Polycystic ovarian syndrome (PCOS ）

1. Polycystic ovarian syndrome(PCOS） Wei Zhang OB/GYN Hospital, Fudan University

2. Content • OVERVIEW of PCOS • PATHOPHYSIOLOGY • SIGNS and SYMPTOMS • DIAGNOSTIC CRITERIA • TREATMENT

3. OVERVIEW

4. PCOS • 1 st described by Stein and Leventhal as a triad of amenorrhea, obesity and hirsutism (1935) • The symptoms and severity of the syndrome vary greatly among affected women • It is one of the leading causes of female infertility

5. Definition & Abbreviations • Definition :Polycystic ovarian syndrome is a common endocrine disfunction typified by oligo-ovulation or anovulation, signs of androgen excess, and multiple small ovarian cysts • Abbreviations • PCOS = Polycystic Ovarian Syndrome • PCO= Polycystic Ovarian

6. Incidence • PCOS is the most common disorder of reproductive-aged women • Affects approximately 4-12% • PCOS appears to equally affect all races and nationalities

7. Etiology • Genetic basis • Aggregation of the syndrome within families • An increased prevalence has been noted between affected individuals and their sisters and mothers • The first-degree male relatives of women with PCOS have significantly higher circulating DHEAS levels .

8. Environment causes • Life style • Exercise • Diet • Androgen exposure, et. al

9. Interaction of Genetics and environment PCOS may be a genetically determined ovarian disorder , the heterogeneity can be explained on the basis of interaction of the disorder with other genes and with the environment

10. PATHOPHYSIOLOGY

11. Reproductive cycle regulated by HPOaxis Hypothalamus GnRH Pituitary Gn FSH LH Ovary Progesterone Estradiol 内膜

13. Pathopysiologyz:What we think we know • Abnormal gonadotropin secretion • Excess LH and low, tonic FSH • Hypersecretion of androgens • Disrupts follicle maturation • Substrate for peripheral aromatization • Negative feedback on pituitary • Decreased FSH secreation • Insulin resistance, Elevated insulin levels

14. Disorder of H-P-O axis • Increased GnRH from hypothalamus • Excessive LH secretion relative to FSH by pituitary gland • LH stimulates ovarian thecal cells to produce excessive androgen • Ineffective suppression of the LH pulse frequency by estradiol and progesterone • Androgen excess increases LH by blocking the hypothalamic inhibitory feedback of progesterone

15. H-P-O axis Dysfunction in PCOS GnRH Estrogen androgen LH, FSH Anovulation

16. Abnormal steroidogenesis • Intraovarian androgen excess results in excessive growth of small ovarian follicles • Follicular maturation is inhibited • Excess androgen causes thecal and stromal hyperplasia

17. PCO • These "cysts" are actually immature follicles. The follicles development stopped at an early antral stage due to the disturbed ovarian function • Polycystic is >12 follicles per ovary less than 10mm in diameter, ovary itself is enlarged

18. Metabolism disorder • Hyperinsulinemia • Excess insulin production and insulin resistance • Hyperinsulinemia contributes to hyperandrogenism through production in the theca cell and through its suppressive effects on sex hormone binding globulin production by the liver • Hyperandrogenism vs. hyperinsulinemia: Which came first? • Dyslipidemia

19. Current theories of pathopysiology Autosomal Dominant Gene Downstream Signal Defect GnRH E2 LH Insulin Resistance PCOS A A=androgens, E2=estradiol

20. SIGNS and SYMPTOM

21. Clinical Features of PCOS • Hyperandrogenism • Hirsutism • Acne • Chronic anovulation (irregular menses) • Irregular menses • Infertility • Endocrine Dysfunction • Obesity • Insulin resistance • Acanthosis Nigricans • Impaired Glucose Tolerance and Type 2 Diabetes Mellitus • Dyslipidemia • Metabolic Syndrome and Cardiovascular Disease • Polycystic ovaries

22. Hyperandrogenism • Hirsutism, acne, male pattern balding, alopecia • 50-90% patients have elevated serum androgen levels • Rare: increased muscle mass, deepening voice,

23. Hirsutism:Ferriman-Gallwey Scoring System • Acne: 50% • Mild • moderate • severe

24. Facial Hirsutism in PCOS

25. Chronic anovulation/oligo-ovulation • Menstrual Dysfunction • Oligomenorrhea : 70-75 % • Amenorrhea: 20 % • Regular cycles: 5-10 % • Infertility: 30-70%

26. Menstrual Dysfunction • Oligo or amenorrhea • Menstrual irregularity typically begins in the peripubertal period • Reduction in ovulatory events leads to deficient progesterone secretion • Chronic estrogen stimulation of the endometrium with no progesterone for differentiation—intermittent breakthrough bleeding or dysfunctional uterine bleeding • Increased risk for endometrial hyperplasia and/or endometrial CA

27. INFERTILITY • Intermittent ovulation or anovulation • Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomid

28. Obesity • Prevalence of obesity varies from 30-75% • 2/3 of patients with PCOS who are not obese have excessive body fat and central adiposity • Obese patients can be hirsute and/or have menstrual irregularities without having PCOS

