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

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Presentation on theme: "Polycystic Ovary Syndrome R. Jeffrey Chang, M.D. Department of Reproductive Medicine University of California, San Diego."— Presentation transcript:

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

2 Commercial Disclosures (9.9.06) EntityActivity 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 Oligomenorrhea70-75 % Amenorrhea 20 % Regular cycles 5-10 %

9 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Hormone Level Estradiol Progesterone FSH LH Menstrual Cycle Day Ovulation Endometrial Thickness 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Normal Menstrual Cycle

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

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

12 Polycystic OvariesCystic Follicles Uterus Tube Anatomic Features of the Polycystic Ovary

13 Ultrasound of the Polycystic Ovary

14 Insulin Sensitivity Insulin LiverMuscle Pancreas Hepatic Glucose Output Glucose Utilization

15 Insulin Resistance Insulin LiverMuscle Pancreas Hepatic Glucose Output Glucose Utilization Increased

16 Glucose Intolerance in PCOS nNGTIGTDM Legro et al (2005) 7139 (55%)25 (35%)7 (10%) Ehrmann et al (1999) 12267 (55%)43 (35%)12 (10%) Norman et al (2001) 6754 (81%)13 (19%)0 16%/yr 2%/yr 9%54% 6/114/14

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

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

22 543210543210 543210543210 0 100 200 300 400 500 Time (min) Plasma LH IU/L E 2 : 67 pg/ml P : 0.4 ng/ml E 2 : 193 pg/ml P : 7.8 ng/ml A B ******* ** A. Baseline: Pulse frequency in a normal woman studied on Day 8-10 of the cycle. Number of pulses = 7. B. Treatment: Pulse frequency in the same woman studied 7 days later following daily E 2 and P 4.. Number of pulses = 2. Effect of Steroid Feedback on LH Pulse Frequency in Normal Women Pastor et al, JCEM, 1998

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

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

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

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

27 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 Effect of Androgen Administration on the Ovary of Non-human Primates 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 Weil et al, JCEM, 1999 Co-localization of Androgen Receptor (AR) and FSH Receptor (FSHR) mRNA Expression in Non-human Primate Ovary

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

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

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

33 Causes of Hyperandrogenism Polycystic Ovary Syndrome Hyperthecosis Congenital adrenal hyperplasia Cushings 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 Total Testosterone (T) DHEA-S (DS) 17-hyroxyprogesterone (17-OHP) T > 200 ng/dl DS > 700 μg/dl Suspect Tumor 17-OHP > 2 ng/ml Suspect CAH T Elevated ± DS Elevated T & DS Normal PCOS Adrenal Idiopathic Laboratory Evaluation

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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