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Polycystic Ovary Syndrome

Polycystic Ovary Syndrome. R. Jeffrey Chang, M.D. Department of Reproductive Medicine University of California, San Diego. Commercial Disclosures (9.9.06). Entity Activity Wyeth Research funding Serono Research support Takeda Research support Berlex Research support.

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Polycystic Ovary Syndrome

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  1. Polycystic Ovary Syndrome R. Jeffrey Chang, M.D. Department of Reproductive Medicine University of California, San Diego

  2. Commercial Disclosures (9.9.06) Entity Activity Wyeth Research funding Serono Research support Takeda Research support Berlex Research support

  3. Learning Objectives • Integrate the altered endocrine-metabolic physiology with the clinical presentation of polycystic ovary syndrome (PCOS) • Describe the evaluation and available treatment options for PCOS

  4. Overview of PCOS • In 5-10% of reproductive aged women • Multi-system reproductive-metabolic disorder • Hypothalamic-pituitary-ovarian axis • Carbohydrate metabolism • Obesity

  5. Clinical Features of PCOS • Androgen excess (hirsutism) • Chronic anovulation (irregular menses) • Insulin resistance (diabetes) • Polycystic ovaries

  6. Androgen Excess • Hirsutism: • Onset and distribution • Growth rate • Hyperandrogenemia: • Total testosterone • Free testosterone • Virilization is rare

  7. Facial Hirsutism in PCOS

  8. Estimated Prevalence of Menstrual Patterns in PCOS • Oligomenorrhea 70-75 % • Amenorrhea 20 % • Regular cycles 5-10 %

  9. 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

  10. 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

  11. Presence of 12 or more follicles in each ovary Increased ovarian volume (>10 ml) No consideration of stroma Ultrasound Description Of Polycystic Ovaries Fertil Steril, 2003

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

  13. Ultrasound of the Polycystic Ovary

  14. Insulin Sensitivity Liver Muscle Hepatic Glucose Output Glucose Utilization Insulin Pancreas

  15. Insulin Resistance Liver Muscle  Hepatic Glucose Output  Glucose Utilization Insulin Increased Pancreas

  16. Glucose Intolerance in PCOS 16%/yr 2%/yr 6/11 4/14 9% 54%

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

  18. Obesity in PCOS • About 50% of PCOS • Android distribution • Associated with insulin resistance • Lowers sex hormone binding globulin • Adverse lipid profile

  19. Other Historical Markers • Peri- or postpubertal onset • Familial occurrence • Infertility

  20. Hypothalamic-Pituitary-Ovarian Dysfunction in PCOS GnRH Estrogen Androgen LH, FSH Anovulation

  21. 24 Hour LH Pulse Secretion Pattern in Normal and PCOS Adult Women Normal # pulses = 9 * * LH mIU/ml * * * * * * * Normal ■ # pulses/22h = 9 ■ Orderly secretion PCOS ■ # pulses/22h = 15 ■ Increased levels ■Chaotic pattern 0 6 12 18 24 PCOS * * * * * * * * * * * * * * * LH mIU/ml # pulses = 15 0 6 12 18 24 Patel K et al, Clin Endocrinol, 2004

  22. Effect of Steroid Feedback on LH Pulse Frequency in Normal Women 5 4 3 2 1 0 A * * * * * * * E2 : 67 pg/ml P : 0.4 ng/ml A. Baseline: Pulse frequency in a normal woman studied on Day 8-10 of the cycle. Number of pulses = 7. Plasma LH IU/L 5 4 3 2 1 0 B * * B. Treatment: Pulse frequency in the same woman studied 7 days later following daily E2 and P4.. Number of pulses = 2. E2 : 193 pg/ml P : 7.8 ng/ml 0 100 200 300 400 500 Time (min) Pastor et al, JCEM, 1998

  23. Effect of Steroid Feedback on LH Pulse Frequency in PCOS Women A 10 8 6 4 2 0 * * * * * * E2 : 73 pg/ml P : 0.7 ng/ml A. Baseline: Pulse frequency in a PCOS woman. Number of pulses = 6. Plasma LH IU/L 10 8 6 4 2 0 B * * * * * B. Treatment: Pulse frequency in the same PCOS woman studied 7 days later following daily E2 and P4. Number of pulses = 5. E2 : 205 pg/ml P : 8.4 ng/ml 0 100 200 300 400 500 Time (min) Pastor et al, JCEM, 1998

