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

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

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

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

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

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)

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

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

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

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

Pathophysiology Exact pathophysiology or initiating event are unknown

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)

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.

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

Treatment Diet, exercise and weight loss Oral contraceptives Studies have shown that androgen production is significantly decreased with a little as 10-15 lbs loss over 6 months Oral contraceptives Antiandrogens (spironolactone) Insulin sensitizers GnRH agonists

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

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

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 2003. 31-41. Franks, Stephen. Diagnosis of Polycystic Ovarian Syndrome: In Defense of the Rotterdam Criteria. Journal of Clinical Endocrinology & Metabolism. 91(3):786-789