1. Polycystic Ovarian Syndrome (PCOS)
Elaine Sunderlin, MD – PGY-2
Morning Report
September 15, 2009

2. Background First described in 1935 by Stein and Leventhal
Affects 5-10% of women of reproductive age making it the most common endocrine disorder is this age group
Characterized by oligomenorrhea, amenorrhea, infertility and hirsutism. Occasionally associated with enlarged ovaries

3. Diagnostic Criteria - ACOG
Major
Chronic anovulation
Clinical signs of androgen excess (hirsutism, acne, alopecia, mentrual disturbance, infertility, virilization
Exclusion of alternative causes of androgen excess
Minor
Insulin resistance
Onset at puberty
Elevated LH:FSH (>2.5-3)
Ultrasound evidence of polycystic ovaries

4. Diagnostic Criteria - Rotterdam
Oligo- or anovulation
Clinical and/or biochemical signs of hyperandrogenism
Polycystic ovaries
2 out of 3 required for diagnosis

5. Menstrual irregularities
Amenorrhea: up to 10% of patients present with primary amenorrhea and 75% present with secondary amenorrhea
May have intermittently regular and fertile cycles despite elevated androgen levels
If pregnancy does occur, there is increased risk of gestational diabetes and pregnancy-induced HTN

6. Hyperandrogenism
Pts w/ PCOS have an increased sensitivity to androgens; up to 70% have elevated androgen levels and the other 30% are in the high-normal range
3 major circulating androgens:
Androstenedione (>90% produced in ovaries, produced by ovarian stromal and thecal cells in response to LH. Normally converted to estradiol by FSH dependent aromatase)
DHEA-S (mainly produced in adrenals)
Testosterone (produced in ovaries and adrenals in equal amounts)

7. Clinical signs of Hyperandrogenism
Hirsutism: excessive growth of terminal, pigmented hair on androgen sensitive areas (chin, upper lip, sideburns, sternal, periareolar, umbilical and sacral areas) with accentuated involvement of the pubic region and upper thighs
Alopecia is much rarer manifestation of PCOS
Acne: severe cystic and persistent acne is usually androgen-dependent
Virilization usually mild. If more severe signs (clitormegaly, deepening of the voice & incr muscle mass) are present, underlying diseases of adrenal and pituitary glands (CAH, hyperprolactinemia, or androgen-secreting tumors) need to be excluded
Hyperandrogenic effects usually progress slowly

8. Metabolic derangements
Insulin resistance with increased risk of development of type 2 DM
Hyperinsulinemia
Increased risk for development of metabolic syndrome
Obesity, especially central visceral obesity, is present in 35-80% of patients

9. Hyperandrogenism causes hyperinsulinemia or vice versa?
Decreasing androgen levels does not reduce hyperinsulinemia in PCOS
Induced hyperandrogenism in females w/o PCOS does not alter insulin sensitivity
Insulin resistance persists after oophorectomy or after ovarian androgen synthesis is suppressed by GnRH agonists

10. Hyperandrogenism causes hyperinsulinemia or vice versa?
Giving insulin to PCOS patients increases circulating androgen levels and lowering insulin by using diazoxide lowers androgen levels
Insulin stimulates androgen production in ovarian thecal cells in PCOS
Insulin amplifies the LH response of granulosa cells, thereby causing an abnormal differentiation of these cells, premature arrest of follicular growth, and so anovulation

11. Pathophysiology
Exact pathophysiology or initiating event are unknown

12. HPG Axis abnormalities
Elevated LH w/ low to nml FSH
In PCOS, normal pulsatile secretion of LH is increased by an increased frequency and amplitude of pulses while FSH is unchanged or muted
Elevated prolactin
Levels are increased in ~25% of pts. Extreme elevations may stimulate adrenal production of dihydroepiandrosterone sulfate (DHEA-S)

13. HPG Axis abnormalities
Increased GnRH: inappropriate secretion of gonadotropins thought to be due to abnormality of GnRH pulse generation in hypothalamus
Primary: study of girls w/ fmhx who were entering puberty showed LH pulses in late afternoon (nml is at night)
Secondary: females develop a PCOS-like condition in Cushings, exposure to anabolic steroids, or w/ androgen-producing tumors.

14. Long-term Consequences
Increased risk of endometrial cancer due to the unopposed effect of estrogen on the endometrium
Tonic and abnormal stimulation of the ovaries felt to be related to elevated risk of ovarian cancer
Type 2 DM
CAD

15. Treatment Diet, exercise and weight loss Oral contraceptives
Studies have shown that androgen production is significantly decreased with a little as lbs loss over 6 months
Oral contraceptives
Antiandrogens (spironolactone)
Insulin sensitizers
GnRH agonists

16. OCPs Establish regular menstrual cycles
Reduce gonadrotropin stimulation of ovaries, thus reducing androgen production
Increase SHBG
Inhibit androgen receptor binding
Use newer progestins (desogestrel, norgestimate) because of minimal androgen effects

17. Spironolactone
Blocks androgen receptor from “seeing” dihydrotestosterone. May also suppress androgen biosynthesis
40-80% reduction in sexual hair growth
Requires 8-14 months before clinical effects can be seen
Use in combination with OCPs as it has minimal effect on free testosterone and androstenedione. Also can cause polymenorrhea due to the effect on the endometrium

18. References
Marx, Theresa and Adi Mehta, MD. Polycystic Ovarian Syndrome: Pathogenesis and treatment over the short and long term. Cleveland Clinic Journal of Medicine. Vol 70, No. 1, January
Franks, Stephen. Diagnosis of Polycystic Ovarian Syndrome: In Defense of the Rotterdam Criteria. Journal of Clinical Endocrinology & Metabolism. 91(3):