Endocrine Abstracts

Hyperandrogenemia (elevated testosterone, T) and metabolic dysfunction are hallmarks of polycystic ovary syndrome (PCOS), which can have varying degrees of ovulatory dysfunction. Adipocyte hypertrophy, induced by obesity and hyperandrogenemia, has been suggested to contribute to the systemic low-grade inflammation thought to be one of the drivers leading to reproductive dysfunction in women with PCOS. However, whether hyperandrogenemia and adipocyte hypertrophy per se induce a proinflammatory response is unknown. Therefore, the primary objective of this study was to focus on the metabolic and immunological effects of WSD and mild hyperandrogenemia on the systemic and tissue-resident proinflammatory milieu using a nonhuman primate (NHP) model. To test whether T+WSD disrupts the immune milieu that may affect normal egg implantation and other relevant reproductive processes, we conducted immune cell profiling during the mid-luteal phase, the interval during the menstrual cycle when the uterine endometrium is permissive for embryo implantation. Individual treatments (i.e., T or WSD alone) were not included in this study because we previously determined that combined treatment led to earlier and more severe metabolic and reproductive impairments, including increased numbers of arrested antral follicles and reduced fertility. Immune cells residing in visceral omental white adipose tissue (OM-WAT), corpus luteum and the contralateral ovary, endometrium, lymph nodes, bone marrow, and peripheral blood mononuclear cells were characterized by flow cytometry during the luteal phase of the reproductive cycle. Following one year of treatment, T+WSD animals became more insulin-resistant and exhibited increased body fat and adipocyte hypertrophy compared to controls. T+WSD treatment did not induce macrophage polarization towards a proinflammatory phenotype in the tissues examined. While the major T-lymphoid cell subsets were not significantly affected by T+WSD treatment, we observed a significant reduction in the frequency of effector memory CD8+ T-cells (Tem) in OM-WAT, but not in other tissues. Notably, OM-WAT Tem frequencies were negatively correlated with insulin resistance as assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Collectively, our data show that short-term T+WSD treatment induces weight gain, insulin resistance, and adipocyte hypertrophy, but does not have a significant effect on systemic and tissue-resident proinflammatory markers, suggesting that adipocyte hypertrophy and mild hyperandrogenemia alone are not sufficient to induce a proinflammatory response. Additionally, hyperandrogenemia may induce immune tolerance in T-cells. Dysregulation of T-cell function can lead to immune-related complications that may affect implantation and early pregnancy outcomes.