Ovarian Dysfunction in a Sheep Model of Polycystic Ovary Syndrome and Impact of Postnatal Obesity

Project Summary/Abstract (< 500 words): Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women, yet the developmental perturbations that lead to this condition are not fully understood. Animal models have demonstrated that prenatal exposure to excess testosterone (T) can recapitulate key features of PCOS—including polycystic ovarian morphology, oligo/anovulation, and metabolic dysfunction—supporting the hypothesis that in-utero hormonal perturbations can program ovarian dysfunction. Further, postnatal external environmental conditions, such as overnutrition, may further unmask or exacerbate these programmed changes in the ovary. Given that a significant proportion of women with PCOS are overweight or obese, it is critical to understand how postnatal metabolic status interacts with the prenatally programmed phenotype to affect ovarian function. The proposed studies aim to improve our understanding of the impact of prenatal exposure to excess T and postnatal overfeeding to induce obesity on ovarian antral follicles in a sheep model of PCOS. We will test the hypotheses that: 1) prenatal T excess from gestational days 60-90 disrupts gene expression in granulosa and theca cells of antral follicles in the adult ovary, and 2) that postnatal obesity exacerbates these transcriptomic disruptions, which will be consistent with the PCO-obese phenotype. Results from the proposed study will define the cell-specific transcriptional signatures of ovarian dysfunction and the interaction between prenatal testosterone excess and postnatal obesity. This work will improve our understanding of the developmental origins of PCOS and obesity-related ovarian dysfunction in women, which provides a foundation for future intervention and prevention strategies to be developed. This aligns with the SSR Mission (Advance the Science of Reproduction, Fertility, and Development for the Benefit of Humans and Animals) and Vision (A Sustainable World Through the Science of Reproduction, Fertility, and Development).