  24. Change in LH Pulse Frequency After E2 + P Treatment Controls PCOS +2 0 -2 -4 -6 -8 ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ Δ in LH pulses/8 hr ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ 0 5 10 15 20 0 5 10 15 20 Day 7 P (ng/ml) Day 7 P (ng/ml) Pastor et al, JCEM, 1998

  25. Change in LH Pulse Frequency After E2 + P with Flutamide Treatment Controls PCOS 0 -1 -2 -3 -4 -5 -6 -7 -8 -9 0 -1 -2 -3 -4 -5 -6 -7 -8 -9 ● ● ● ● ● ● ● ● ● Change in LH pulses/12 hr ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 2 4 6 8 10 0 2 4 6 8 10 Day 7 P (ng/ml) Day 7 P (ng/ml) Eagleson et al, JCEM, 2001

  26. Hypothalamic-Pituitary-Ovarian Dysfunction in PCOS GnRH Estrogen Androgen LH, FSH Anovulation

  27. Effect of Androgen Administration on the Ovary of Non-human Primates • ▪ Female Rhesus monkeys, 6-13 yrs • ▪ Testosterone subcutaneous pellets • - 4 mg/kg x 3 days - 0.4 mg/kg x 10 days • ▪ Recombinant FSH treatment Weil et al, JCEM, 1999

  28. Effect of dose and duration of test- sterone treatment on ovarian size and follicle number Testosterone effect on granulosa cell proliferation and apoptosis. Apoptosis index = # granulosa cell apoptotic nuclei per 100 cells Vendola et al, JCI, 1998

  29. Co-localization of Androgen Receptor (AR) and FSH Receptor (FSHR) mRNA Expression in Non-human Primate Ovary Weil et al, JCEM, 1999

  30. FSH Receptor Gene Expression in Follicles from Testosterone Treated Monkeys Weil et al, JCEM, 1999

  31. Effect of Androgen Administration on the Ovary of Non-human Primates • Increased ovarian size and follicle number • Increased granulosa cell proliferation • Decreased granulosa cell apoptosis • May influence granulosa cell response to FSH

  32. Hypothalamic-Pituitary-Ovarian Dysfunction in PCOS GnRH Estrogen Androgen LH, FSH Anovulation

  33. Causes of Hyperandrogenism • Polycystic Ovary Syndrome • Hyperthecosis • Congenital adrenal hyperplasia • Cushing’s syndrome • Androgen producing tumor

  34. 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)

  35. 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

  36. Other Lab Considerations • LH:FSH ratio • Measure of insulin resistance

  37. Treatment Options in PCOS • Lifestyle modification • Androgen suppression • Anti-androgens • Insulin lowering agents

  38. The Fertility Fitness Progamme • Discussed role of weight and body composition on reproductive health • Agreement to seek lifestyle changes for 6 months • Group meeting with partners for cooperation • Weekly meetings for 2-5 hours with women • Gentle aerobic exercise for 1 hr (walking, etc.) • Lecture for 1 hr (eating, smoking, nutrition, etc) Modified from Norman RJ et al, Trends Endocrinol Metab, 2002

  39. Results • 15 obese (37 BMI) anovulatory PCOS women • Mean weight loss was 2-5% • Improvement in abdominal fat, psychological measures, androgenicity, and insulin sensitivity • 9 women resumed ovulation • 2 pregnancies Modified from Norman RJ et al, Trends Endocrinol Metab, 2002

  40. Androgen Suppression • Sex steroid administration • GnRH agonist therapy • Glucocorticoid administration

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

  42. Anti-androgens • Spironolactone • Flutamide • Finasteride

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

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

  45. Insulin Lowering Agents • Metformin (Glucophage) - 1500-2000 mg/day • Thiazolidinediones - Rosiglitazone (Avandia) 2-8 mg/day • Pioglitazone (Actos) 30-45 mg/day

  46. Insulin Lowering Agents • Induction of ovulation (30%) • Some reduced hair growth • Improved glucose utilization • Lowered serum insulin • Lipid lowering properties

  47. Use of Insulin Lowering Drugs In Ovulation Induction • Baseline hepatic and renal function tests • Metformin (Category B) - Lactic acidosis • - Iodine containing contrast dye • Thiazolidinediones (Category C) • - Monitor liver function • - Edema

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