Role of cytochrome P450c17 in polycystic ovary syndrome.

The hyperandrogenism of polycystic ovary syndrome (PCOS) appears to be due to dysregulation of steroidogenesis within the ovaries and adrenal glands. P450c17 is the key enzyme that regulates androgen synthesis. It is the only enzyme known to have the capacity to convert C21-precursors to the androgen pre-hormones, the 17-ketosteroids. It is a single enzyme with two activities, 17-hydroxylase and 17,20-lyase. Thus, its regulation is a significant factor in the expression of hyperandrogenism. Androgen secretion is LH-dependent in the ovary and ACTH-dependent in the adrenal glands. The androgenic response to each of these tropic hormones seems to be modulated by intra-ovarian or intra-adrenal autocrine and paracrine mechanisms. This modulation serves to regulate steroid hormone secretion in tissue-specific ways. Insulin, IGFs and inhibin are among the many growth factors capable of augmenting the response to LH and ACTH. The insulin/IGF system stimulates P450c17 mRNA expression and activities in the ovaries and adrenal glands. An integrating link between insulin resistance and hyperandrogenemia may be serine phosphorylation, which inhibits activity of the insulin receptor and promotes the 17,20-lyase activity of P450c17. However, it must be kept in mind that there is some evidence for the existence of P450c17-independent pathways of androgen biosynthesis.