Current Concepts in Polycystic Ovarian Syndrome

1. Current Concepts inPolycystic Ovarian Syndrome Mark N. Simon, MD Exempla Uptown Women’s Healthcare Specialists October 17, 2003

2. Disclosure Dr. Simon has no significant financial interests or other relationships with industry relative to the subject of this lecture.

3. Objectives • Cite the physical manifestations of PCOS. • Describe the pathophysiology of PCOS. • Formulate a treatment plan for patients with PCOS.

4. Scope of the Problem • PCOS is the MOST common endocrine disorder of reproductive age women • Effects 5-10% of these women • Commonly presents to primary care providers

5. Diagnosis • North America (NIH Consensus): • Menstrual Irregularity (oligo- or anovulation) • Hyperandrogenism • Clinical evidence OR • Laboratory evidence • Absence of other endocrine disorders • Congenital Adrenal Hyperplasia • Hyperprolactinemia • Thyroid dysfunction

6. Diagnosis • Europe: • Morphological features of polycystic ovaries • Menstrual disturbance AND/OR • Hyperandrogenism • Hirsuitism • Acne • Alopecia • Laboratory data are not needed

7. Ultrasound • Polycystic Ovaries • Found in around 20% of general population • May be a predictor of future development of PCOS • Found in 80% of women with PCOS • Appearance • Many, peripheral, small follicles • Increased ovarian stroma

8. European Diagnosis • Increases prevalence to about 15% • Proposed unifying protocol: • Determine if symptoms are present • If present, proceed with ultrasound • If ultrasound positive – diagnosis confirmed • If ultrasound negative – check lab tests Homberg, Human Reproduction, 2002

9. Diagnosis • North America (NIH Consensus): • Menstrual Irregularity (oligo- or anovulation) • Hyperandrogenism • Clinical evidence OR • Laboratory evidence • Absence of other endocrine disorders • Congenital Adrenal Hyperplasia • Hyperprolactinemia • Thyroid dysfunction

10. Patient Presentation • Symptoms of hyperandrogenism • Irregular menstrual cycles • Infertility – Most Common Presentation

11. Symptoms of Hyperandrogenism • Hirsutism • Acne • Rarely see Virilization • Male pattern balding • Clitoromegaly • Deepening of voice • Increased muscle mass

12. Hirsutism • Occurs in 80% of PCOS patients • Excess terminal body hair • Male Pattern • Back, Sternum, Upper Abdomen, Shoulder • More common areas • Upper Lip, Around breast nipples, Linea alba • ¼ of women have hair in these areas • Excluding Scandinavian, Asian

13. Hirsutism - DDx • Idiopathic • PCOS • Drugs (Danazol) • Hyperthecosis • Ovarian Tumors • Adrenal Tumors • CAH

14. Ovarian Hyperthecosis • Ovary has nests of luteinized theca cells • Signs and Symptoms • Hirsutism, Alopecia, Obesity • HTN • Clitoromegaly • Markedly elevated testosterone

15. Red Flags with Hirsutism • Rapid onset of hirsutism • Rapid progression of hirsutism • Late onset • Outside of early reproductive years • Virilization

16. Tumors • RED FLAGS • Testosterone > 150ng/dL (> 200ng/dL) • LH low • DHES > 800mcg/dL • Further investigation warranted • MRI abdomen/pelvis

17. Nonclassic Congenital Adrenal Hyperplasia • Partial deficiency of 21-hydroxylase • Elevation of 17-hydroxyprogesterone • Precursor of androgens • Rare • Do NOT have adrenal insufficiency • Treat with anti-androgen therapy

18. Nonclassic Congenital Adrenal Hyperplasia • Consider in patients not responding to typical PCOS treatment • Measure 17-hydroxyprogesterone • Follicular phase • Morning • Levels > 2 ng/mL need to be tested further • Adrenal stimulation

19. Acne • Common in adolescent girls (30-50%) • Severe acne is uncommon (<1%) • Severe acne is a predictor of PCOS

20. Irregular Menses • Most common to have erratic menses • Due to Anovulation • Patients present with oligomenorrhea or amenorrhea

21. PCOS with Regular Menses? • Androgens converted to estrogens • Peripheral conversion • Aromatase • Estrogens stimulate uterine lining • Can have regular shedding of endometrial lining despite anovulation

22. PCOS with Regular Menses? • Hyperandrogenism does NOT automatically cause anovulation • Women with hyperandrogenism and polycystic ovaries may still ovulate regularly • Affect on fertility is unclear

23. Infertility • Usually long-standing infertility • PCOS typically develops in early reproductive years • Infertility usually due to anovulation

24. Clinical Presentations • Hyperandrogenism • Hirsutism • Acne • Menstrual Irregularity • Infertility

25. Initial Evaulation • History to determine onset • PCOS usually has long course • Rapid onset of hirsutism – Red Flag • Usually develops early in reproductive years • PCOS is diagnosis of exclusion • Lab tests help to exclude other problems

