PCOS

1. นพ.โอฬาริก มุสิกวงศ์ ผศ. พญ. ศรีนารี แก้วฤดี PCOS

2. Objectives • Define PCOS • Understand pathophysiology • Form an appropriate differential diagnosis • Establish the work-up for PCOS • Develop an array of therapies to treat complaints and prevent bad outcomes

3. PCOS is a complex endocrine disorder affecting women of childbearing age characterized by increased androgen production and ovulatory dysfunction Prevalence 6-8% of normal population Leading cause of anovulatory infertility and hirsutism Women with PCOS have an increased risk of miscarriage, insulin resistance, hyperlipidemia, type 2 diabetes, cardiovascular disease, and endometrial cancer POLYCYSTIC OVARIAN SYNDROME (PCOS) OVERVIEW

4. PCOS and Stein-Leventhal Syndrome • PCOS was first identified by Stein and Leventhal in 1935 • They described a group of women who were obese and infertile, with enlarged ovaries with multiple cysts • Few of these original features are now considered consistent findings in PCOS

5. PATHOPHISIOLOGY

6. Insulin secretion and action • Gonadotropin secretion and action • Androgen biosynthesis and action • Weight and energy regulation • Environment factor

8. DIAGNOSTIC CRITERIA AND CLINICAL MANIFESTATIONS

9. NIH Criteria • 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)

10. Rotterdam Criteria (2 out of 3) • Menstrual irregularity due to anovulation oligo-ovulation • Evidence of clinical or biochemical hyperandrogenism • Polycystic ovaries by US • presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume * In addition, other etiologies (congenital adrenal hyperplasias, androgen-secreting tumors, Cushing's syndrome) must be excluded.

11. AES criteria presence of three features • androgen excess (clinical and/or biochemical hyperandrogenism) • ovarian dysfunction (oligo-anovulation and/or polycystic ovarian morphology) • exclusion of other androgen excess or ovulatory disorders

12. MENSTRUAL DYSFUNCTION • Oligo or amenorrhea • Menstrual irregularity typically begins in the peripubertal period • Delayed menarche • 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

13. Normal Menstrual Cycle Estradiol Progesterone FSH LH Ovulation Hormone Level 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Endometrial Thickness 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Menstrual Cycle Day

14. Anovulatory Bleeding in PCOS Estradiol Progesterone Hormone Level Lower limit of normal 0 2 4 6 8 10 12 14 16 18 20 Endometrial Thickness Breakthrough Withdrawal 0 2 4 6 8 10 12 14 16 18 20 Weeks

15. HYPERANDROGENISM • Hirsutism, acne, male pattern balding, alopecia • 50-90% patients have elevated serum androgen levels • Free testosterone levels most sensitive • Rare: increased muscle mass, deepening voice, clitormegaly (should prompt search for underlying neoplasm)

17. OVARIAN ABNORMALITIES • Thickened sclerotic cortex • Multiple follicles in peripheral location • 80% of women with PCOS have classic cysts

19. Anatomic Features of the Polycystic Ovary Tube Uterus Polycystic Ovaries Cystic Follicles

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

21. 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

22. OBESITY AND INSULIN RESISTANCE • ½ patients with PCOS are obese • > 80% are hyperinsulinemic and have insulin resistance (independent of obesity) • Hyperinsulinemia contributes to hyperandrogenism through production in the theca cell and through its suppressive effects on sex hormone binding globulin production by the liver

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

24. DIFFERENTIAL DIAGNOSIS • Hyperprolactinemia • Prominent menstrual dysfunction • Little hyperandrogenism • 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

25. 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

26. TESTING • Serum HCG • Serum prolactin • Thyroid function test • FSH: r/o ovarian failure • Serum luteinizing hormone (LH)—elevated • Serum estradiol—normal • Serum estrone—elevated

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

28. 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 Suspect CAH

29. TREATMENT

30. Depend on goal of treatment

31. WEIGHT LOSS • Weight loss • Weight loss • Weight loss

32. Hirsutism • Mechanical hair removal • Vaniqa (eflornithine hydrochloride) • OCPs with minimal androgenicity • OCP plus antiandrogen (spironolactone) • Spironolactone, 50-200 mg per day • Flutamide • Potential hepatic dysfunction

33. Oral Contraceptives • Suppress ovarian androgen • Increase SHBG • Regular menstrual cyclicity • Progestin opposition • Contraception

