The serine phosphorylation hypothesis of polycystic ovary syndrome: a unifying mechanism for hyperandrogenemia and insulin resistance  Andrew A. Bremer, M.D., Ph.D., Walter L. Miller, M.D.  Fertility and Sterility  Volume 89, Issue 5, Pages 1039-1048 (May 2008) DOI: 10.1016/j.fertnstert.2008.02.091 Copyright © 2008 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Integrated view of human steroidogenesis, showing adrenal and gonadal pathways. Reaction 1: P450scc converts cholesterol to pregnenolone. Reaction 2: 3β-HSD converts Δ5 steroids (pregnenolone, 17OH-pregnenolone, DHEA, androstenediol) to the corresponding Δ4 steroids (progesterone, 17OH-progesterone, androstenedione, testosterone). Reaction 3: P450c17 catalyzes the 17α-hydroxylation of pregnenolone and progesterone. Reaction 4: The 17,20-lyase activity of P450c17 converts 17OH-pregnenolone to DHEA; the conversion of 17OH-progesterone to androstenedione occurs in cattle and rodents, but human P450c17 cannot catalyze this reaction efficiently. Reaction 5: P450c21 catalyzes the 21-hydroxylation of progesterone and 17OH-progesterone. Reaction 6: Deoxycorticosterone (DOC) can be converted to corticosterone by either P450c11AS (in the adrenal zona glomerulosa) or P450c11β (in the adrenal zona fasciculata). Reaction 7: P450c11β converts 11-deoxycortisol to cortisol. Reactions 8 and 9: P450c11AS catalyzes 18 hydroxylase (reaction 8) and 18 methyl oxidase activities (reaction 9) to produce aldosterone in the adrenal zona glomerulosa. Reaction 10: Two isozymes of 17βHSD activate sex steroids: 17β-HSD1 produces estradiol and 17β-HSD3 produces androgens. In peripheral tissues 17β-HSD5 has similar activity to 17β-HSD3, and 17β-HSD2 and -4 catalyze the “reverse” reactions to inactivate sex steroids. Reaction 11: P450aro aromatizes C19 androgenic steroids to C18 estrogens. Fertility and Sterility 2008 89, 1039-1048DOI: (10.1016/j.fertnstert.2008.02.091) Copyright © 2008 American Society for Reproductive Medicine Terms and Conditions

Figure 2 The differential effects of tyrosine (Tyr) vs. serine (Ser) phosphorylation of the IR. Tyrosine phosphorylation of IRβ after the binding of insulin to IRα leads to tyrosine phosphorylation of IRS-1 and the activation of downstream effector molecules. However, serine phosphorylation of IRβ inhibits IRS-1 activation. Fertility and Sterility 2008 89, 1039-1048DOI: (10.1016/j.fertnstert.2008.02.091) Copyright © 2008 American Society for Reproductive Medicine Terms and Conditions

Figure 3 The serine phosphorylation hypothesis. The serine phosphorylation hypothesis proposes that a dominantly inherited kinase (or kinases) serine phosphorylates both IRβ and P450c17, leading to insulin resistance and increased androgen production, respectively. Both positive and negative regulatory factors may modulate kinase activity. Fertility and Sterility 2008 89, 1039-1048DOI: (10.1016/j.fertnstert.2008.02.091) Copyright © 2008 American Society for Reproductive Medicine Terms and Conditions

Figure 4 Regulation of 17,20-lyase activity by reversible phosphorylation of P450c17. Arrows indicate stimulation, and blocked lines indicate inhibition. A cyclic adenosine monophosphate (cAMP)–dependent serine/threonine (S/T) kinase stimulates the 17,20-lyase activity of P450c17 and a tyrosine (Y) kinase, SET and okadaic acid (OA) inhibit protein phosphatase 2A (PP2A). The nature of the kinases that regulate SET and that presumably regulate S/T kinases are unknown. ATP = adenosine triphosphate; ADP = adenosine diphosphate; OR = P450 oxidoreductase; b5 = cytochrome b5. [Derived from A.V. Pandey et al. J Biol Chem 2003;278:2837–44. (131)] Fertility and Sterility 2008 89, 1039-1048DOI: (10.1016/j.fertnstert.2008.02.091) Copyright © 2008 American Society for Reproductive Medicine Terms and Conditions