THE REGULATION OF HUMAN P450C17 ACTIVITY - RELATIONSHIP TO PREMATURE ADRENARCHE, INSULIN-RESISTANCE AND THE POLYCYSTIC-OVARY-SYNDROME

The polycystic ovary syndrome (PCOS) is characterized by hyperandrogen ism and insulin resistance, but the connection between these two featu res has been unclear. Androgen synthesis is regulated in part by the r atio of the 17 alpha-hydroxylase and 17,20 lyase activities of P450c17 . Three separate lines of evidence show that the ratio of lyase to hyd roxylase activity is regulated by electron flow from P450 oxidoreducta se. Lyase activity and androgen synthesis are particularly dependent o n the serine phosphorylation of P450c17. Serene phosphorylation of the insulin receptor beta chain causes insulin resistance, and some PCOS women have hyperphosphorylated receptors. We hypothesize that an overa ctive serine/threonine kinase hyperphosphorylates both the insulin rec eptor and P450c17 in PCOS, accounting for the characteristic insulin r esistance and hyperandrogenism of this disease.