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 %
Amenorrhea %
Regular cycles %

9. Normal Menstrual Cycle Endometrial Thickness
Estradiol
Progesterone
FSH LH
Ovulation
Hormone Level
Endometrial Thickness
Menstrual Cycle Day

10. Anovulatory Bleeding in PCOS Endometrial Thickness
Estradiol
Progesterone
Hormone Level
Lower limit of normal
Endometrial Thickness
Breakthrough
Withdrawal
Weeks

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

13. Ultrasound of the Polycystic Ovary

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

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

16. Glucose Intolerance in PCOS
NGT
IGT DM
Legro et al
(2005) 71
39 (55%)
25 (35%)
7 (10%)
Ehrmann et al (1999)
122
67 (55%)
43 (35%)
12 (10%)
Norman et al (2001) 67
54 (81%)
13 (19%)
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
LH mIU/ml * * * * * * * * *
Normal
■ # pulses/22h = 9
■ Orderly secretion
PCOS
■ # pulses/22h = 15
■ Increased levels
■ Chaotic pattern
PCOS * * * * * * * * * * * * * * *
LH mIU/ml
# pulses = 15
Patel K et al, Clin Endocrinol, 2004

22. Effect of Steroid Feedback on LH Pulse Frequency in Normal Women5 4 3 2 1 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 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
Time (min)
Pastor et al, JCEM, 1998

23. Effect of Steroid Feedback on LH Pulse Frequency in PCOS Women10 8 6 4 2 * * * * * *
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 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
Time (min)
Pastor et al, JCEM, 1998

24. Change in LH Pulse Frequency After E2 + P Treatment
Controls PCOS +2 -2 -4 -6 -8 ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
Δ in LH pulses/8 hr ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
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 -1 -2 -3 -4 -5 -6 -7 -8 -9 -1 -2 -3 -4 -5 -6 -7 -8 -9 ● ● ● ● ● ● ● ● ●
Change in LH pulses/12 hr ● ● ● ● ● ● ● ● ● ● ● ● ● ●
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 Elevated
DS Elevated
T > 200 ng/dl
DS > 700 μg/dl
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: mg/day

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

45. Insulin Lowering Agents
Metformin (Glucophage)
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