Molecular mysteries of polycystic ovary syndrome.

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women of reproductive age, affecting from 5–10% of women in this age group (1, 2). The symptoms of PCOS include hirsutism and acne, evidence of excessive androgen production, menstrual disturbances and, consequently, anovulation and infertility. Symptoms often appear soon after menarche, and biochemical abnormalities may be present at the time of adrenarche. A common feature of PCOS is follicular maturation arrest resulting in the accumulation of small subcortical follicle cysts and increased ovarian stromal volume, yielding a characteristic ultrasound image and a basis for the most commonly used appellation for the syndrome. Insulin resistance and pancreatic b-cell dysfunction, both independent of obesity and unrelated to the actions of androgens on insulin dynamics, are strongly associated with PCOS (3, 4). Physicians have only recently come to appreciate the potential long-term consequences of PCOS, which include type 2 diabetes mellitus, hypertension, and cardiovascular disease (5). Moreover, PCOS women who become pregnant have an increased risk of preeclampsia (6). In addition, endometrial hyperplasia and endometrial cancer also occur frequently in women with PCOS who do not receive treatment. Therefore, PCOS is a major women’s health issue with ramifications well beyond the reproductive endocrine abnormalities that usually bring women with PCOS to medical attention. Indeed, significant health risks may remain after the reproductive dysfunction has been treated by hormonal therapy or disappear as a result of reproductive aging (i.e. the menopause). Since PCOS was identified as a gynecological syndrome more than 60 yr ago by Stein and Leventhal (7), the diagnosis and even the name of the syndrome have been topics of continuous debate. Despite the recommendations of conferences, clinicians still do not use uniform criteria to make the diagnosis of PCOS (8). The resulting heterogeneity of phenotypes included under this umbrella confounds the literature on pathophysiology and outcomes of therapeutic interventions. For the purpose of this discussion, we define PCOS as a syndrome of hyperandrogenism and anovulation/oligoovulation in the absence of other hypothalamic, pituitary, ovarian, or adrenal disease. Unfortunately, the quest to bring some order to the field has not been helped by the absence of relevant animal models. Although cystic ovaries and anovulation can be produced in laboratory and domestic animal species with various pharmacological manipulations or transgenic approaches, none of these animal models faithfully replicate the human disorder. Theories of the pathophysiology of PCOS have implicated primary defects in hypothalamic-pituitary function, ovarian activity, and insulin action; but alas, none of these can comfortably accommodate the multiple abnormalities associated with PCOS. This state of relative confusion is not an indictment of investigators working on PCOS, but rather a reflection of the complexity of the disorder. The existing theories, however, do direct attention to specific hormones and/or processes including LH, thecal and adrenal androgen biosynthesis, and insulin/insulin-like growth factor action. Observations from therapeutic interventions provide validation for the notions that PCOS is associated with abnormal gonadotropin secretion, defects in ovarian steroidogenesis, and insulin resistance. The symptoms of hyperandrogenism can, in most cases, be treated by suppression of LH secretion, suggesting 0888-8809/99/$3.00/0 Molecular Endocrinology Copyright © 1999 by The Endocrine Society