OR11-05 Insulin Signaling In The PCOS Ovary

Abstract Disclosure: K. Vann: None. A. Weidner: None. A. Roy: None. O. Astapova: None. Polycystic ovary syndrome (PCOS) is a common and life-long endocrinopathy that affects around 10% of women and causes reproductive and metabolic derangements, culminating in infertility, increased cardiovascular risk and reduced quality of life. Its pathophysiology is driven by a vicious cycle of hypothalamic-pituitary-gonadal and metabolic hormone imbalance in which hyperandrogenism and insulin resistance potentiate each other through poorly understood mechanisms. To investigate the ovarian implications of systemic insulin resistance in PCOS, we utilized a chronic postnatal dihydrotestosterone (DHT)-exposed mouse model and verified that it develops both reproductive and metabolic manifestations of PCOS, including antral follicle arrest, cystic follicles and anovulation, excess adiposity, insulin resistance and compensatory hyperinsulinemia. Further, we isolated and cultured primary hepatocytes from these PCOS mice and confirmed that both insulin-induced hepatic AKT phosphorylation and FOXO1 nuclear export are impaired, as expected in insulin resistance. However, in primary ovarian granulosa and theca cells isolated from the same PCOS mice, there was no defect in these measures of insulin signaling, despite systemic insulin resistance, suggesting that the PCOS ovary is uniquely insulin-sensitive and exposed to chronic hyperinsulinemia due to systemic insulin resistance. To better understand the effect of hyperandrogenemia on ovarian insulin signaling, we treated primary mouse granulosa cells with DHT for 24 hours before stimulation with insulin. Both insulin-induced AKT phosphorylation and FOXO1 nuclear export were significantly reduced or absent after DHT exposure in this setting, indicating that hyperandrogenemia can initially impair insulin signaling in granulosa cells, but in PCOS the ovaries may overcome this defect over time. Thus, insulin stimulation of the PCOS ovary may be excessive due to chronic hyperinsulinemia and may contribute to ovarian dysfunction. In fact, PCOS theca cells demonstrated increased testosterone production when stimulated with both insulin and human chorionic gonadotropin. In summary, we show that the PCOS ovary is insulin-sensitive despite systemic insulin resistance, leading to excessive insulin stimulation due to chronic hyperinsulinemia, which may contribute to ovarian dysfunction in PCOS. Presentation: Saturday, July 12, 2025