Endocrine Abstracts

Polycystic Ovary Syndrome (PCOS) is an endocrine disorder affecting 10-15% of women worldwide, characterized by high androgen levels, anovulation and/or polycystic ovarian morphology. Chronic low-grade inflammation is associated with the disorder as well as many of its comorbidities, such as obesity and type-2 diabetes. To determine the role of the immune system in the pathophysiology of PCOS, we characterized the immune profile of the dihydrotestosterone (DHT)-induced PCOS-like mouse model. Prepubertal female mice implanted with a DHT-pellet displayed reproductive dysfunction, with a disrupted estrous cyclicity and increased anogenital distance, and a metabolic phenotype similar to the comorbidities seen in women with PCOS, with increased body weight and fat mass (EchoMRI), higher fasting glucose and impaired glucose uptake following oral glucose tolerance test. The immune profiles of reproductive, immunological, and metabolic tissues were analyzed by flowcytometry. The number of eosinophils in endometrium was decreased in the DHT-induced PCOS model compared to control, whereas infiltration of peripheral NK cells was increased. Moreover, an overall shift towards a pro-inflammatory M1 phenotype was seen among macrophages in endometrium of DHT exposed mice, indicated by a higher proportion of macrophages expressing MHC-II, and a trend suggested an increased total number of macrophages. The same effect on eosinophils was seen in visceral adipose tissue (VAT), with no effect on circulating eosinophils. Macrophage immune-phenotype and number followed the same pattern in VAT as in endometrium. Next, an increased number of NK cells was found in the spleen as in endometrium, while there was no difference in number of NK cells in blood in DHT-exposed mice. Strikingly, these mice had a clear reduction in CD8+ cytotoxic T cells in the spleen and in blood, as well as an overall reduction in the CD3+ lymphocyte population in blood. Interestingly, there was no difference in the number of CD4+ T helper cells, neither in blood nor spleen. The altered T cell populations could be due to androgen receptor activation on thymic epithelial cells as androgens suppress thymopoiesis in male mice. This hypothesis is supported by the decreased thymic weight in the DHT-induced PCOS model. In summary, we show that the prepubertal PCOS-like model displays an altered immune profile in a wide range of tissues. Whether these alterations are a result of androgen receptor activation and/or a result of metabolic dysfunctions remains to be elucidated, and it remains to define what impact these immune alterations have on reproductive and metabolic function.