Developmental Programming of Polycystic Ovary Syndrome: Role of Prenatal Androgen Excess

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine/metabolicdisorder in women, characterized by hyperandrogenism, chronicanovulation, and/or polycystic ovaries in association with android fatdistribution and insulin resistance/hyperinsulinism. The etiology ofPCOS remains elusive but there is increasing evidence that thephenotypic traits of the syndrome may be programmed in utero by androgenexcess. Thus, female primates, exposed to androgen excess during fetallife, exhibit the reproductive and metabolic features of PCOS inadulthood. Women with congenital 21-hydroxylase deficiency andcongenital adrenal virilizing tumors develop features characteristic ofPCOS during adult life, despite the normalization of androgen excessafter birth. Rare cases of women with congenital sex hormone-bindingglobulin (SHBG) and P450 aromatase deficiency may also develop some ofthe features of PCOS in adulthood.The potential sources of gestational hyperandrogenism to account for thedevelopmental programming of PCOS in humans are not clearly understood.However, maternal and/or fetal hyperandrogenism, in association withreduced placental SHBG and/or aromatase activity, can provide aplausible mechanism and this, in part, may be genetically determined.Indeed, genetic association studies have indicated that common variantsof genes determining androgen activity or genes that influence theavailability of androgens to target tissues are associated with PCOS andincreased androgen levels. These genetic variants may provide thegenetic link to prenatal androgenization in human PCOS.It appears, therefore, that prenatal androgenization of the femalefetus, induced by genetic factors and environmental signals, or by theinteraction of both, may program the differentiating target tissuestoward the development of PCOS in adult life.