POLYCYSTIC OVARY SYNDROME

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Polycystic ovary syndrome (PCOS) refers to a heterogeneous group of gynecologic disorders with variable degrees of ovarian and adrenal hyperandrogenism. Although its precise definition remains elusive, the classic description in 1935 by Stein and Leventhal49 was rigidly based on the clinical findings of amenorrhea, hirsutism, and bilaterally enlarged ovaries. Radioimmunoassays later demonstrated that the endocrinologic characteristics of PCOS included luteinizing hormone (LH) hypersecretion, hyperandrogenemia, and acyclic estrogen production. Developments in pelvic ultrasound enabled detailed morphologic descriptions of bilaterally enlarged cystic ovaries.1 Although a concordance exists between these clinical or biochemical parameters and ultrasound appearance, PCOS remains clinically heterogeneous and indistinguishable from other endocrinopathies. Therefore, in 1990 the National Institutes of Health (NIH)–National Institute of Child Health and Human Development Conference on PCOS proposed that the new diagnostic criteria for this disorder should be hyperandrogenism and chronic anovulation, excluding other causes such as adult-onset congenital adrenal hyperplasia (CAH), hyperprolactinemia, and androgen-secreting neoplasms.15 Because these criteria are less stringent, some hyperandrogenic anovulatory women are included in this definition who would otherwise not fulfill the strict definition of classic PCOS.

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POLYCYSTIC OVARIES

Based on the two-cell, two-gonadotropin theory of ovarian steroidogenesis, androgens produced by LH-stimulated thecal cells undergo aromatization to estrogens by follicle-stimulating hormone (FSH)–stimulated granulosa aromatase.48 A shift from an androgenic to an estrogenic ovarian microenvironment occurs as aromatase activity increases within the developing follicle. In hyperandrogenic anovulatory women, because the preovulatory follicle does not develop, multiple small subcapsular follicles

GENETIC STUDIES

Because PCOS is a heterogeneous disorder, it is unlikely that its variability is the result of the dysfunction of a single gene. Moreover, determining the inheritance of PCOS is difficult because the disorder affects reproductive-aged women, and there is no clearly described male phenotype. Nevertheless, familial groupings of PCOS suggest an autosomal dominant mode of inheritance with reduced penetrance and premature balding in men as a possible male phenotype.24 A high degree of discordance

Menstrual Irregularity

Hyperandrogenic anovulatory women usually notice the peripubertal onset of amenorrhea or menstrual irregularity defined as menses occurring at less than 21 or greater than 35 day intervals. Patients wishing to conceive also experience infertility from anovulation. The acyclic estrogen production unopposed by progesterone stimulates endometrial proliferation, thereby increasing the risk for endometrial hyperplasia and cancer23 and, possibly, breast cancer.51

Hirsutism

Most hyperandrogenic anovulatory women

Hypothalamic-Pituitary Unit

Serum immunoactive and bioactive LH levels are elevated in approximately 70% of women with hyperandrogenic anovulation. An elevated LH pulse amplitude accompanied by an increased LH pulse frequency in some individuals causes a two to three fold elevation in serum LH in comparison with FSH.42 LH hypersecretion, in part, reflects the consequence of acyclic estrogen production unopposed by progesterone, because estrogen sensitizes the pituitary to gonadotropin-releasing hormone (GnRH), enhances

Sex Steroid Abnormalities

Women with classic PCOS have elevated serum levels of T, A4, DHEA, DHEAS,53 and 17-OHP.33 The ovary is the source of excess A4, T, and 17-OHP; the adrenal is responsible for increased amounts of DHEA and DHEAS. Hyperandrogenemia stimulates androgen-dependent target tissues; suppresses hepatic SHBG production, thereby increasing the portion of T not bound to SHBG (free T); and increases extraglandular aromatization by skin, muscle, brain, and adipose tissue.54

Estrone (E1), the major serum

LABORATORY ANALYSIS

Based on the NIH definition of PCOS, the purpose of diagnostic testing in hyperandrogenic anovulatory women is to exclude other endocrinopathies, including virilizing tumors, adult-onset CAH, hyperprolactinemia, and Cushing's syndrome.32 Other causes of androgen excess and menstrual irregularity include drugs [e.g., anabolic steroids, 19-norsteroids, danazol (Danocrine), synthetic progestins] and conditions unique to pregnancy (e.g., luteoma, hyperreactio luteinalis).

The diagnosis of

IMAGING STUDIES

The presence of virilization or severe rapidly progressive hirsutism regardless of serum T and DHEAS levels may require a complete evaluation to distinguish patients with severe PCOS from those with a possible virilizing tumor.

Transvaginal ultrasonography (TVUS) detects ovarian masses less than 1 cm in size and identifies 90% of all virilizing ovarian tumors.38 TVUS does not always distinguish an ovarian tumor from a corpus luteum cyst, thus any abnormal ovarian finding on sonography must be

THERAPY

The goals of therapy are to normalize the endometrium, antagonize androgen action on target tissues, reduce insulin resistance, and correct anovulation, if necessary.

SUMMARY

The cardinal clinical features of PCOS are hirsutism and menstrual irregularity from anovulation. Obesity occurs in approximately 50% of hyperandrogenic anovulatory women, some of whom also have non–insulin-dependent diabetes mellitus. Underlying these clinical findings are several biochemical abnormalities, including LH hypersecretion, hyperandrogenism, acyclic estrogen production, decreased SHBG capacity, and hyperinsulinemia, all of which contribute to increased ovarian production of

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