34. Anti-androgens • Spironolactone • Flutamide • Finasteride

35. Spironolactone • Androgen receptor blockade • Steroid enzyme inhibition • Aldosterone antagonism • Lower blood pressure • Potassium sparing • Dose: 100-200 mg/day

36. Flutamide • Non-steroidal, selective anti-androgen • Liver function tests • Dose: 125-250 mg/day

37. Oligomenorrhea • Combination estrogen-progestin pill first line when fertility is not desired • Decrease in LH secretion and decrease in androgen production • Increase in hepatic production of sex-hormone binding globulin • Decreased bioavailablity of testosterone • Decreased adrenal androgen secretion • Regular withdrawal bleeds • Prevention of endometrial hyperplasia

38. TREATMENT—no fertility desired • Monophasic antiandrogenic OCP • ON 1/35 (norethindrone) • Orthocyclen (norgestimate) • Desogen or Orthocept (desogestrel) • Yasmin

39. insulin-sensitizing agents • Metformin • will restore ovulation and menses in > 50% of patients • Treat with cyclic progestin to reduce endometrial hyperplasia if regular menses not attained • 10 mg for 7 to 10 days every two to four months

40. METFORMIN • Decreases hepatic glucose production • Reduces need for insulin secretion • Improves insulin sensitivity (increases peripheral glucose uptake and utilization) • Antilipolytic effect—reduces fatty acid concentrations and reduces gluconeogenesis

41. SIDE EFFECTS • Diarrhea, nausea, vomiting, flatulence, indigestion, abdominal discomfort • Caused by lactic acid in the bowel wall • Minimized by slow increase in dosage • Lactic acidosis—rare • Avoid in CHF, renal insufficiency, sepsis • Discontinue for procedures using contrast (withhold X 48 hours) • Temporarily suspend for all surgical procedures that involve fluid restriction • Cimetidine causes increased metformin levels

42. INFERTILITY TREATMENT • Metformin • Metformin 500 mg once a day with breakfast for 4 days • Metformin 500 mg twice a day with breakfast and dinner for 4 days • Metformin 500 mg with breakfast and 1,000 mg with dinner for 4 days • Metformin 1,000 mg twice daily • Clomid • 50 mg days 3-7 for 3 months • 100 mg days 3-7 for 3 months

43. METFORMIN DOSING • Target—1500-2000 mg per day • Clinically significant responses not regularly observed at doses less than 1000 mg per day

44. Infertility • Weight loss—reduction in serum testosterone concentration and resumption of ovulation • Clomid: 80% will ovulate, 50% will conceive • Metformin: when added to clomid, improves ovulatory rates • Laparoscopic surgery: wedge resections, laparoscopic ovarian laser electrocautery • IVF

45. Key point PCOS is the most common endocrine disorder in reproductive-aged women. PCOS is a lifelong disease beginning in fatal life and extending into the postmenopausal period. Hyperinsulinemia is the pivotal factor in the pathogenesis. PCOS is an inherited disorder the follows an autosomal dominant inheritance pattern although the gene or genes involve are unknown

46. Hyperandrogenemia with or without hyperandrogenism along with oligomenorrhea are hallmark features of PCOS • Anovulatory resulting in infertility is a common presentation • Obesity worsens metabolic abnormalities such as hyperinsulinemia and hyperandrogenemia.

47. Diabetes, lipid disorder, heart disease and endometrial cancer are metabolic sequelae of PCOS. • Insulin-sensitizing agent heave dramatically changes the management of PCOS. Metformin, an insulin-sensitizing agent, is now first choice for the treatment of anovulation in PCOS. Weight loss and exercise are the best long term therapy to decrease the metabolic sequelae of PCOS.

48. References • Berek & Novak’s Gynecology • Clinical gynecology / [edited by] Eric J. Bieber, Joseph S. Sanfilippo, Ira R. Horowitz • Uptodate.com • Polycystic ovary syndrome : a guide to clinical management / Adam Balen ... [et al.] • Polycystic ovary syndrome / edited by R. Jeffrey Chang, Jerrold J. Heindel, Andrea Dunaif. • ACOG practice bulletin, polycystic ovary syndrome • The ovary / editors, Peter C.K. Leung, Eli Y. Adashi • Clinical gynecologic endocrinology and infertility / Leon Speroff, Marc A. Fritz

49. Thank You