Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent hyperandrogenic infertility and cardiometabolic disorder that increases a woman's lifetime risk of type 2 diabetes mellitus. It is heritable and intensely familial. Progress toward a cure has been delayed by absence of an etiology. Evidence is mounting, however, for in utero T excess, together with gestational hyperglycemia, contributing to either early differentiation of PCOS or phenotypic amplification of its genotypes. Abnormal endocrine, ovarian, and hyperinsulinemic traits are detectable as early as 2 months of age in daughters of women with PCOS, with adiposity enhancement of hyperinsulinemia during childhood potentially contributing to hyperandrogenism and LH excess by adolescence. These findings encourage increasing clinical focus on early childhood markers for adiposity and hyperinsulinemia accompanying ovarian and adrenal endocrine abnormalities that precede a diagnosable PCOS phenotype. They raise the possibility for lifestyle or therapeutic intervention before and during pregnancy or during childhood and adolescence alleviating the manifestations of a familial genetic predisposition to PCOS.

Figure 1

Proposed ontogeny of PCOS with manifestations starting in childhood: Interaction of genetic and environmental factors shape the intrauterine environment leading to epigenetic changes and alteration of organ function at several levels. Childhood obesity and its associated insulin resistance further enhance the manifestations of genetic/epigenetic traits predisposing to hyperandrogenism, including effects on steroidogenesis and hypothalamic/pituitary function. The dashed lines represent relationships that have not been clearly established.