Endocrine Abstracts

PCOS is associated with increased androgens, elevated insulin and obesity. As obesity and androgens promote insulin resistance and hyperinsulinemia increases ovarian androgen production, and the likelihood of obesity, the interaction between these factors is complex. We investigated the development of insulin resistance, hyperandrogenism and obesity using a clinically realistic ovine model of PCOS. Exposure of the pregnant ewe to increased testosterone from d62 to d102 of gestation (d147) programs female offspring to develop a PCOS-like condition. These offspring have normal external genitalia and a normal birthweight. However in adulthood they become obese with hyperinsulinemia, increased ovarian and adrenal androgens and anovulation. Increased androgen and insulin concentrations are manifest in adolescence when the sheep are ovulatory and of normal weight. However there are fetal antecedents of hyperinsulinemia in the pancreas and of hyperandrogenism in the ovary. This suggests that insulin and androgen dysregulation develop in parallel, with fetal origins, as a consequence of prenatal androgen action. Androgen administration to control adult females reduced insulin sensitivity to that of the PCOS-like adults while androgen treatment of PCOS-like sheep did not cause any further deterioration. Metabolic assessment of prenatally programmed PCOS-like adult sheep demonstrated a reduction in postprandial thermogenesis, not seen in weight matched control sheep with intake-driven obesity, which was correlated with insulin resistance. This was associated with molecular alterations in subcutaneous adipocyte function, which could first be detected in adolescence before the development of obesity. Androgens alter energy balance in females but in PCOS it is likely that prenatal exposure to increased androgens, rather than ongoing postnatal exposure, is a major factor in the dysregulated energy balance. Women with PCOS have reduced post-prandial thermogenesis and this is recapitulated in the ovine model of PCOS. This suggests that women with PCOS have a driver towards obesity with developmental origins.