Regulation of Androgen Receptor Expression Alters AMPK Phosphorylation in the Endometrium: In Vivo and In Vitro Studies in Women with Polycystic Ovary Syndrome

The failure of reproductive success in polycystic ovary syndrome (PCOS) patients could be in part due to endometrial dysfunction. However, no studies have investigated any causality between androgen, androgen receptor (AR) expression, and adenosine monophosphate activated protein kinase (AMPK) activation in the endometrium under physiological and pathological conditions. In the present study, we show that 1) endometrial AR expression levels fluctuate in non-PCOS and PCOS patients during the menstrual cycle; 2) the menstrual phase-dependent alteration of p-AMPK alpha expression occurs in non-PCOS patients but not in PCOS patients; 3) AR expression is higher in PCOS patients than non-PCOS patients during hyperplasia while AMPK alpha activation (indicated by the ratio of p-AMPK alpha to AMPK alpha); and 4) co-localization of AR and Ki-67 in epithelial cell nuclei is observed in endometrial hyperplasia. Importantly, using in vitro human tissue culture and an in vivo 5 alpha-dihydrotestosterone-treated rat model, we show that the action of androgen on AMPK alpha activation is likely mediated through nuclear AR, especially in epithelial cells. Collectively, we present evidence that AR expression and AMPK alpha activation depend on menstrual cycle phase and the presence of PCOS, and the data suggest that AR-mediated regulation of AMPK alpha activation might play a role in the development of endometrial hyperplasia.