Figure 1. Basic Pathophysiology of Hyperandrogenemia in the Polycystic Ovary Syndrome.

Since ovarian steroidogenesis requires gonadotropin stimulation, luteinizing hormone (LH) is a key factor in the hyperandrogenemia of the polycystic ovary syndrome.² Progesterone is the primary regulator of gonadotropin-releasing hormone (GnRH) pulse frequency; however, in the polycystic ovary syndrome, the GnRH pulse generator is relatively resistant to the negative feedback effects of progesterone.³ This resistance to progesterone negative feedback appears to be mediated by androgen excess (since it is reversed by the androgen-receptor blocker flutamide).⁴ Resulting high GnRH pulse frequencies favor production of LH and limit production of follicle-stimulating hormone (FSH), which promote androgen production and interfere with normal follicular development. The polycystic ovary syndrome is associated with inherent abnormalities of ovarian (and adrenal) steroidogenesis: cultured ovarian theca cells from women with the polycystic ovary syndrome secrete excess androgens and precursors,⁵ and women with the polycystic ovary syndrome have exaggerated ovarian steroidogenic responses to gonadotropin stimulation.⁶ A recent study suggests that increased expression of a DENND1A splice variant drives a polycystic ovary syndrome–like steroidogenic phenotype in theca cells.⁷ The polycystic ovary syndrome is associated with insulin resistance — which is at least partly independent of obesity — and compensatory hyperinsulinemia.⁸ Hyperinsulinemia contributes to hyperandrogenemia in several ways: it augments LH-stimulated androgen production by ovarian theca cells, it potentiates corticotropin-mediated adrenal androgen production, and it inhibits hepatic synthesis of sex hormone–binding globulin (SHBG), which increases free testosterone levels. The precise effects of hyperinsulinemia on gonadotropin secretion remain unclear. 3ß-HSD denotes 3ß-hydroxysteroid dehydrogenase, 17ß-HSD 17ß-hydroxysteroid dehydrogenase, SCC cholesterol side-chain cleavage enzyme, and StAR steroidogenic acute regulatory protein.