Polycystic ovary syndrome, or PCOS, is among the most common female endocrine disorders in the world. It is typically recognized during puberty and is estimated to affect 5–10% of reproductive age women. There is a familial disposition for the condition, but no definitive attributions to specific genes have yet been possible. In 1935, Stein and Levanthal formalized the recognition of the association of hyperandrogenism, as evidenced by hirsutism, amenorrhea (irregular or absent menses), and polycystic ovaries, in the syn drome that would carry their name for decades. The ovaries contain on the order of 12 antral follicles in which growth of the granulosa cells is arrested by an unknown mechanism. A decreased rate of follicular atresia accounts for the high number of antral follicles.
The thecal cells of the follicles in PCOS, which are hypertrophic and may also have an increased sensitivity to LH, are responsible for the high circulating testosterone and androstenedione levels seen in this condition. Estrogen levels in the follicular fluid in PCOS are low, but circulating levels are in the nor mal range due to peripheral aromatization of circulating testosterone and androstenedione. Levels of SHBG, the sex steroid specific serum binding protein, are decreased, further increasing the bioavailability of both androgens and estrogens. LH, but not FSH, secretion is increased through an increase of both frequency and amplitude of its pulses. Although several hypotheses have been and continue to be studied, the primary defect in reproductive hormone secretion has yet to be elucidated.
The above changes in reproductive hormone status in PCOS are often accompanied by metabolic dysfunction which includes insulin resistance, obesity, and dyslipidemia. Insulin resistance is the inability of the body to respond to a given dose of insulin in terms of glucose uptake and utilization. The mechanism of the insulin resistance is not clear; both the number and binding effectiveness of insulin receptors appear to be normal, suggestive of a defect in a downstream signaling step. In PCOS fat deposition tends to be in central and upper body areas with an increased waist to hip ratio compared to obese females without PCOS. This type of fat distribution is termed android obesity as it occurs more typically in males than in females. Total and LDL cholesterol, as well as triglycerides are increased while HDL cholesterol is decreased. Although the pathogenic mechanisms of PCOS, along with the relationship between the reproductive and metabolic symptoms, have not yet been elucidated, it has been found that insulin suppresses the response to GnRH in women with and without PCOS. Thus insulin resistance in PCOS could at least contribute to greater LH, resulting in hypertrophic thecal cells producing increased androgens.
In addition to antidiabetic drugs such as metformin, treatment of PCOS relies on oral contraceptives to reduce LH secretion and therefore androgen production, thus addressing one of the most pressing problems for these individuals, excessive and inappropriate hair growth. The use of oral contraceptives also addresses the long-term deleterious consequences of unopposed actions of estrogens on the endometrium and provides contraception for those not wishing to become pregnant. For those who do wish to become pregnant clomiphene citrate (Figure1 ), an ER ligand with mixed agonist/ antagonist properties, is used to normalize, probably at the hypothalamus, secretion of LH and FSH.
Fig1. Estrogens and related molecules. A. The naturally occurring estrogens, of which 17β-estradiol is by far the most active, are shown. B. An estrogen antagonist (clomiphene) and three SERMs (selective estrogen receptor modulators) with mixed agonist/antagonist activities are shown.
