Developmental Origins of Polycystic Ovary Syndrome: Very Early Phenotypes During the Mini Puberty of Infancy and Beyond

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PROJECT SUMMARY Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women of reproductive age and is associated with significant negative reproductive and metabolic outcomes. As PCOS is highly heritable, daughters of affected women have increased risk, with reported prevalence rates as high as ~70%. Several studies have established that distinct reproductive and metabolic phenotypes can be observed in PCOS daughters prior to puberty, suggesting the pathogenesis of PCOS begins at an early developmental stage in these at-risk girls. Further, studies in animal models of PCOS have demonstrated that exposure to androgens or anti-Mullerian hormone (AMH) during critical developmental periods such as fetal life, the neonatal period, or puberty can program the offspring to develop the reproductive and/or metabolic phenotypes of PCOS during reproductive maturity. Prior to puberty, the hypothalamic-pituitary-gonadal (HPG) axis is quiescent, except during the “mini puberty of infancy”, a transient developmental stage during the first several months of life. The HPG axis is active during this time and gonadotropin and sex steroids reach pubertal levels. Our overarching hypothesis is that mini puberty will unmask an early reproductive phenotype in daughters of women with PCOS, characterized by alterations in gonadotropin and AMH secretion. Studies during this very early age have been limited due to the challenges of pursuing invasive testing in this age group. We will employ minimally invasive methods which will allow us to examine early metabolic and reproductive phenotypes in PCOS daughters without risk of harm to these young girls. Three Aims will test the hypotheses that: 1) PCOS daughters have a distinct reproductive phenotype during the mini puberty of infancy characterized by increased gonadotropin and AMH levels and decreased sex hormone binding globulin (SHBG); 2) PCOS daughters will develop a metabolic phenotype characterized by increased body fat accrual and decreased insulin sensitivity in the first two years of life; 3) LH and AMH levels in PCOS daughters during the mini puberty of infancy will be positively associated with maternal testosterone and AMH levels and negatively associated with maternal insulin sensitivity and adiponectin levels during the second trimester of gestation. We will enroll 120 women with PCOS and 120 control women early in their second trimester of pregnancy. We will measure reproductive hormones and markers of insulin sensitivity and secretion in these women between 24 and 28 weeks gestation. We will collect timed urine samples for assessment of C-peptide, gonadotropin secretion, and steroid hormone metabolism in their infant daughters at 1, 2, and 3 months of age. We will obtain measures of adiposity and capillary blood samples for measurement of SHBG, AMH, and adiponectin at 3, 6, 12, 18, and 24 months of age in the infant daughters. If the Aims are achieved, the impact of this research will result in a paradigm shift in our understanding of the early mechanisms of PCOS. Through the proposed study, we will also establish a cohort for continued longitudinal studies in girls at increased risk for PCOS.