TGF‐β1 stimulates aromatase expression and estradiol production through SMAD2 and ERK1/2 signaling pathways in human granulosa‐lutein cells

Abstract Estradiol (E2), one of the main steroid hormones secreted by the ovaries, plays an important role in maintaining normal female reproductive function. Ovarian granulosa cells are the main source of E2 production because these cells express aromatase, which is encoded by the CYP19A1 gene and catalyzes the final step in E2 biosynthesis from androgens. Transforming growth factor‐beta 1 (TGF‐β1) and its receptors are expressed in human granulosa cells, and TGF‐β1 expression can be detected in human follicular fluid. To date, TGF‐β1 has been shown to regulate various ovarian functions. However, whether aromatase can be regulated by TGF‐β1 in human granulosa cells has not been determined. In the present study, we demonstrate that TGF‐β1 stimulates aromatase expression in primary human granulosa‐lutein cells and in the human ovarian granulose‐like tumor cell line, KGN. We used pharmacological inhibitors and small interfering RNA‐mediated knockdown approaches to reveal that the SMAD2 and ERK1/2 signaling pathways are involved in TGF‐β1‐induced aromatase expression and E2 production. These results not only provide important insights into the molecular mechanisms that mediate TGF‐β1‐induced aromatase expression and E2 production in human granulosa cells but also increase the understanding of the normal physiological roles of TGF‐β1 in the ovary.