29. Insulin Resistance • > 80% are hyperinsulinemic and have insulin resistance (independent of obesity)

30. Acanthosis Nigricans • Velvety plaques on • nape of neck and • intertriginous • areas • Epidermal • hyperkeratosis • Associated with • insulin resistance

31. Ovarian Abnormalities • Thickened sclerotic cortex • Multiple follicles in peripheral location • 80% of women with PCOS have classic cysts

33. Associated Medical Conditions • Increased risk of developing Type 2 Diabetes and Gestational diabetes • Low HDL and high triglycerides • Sleep apnea • Nonalcoholic steatohepatitis • Metabolic syndrome—43% of PCOS patients (2 fold higher than age-matched population) • Elevated heart disease • Advanced atherosclerosis

34. Consequences of PCOS • Short-term consequences • Irregular menses • Hirsutism/acne/androgenic alopecia   • Infertility • Obesity  • Metabolic disturbances : Abnormal lipid levels/glucose intolerance • Long-term consequences • Diabetes mellitus (DM) • Cardiovascular disease(CVD) • Endometrial cancer

35. Consequences of PCOS Short-term consequences Hirsutism, acne Menstrual irregularity hyperandrogen infertility Obesity PCOS hyperplasia/cancer Long-term consequences CVD Elevated insulin Dyslipidemia diabetes

36. DIAGNOSTIC CRITERIA

37. Difficult to diagnosis • Changing criteria • Varying symptoms over time • Not all women with PCOS have polycystic ovaries (PCO), nor do all women with ovarian cysts have PCOS • although a pelvic ultrasound is a major diagnostic tool, it is not the only one • The diagnosis is straightforward using the Rotterdam criteria

38. NIH Criteria(1990) • Menstrual irregularity due to anovulation or oligo-ovulation • Evidence of clinical or biochemical hyperandrogenism • Hirsutism, acne, male pattern baldness • High serum androgen levels • Exclusion of other causes (CAH, tumors, hyperprolactinemia)

39. 2003 Rotterdam Criteria (2 out of 3) • Menstrual irregularity due to anovulation oligo-ovulation • Evidence of clinical or biochemical hyperandrogenism • Polycystic ovaries by US • 12 or more follicles measuring 2-9 mm in diameter • Increased ovarian volume (>10 cm 3 ) • Exclusion of other causes (CAH, tumors, hyperprolactinemia) In 2003 in Rotterdam, Netherlands, a consensus meeting between the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM) redefined PCOS

40. Differential Diagnosis • Hyperprolactinemia • Prominent menstrual dysfunction • Little hyperandrogenism 2. Congenital Adrenal Hyperplasia • morning serum 17-hydroxyprogesterone concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis • confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL

41. 3. Ovarian and adrenal tumors • serum testosterone concentrations are always higher than 150 ng/dL • adrenal tumors: serum DHEA-S concentrations higher than 800 mcg/dL • LOW serum LH concentrations 4. Cushing’s syndrome 5. Drugs: danazol; OCPs with high androgenicity

42. Diagnostic Approaches • Clinical history (hair growth rate, • onset of symptoms) • Physical examination (hirsutism or • virilization, rounded facies, buffalo hump) • Laboratory testing (hormones) • Ultrasonography (ovary, endometrium)

43. LaboratoryTesting • Fasting glucose: elevated • 2 hour OGTT: elevated • Fasting insulin: elevated • Free testosterone: elevated • DHEA-S: normal • 17-hydroxyprogesterone: normal • Pelvic US • Lipids profile

44. Laboratory Evaluation Total Testosterone (T) DHEA-S (DS) 17-hyroxyprogesterone (17-OHP) T > 200 ng/dl DS > 700 μg/dl T Elevated ± DS Elevated DS Elevated Adrenal Suspect Tumor PCOS T & DS Normal 17-OHP > 2 ng/ml Idiopathic SuspectCAH

45. TREATMENT

46. Treatment • Goals of PCOS Treatment • Restoration a normal cycle and fertility • Lowering of insulin levels • Treatment of hirsutism, acne • Prenvention of endometrial cancer • Prevention of DM,CVD and metabolic syndrome

47. Treatment Option • Lifestyle modification • Anti-androgens • Insulin lowering agents • Induced ovulation-for pregnancy desired

48. Lifestyle modification • Weight loss: • Low-carbohydrate diets • sustained regular exercise • 90% of anovulatory women restored to full ovulation despite relatively small amounts of weight loss following exercise and change of diet • BMI of 21 is ideal but the patient often respond to much less stringent body mass index

49. Anti-Androgen • OCPs: first option when fertility is not desired • Decrease in LH secretion and decrease in androgen production • Increase in hepatic production of sex-hormone binding globulin(SHBG) • Decreased bioavailablity of testosterone • Decreased adrenal androgen secretion • Regular withdrawal bleeding • Prevention of endometrial hyperplasia

50. Spironolactone, 50-200 mg per day • Androgen receptor blockade • Steroid enzyme inhibition • Aldosterone antagonism • Lower blood pressure • Potassium sparing