Proinflammatory environment and role of TNF-α in endometrial function of obese women having polycystic ovarian syndrome

Abstract

BACKGROUND/OBJECTIVES: A high percentage of women having polycystic ovarian syndrome (PCOS) exhibit hyperinsulinemia and obesity. Transforming necrosis factor-alpha (TNF-alpha) is an adipokine that increases in obesity and negatively affects insulin action in several tissues, including the endometrium. In fact, it has been reported that insulin signaling is altered in the endometrium of PCOS women, affecting its reproductive function. The aim of this study was to determine the proinflammatory environment and TNF-alpha signaling in endometrium from obese women with PCOS, and also to evaluate the effect of TNF-alpha on endometrial cell energy homeostasis.

METHODS: Serum and endometrial tissues were obtained from four study groups: normal-weight, normal-weight-PCOS, obese and obese-PCOS (hyperandrogenemia/hyperinsulinemia) (n = 7 per group). Serum TNF-alpha level was assayed by enzyme-linked immunosorbent assay (ELISA); endometrial TNF-alpha level and its receptors (TNFR1/TNFR2) as well as nuclear factor (NF)-kappa B content were determined by immunohistochemistry. Finally, we evaluated TNF-alpha effect on glucose uptake in cultured human endometrial stromal cells (T-HESC) treated or not with testosterone/insulin resembling partially the PCOS condition.

RESULTS: TNF-alpha plasma levels were similar between groups, whereas cytokine levels and macrophage number increased in endometrium from obese-PCOS women (P < 0.001). Both receptor types were higher in obese vs normal-weight women, particularly TNFR2 content in the obese-PCOS group (P < 0.001). Furthermore, an increased NF-kappa B nuclear content in endometrium from obese-PCOS was observed (P < 0.001). Finally, TNF-alpha treatment of T-HESC cultures exhibited a decrease of glucose uptake (P < 0.05), although similar to cells treated with testosterone or testosterone/insulin/TNF-alpha.

CONCLUSIONS: These results suggest that the PCOS condition induces an inflammatory state exacerbated when obesity is present, where a higher TNF-alpha signaling is observed, all of which could affect glucose uptake in the tissue and may cause fertility failures in these women