Androgen receptor and uterine histoarchitecture in a PCOS rat model

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenemia and uterine abnormalities. Our aim was to investigate the uterine effects of PCOS that are mediated through the androgen receptor (AR). After weaning, female rats were treated with sesame oil (Control), dehydroepiandrosterone (DHEA), or DHEA + flutamide (FLU, an AR antagonist) for 20 consecutive days. On postnatal day 41, serum, ovarian and uterine tissues were collected. DHEA and DHEA + FLU rats showed increased testosterone levels. DHEA rats showed increased epithelial height, glandular density, subepithelial stroma and myometrial thickness, associated with decreased nuclei density. These rats also showed increased uterine water content, with decreased aquaporin (AQP) 3, 7 and 8 expression in the uterine epithelium and increased AQP8 expression in the myometrium. DHEA rats also showed decreased uterine collagen remodeling, decreased cell proliferation in the subepithelial stroma, and increased apoptosis in the luminal and glandular epithelium and in the myometrium. They also showed an increase in insulin-like growth factor-1 and a decrease in phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. The uterine stroma of DHEA rats showed no changes in progesterone receptor or estrogen receptor alpha (ERα) and increased AR expression. DHEA + FLU rats showed a smaller increase in the myometrial thickness, an increase in the uterine water content without AQP8 induction and a smaller decrease in collagen remodeling. These rats also showed no apoptosis induction and decreased proliferation in the myometrium, decreased ERα in the subepithelial stroma and myometrium and no modifications in AR. Our results demonstrate that the uterine cell turnover and collagen remodeling in DHEA rats are regulated through AR, directly or indirectly associated with ERα expression.