Bone Mineral Density, Androgens, and the Polycystic Ovary: The Complex and Controversial Issue of Androgenic Influence in Female Bone

Polycystic ovary syndrome (PCOS), characterized by chronic anovulation, hyperandrogenemia, obesity, central adiposity, and insulin resistance (1–3), represents a unique, natural model for study of the influences of androgenic hormones on bone mass among women. PCOS usually manifests at puberty and is currently recognized as one of the most common endocrine disorders among women of reproductive age, affecting approximately 4% of this population (4). Women with PCOS typically have acyclic production of 17β-estradiol, with circulating concentrations similar to those seen in the follicular phase of cycling women, but considerably lower than the mean 17β-estradiol concentration observed across the normal menstrual cycle (1). This static level of 17β-estradiol, with the absence of the estradiol surge associated with ovulation, would intuitively be expected to negatively affect bone density. Testosterone and androstenedione, however, are produced in excess by the PCOS ovary and perhaps by the adrenals of some affected women. This chronic elevation in androgens may exert a positive influence on bone in PCOS women, either directly through androgen receptors on bone-related cells or indirectly after conversion to 17β-estradiol and estrone, respectively, in peripheral tissues. Moreover, elevated circulating insulin levels, also associated with PCOS, may offer some additional protection against a reduction in bone mass in these women. Hyperinsulinemia has been shown to positively affect bone density (5, 6) through direct stimulatory effects on osteoblastic activity (7) and by the suppressive influences exerted by insulin on the production of sex hormone-binding globulin (SHBG) (8) and insulin-like growth factor (IGF)-binding proteins (IGFBPs) (9). This insulininduced suppression of these binding proteins may result in increased exposure of target tissues, including bone, to the stimulatory effects of elevated concentrations of free sex steroids and IGFs.