26. What tests to order • Prolactin • Rule out hyperprolactinemia • Cause of menstrual dysfunction • Little signs of hyperandrogenism • Lactotroph stimulation from estrogen • Testosterone • DHEAS

27. Laboratory Tests • 17-Hydroxyprogesterone • In patients suspected of NCAH • TSH • When symptoms warrant • Glucose Tolerance Test • Fasting Lipid Profile

28. Laboratory Tests • LH, FSH • Little benefit • Insulin

29. Pathophysiology • Exact problems have not been identified • Hypothalamic-pituitary abnormalities • Elevated LH • Increased frequency and amplitude of pulses • Low-normal FSH • LH:FSH ratio increased • GnRH pulse generator may be disrupted causing the elevated LH

30. Hyperandrogenism • Androstenedione • Produced in ovarian thecal cells • Production is stimulated by LH • Converted to estradiol by FSH-stimulated aromatase • Excess is converted to estrone which suppresses FSH and is tonic to LH

31. Hyperandrogenism LH FSH + Ovary - Testosterone Androstenedione - Estradiol SHBG Estrone

32. Insulin Resistance • Feature of PCOS • Both obese and lean women are affected • Affects a number of systems • Reduction in tissue response to insulin

33. Insulin Resistance • Insulin causes androgen production • In women with PCOS • Insulin • Amplifies LH response in granulosa cells • Arrest of follicular development

34. Insulin Resistance • Insulin-like growth factor 1 (IGF-1) • Amplifies LH and androgen synthesis • Helps to regulate follicular maturation • Insulin-like growth factor binding protein 3 (IGFBP-3) • Decreased in patients with ovarian hirsuitism • When decreased, more bioavailability of IGF-1 • Shobokshi, et al, J Soc Gynecol Investig, 2003

35. Insulin Insulin + - Peripheral Glucose Uptake Glycogenolysis - Gluconeogenesis

36. Insulin Resistance Insulin Granulosa Cells + Ovarian Androgen Secretion Anovulation

37. Summary of Pathophysiology • Elevated LH • Leads to elevated Androgens • Hyperandrogen symptoms • Insulin Resistance

38. Treatment • Depends on symptoms • Depends on patient’s goals

39. Lifestyle Modification • Exercise • 150 minutes per week • Moderate exertion • Diet • Weight Loss • Most effective with obese patients

40. Weight Loss • Improves ovulatory and fertility rates • 5-7% loss • Restored ovulation in 75% • Decreases LH pulse amplitude • Decreases androgen production • Reduces insulin levels • Kiddy et al., Clin Endocrinol, 1992.

41. Insulin Sensitizers • Metformin • Most extensively studied • Increases peripheral uptake of glucose • Decreases gluconeogenesis • Does not cause hypoglycemia • Relatively inexpensive • Generic 500mg, 60 tabs $33.99 (drugstore.com 10/15/03)

42. Metformin • Side Effects • Gastrointestinal distress • Most common in first few weeks of use • Improves over time • Lactic acidosis • Dosage is 500mg TID or 875mg BID

43. Metformin • Lactic Acidosis • Severe, potentially fatal • Concern with elevated creatinine (>1.4 mg/dL) • Contraindicated in – • CHF, Sepsis, Liver disease, history of lactic acidosis • Surgery

44. Rosiglitazone • Insulin-sensitizing agent • Stimulate production of glucose transporter proteins • Few studies in PCOS • Dosage is 4mg BID • More expensive • 4mg, 30 tabs cost $77.99 (drugstore.com, 10/15/03)

45. Rosiglitazone • Improved clinical symptoms • Corrects insulin resistance • Improves ovulation rates • Fewer side effects • Especially GI • Fertility rates not studied • Shobokshi, et al, J Soc Gynecol Investig, 2003 • Ghazeeri, et al, Fertil Steril, 2003

46. Treatment Algorithms • Path depends primarily on fertility desires • Also depends on primary symptoms of patient

47. Desires Fertility • The Problem: Anovulation • The Solution: Reestablish Ovulation • Question for patient: Willingness to wait? • Weight Loss • Insulin-sensitizers may take 3-5 months • Ovulation induction much quicker • Harborne et al, The Lancet, April 8, 2003.

48. Weight Loss • Modest weight loss (5%) can help • Lower androgen levels • Induce regular cycles • Other health benefits for pregnancy • Diabetes • Hypertension

49. Metformin • 5 weeks of treatment • Ovulation rate of 34 % vs. 4% in placebo • No ovulation – Given Clomiphene citrate • Increased ovulation rate to 90% • Nestler et al, NEJM, 1998

50. Metformin and Pregnancy • Pregnancy Class B • PCOS increases risk of miscarriage • 30-50% higher • Plaminogen activator inhibitor (PAI) • Causes placental insufficiency • Increases with increased insulin levels • Kosasa, Contemporary OB/Gyn, March 2003