Androgen excess is a key feature of the polycystic ovary syndrome (PCOS), which affects 510% of the female population and comes with a significantly increased metabolic risk. Rare disorders often teach us important lessons about common disease and this is highlighted by two novel variants of congenital adrenal hyperplasia we recently identified.
In 1985, a patient with combined deficiencies of 17-hydroxylase and 21-hydroxylase was reported. However, the encoding genes were normal. We identified the molecular basis of this disorder, inactivating mutations in P450 oxidoreductase (POR), the mandatory electron donor for 17-hydroxylase and 21-hydroxylase. Uniquely, both affected 46,XX and 46,XY individuals present with disordered sex development. Male undervirilisation is a logic consequence of 17-hydroxylase deficiency and subsequent lack of synthesis of DHEA, the crucial precursor of human sex steroid synthesis. However, virilisation in affected girls was an apparently contradictory finding, which we now have shown to be explained by the existence of an alternative pathway towards active androgens, with important implications for normal and disordered human fetal development.
DHEA is efficiently converted to active androgens or alternatively to its sulfate ester, DHEAS. We have shown that DHEA and DHEAS are not interconverted freely and continuously as previously assumed; thus, the conversion of DHEA to DHEAS represents a permanent inactivation. Impairment of DHEA sulfation will therefore result in an increased flux of DHEA towards androgen synthesis. We have analysed a girl presenting with premature pubic hair development, followed by the onset of acne, hirsutism, oligo- and eventually amenorrhoea, i.e. hallmark features of early-onset PCOS, increasingly frequent in young girls due to the increase in obesity rates. However, in this girl DHEAS levels were undetectable whereas DHEA and active androgens were high, suggesting a defect in DHEA sulfation. We have identified the underlying molecular defect, highlighting novel candidate genes for PCOS.