Endocrine Abstracts

Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. Rodent models of insulin and human chorionic gonadotropin (hCG) treatment have provided systems in which to study ovarian insulin resistance, ovarian stromal hyperplasia, follicular cyst formation, and impaired mitochondrial function in oocytes as well as to identify the underlying molecular mechanisms behind hyperinsulinemia and hyperandrogenism. Using these rodent models, this study was designed to answer whether the uterus develops insulin resistance in vivo. We showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Next, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. The results of this study highlight for the first time the in vivo effects of chronic insulin and hCG exposure on the development of uterine insulin resistance. In addition, our results demonstrate that dysregulation of the IR-mediated PI3K/Akt signaling pathway and glycolytic metabolism in the uterus is strongly associated with insulin resistance and hyperandrogenism.