Developmental Programming: Impact of Prenatal Testosterone Excess and Postnatal Weight Gain on Insulin Sensitivity Index and Transfer of Traits to Offspring of Overweight Females

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women and is exacerbated by obesity. Exposure of ewes to excess testosterone (T) from d 30-90 of gestation culminates in anovulation, functional hyperandrogenism, LH excess, and polyfollicular ovaries, features similar to those of women with PCOS, with some reproductive defects programmed by androgenic actions of T and others not. Excess weight gain during postnatal life increases the severity of these reproductive defects. Prenatal T-treated ewes also manifest reduced insulin sensitivity, a feature found in more than 70% of PCOS women. We tested the hypotheses that reduced insulin sensitivity of prenatal T-treated ewes is programmed by androgenic actions of T, and excess postnatal weight gain exaggerates this defect. In addition, we tested whether disruptive effects of excess weight gain on insulin sensitivity index are transferred to female offspring. Insulin sensitivity was assessed using iv glucose tolerance tests. Results revealed that disruptive effects of prenatal T excess on insulin sensitivity were programmed by androgenic action of T and postnatal overfeeding-impaired insulin sensitivity in both T-treated and controls and that prenatal T-treated sheep tend to manifest such overfeeding impairments earlier than controls. Importantly, offspring of overweight controls also manifest defects in insulin dynamics supportive of intergenerational transfer of obesity-related traits. The findings are of relevance in the context of developmental programming of insulin resistance by prenatal steroids and excess weight gain.