002 ) 1. Weight loss: If BMI >30 K/m 2 2. Clomiphene citrate 3. CC + corticosteroids if DHES > 2ug/ml 4. CC + Metformin 5. Low dose FSH injection 6. Low dose FSH injection + Metformin 7. Ovarian drilling 8. IVF

31. Mx of Hirsutism Cosmetic Medical- 6-7 months Cyproterone acetate+ EE, Spironolactone Reliable contraception Flutamide & Finasteride - Rare

32. Reproductive Endocrinologist S.testosterone > 5nmol/L Rapid onset hirsutism IGT/ Type2 DM Refractory symptoms Amen. > 6 months Subfertility

33. Guidelines (RCOG, May 2003) 1-Patients presenting with PCOS particularly if they are obese, should be offered measurement of fasting blood glucose and urine analysis for glycosuria. Abnormal results should be investigated by a glucose tolerance test Such patients are at increased risk of developing type II diabetes (Evidence level IIb[C]) 2- Women diagnosed as having PCOS before pregnancy should be screened for gestational diabetes in early pregnancy Refer to specialized obstetric diabetic service if abnormalities detected (evidence level IIb[B])

34. Guidelines (RCOG, May 2003) 3-Measurement of fasting cholesterol, lipids and triglycerides should be offered to patients with PCOS, since early detection of abnormal levels might encourage improvement in diet and exercise (Evidence level III[C]) 4- Olig- and amenorrhoeic women with PCOS may develop endometrial hyperplasia and later carcinoma. It is good practice to recommend treatment with progestogens to induce withdrawal bleed at least every 3-4 months (Evidence level IIa[B])

35. Guidelines (RCOG, May 2003) 5- Evidence has accumulated demonstrating safety and efficacy of insulin-sensitizing agents in the management of short-term complications of PCOS, particularly anovulation. Long-term use of these agents for avoidance of metabolic complications of PCOS cannot as yet be recommended (Evidence level IV[B]) 6- No clear consensus regarding regular screening of women with PCOS for later development of diabetes and dyslipidemia Obese women with strong family history of cardiac disease or diabetes should be assessed regularly in a general practice or hospital outpatient setting. Local protocols should be developed and adapted (Evidence level IV[C])

36. Guidelines (RCOG, May 2003) Young women diagnosed with PCOS should be informed of the possible long-term risks to health that are associated with their condition. They should be advised regarding weight and exercise (Evidence level III[C])