Abstract
Objective: Differentiation of endometrial stromal cells (ESC) into morphologically and functionally specialized decidual cells (decidualization) is indispensable for the establishment and maintenance in human pregnancy. Progesterone (P4) is the major steroid hormone that induces decidualization in human ESC. Recently, it has been reported that testosterone and its active derivative, dihydrotestosterone which is converted by 5α-reductase promote decidualization. Although P4 is metabolized by 5α-reductase to allopregnanolone in the mammalian brain, whether the enzymes metabolize P4 in ESC has not been determined. In this study, we explored the role of 5α-reductases in P4 metabolism in the process of ESC differentiation.
Methods: Human ESC was pretreated with P4 and dibutyryl cAMP (P4/db-cAMP) for 2 days to induce decidualization, and then incubated for additional 2 days with P4. The level of P4 and its metabolite allopregnanolone in culture media was compared with the unstimulated control and P4/db-cAMP-stimulated decidual cells. The effects of dutasteride, an inhibitor of both type 1 and type 2 5α-reductase and finasteride, an inhibitor of type 2 5α-reductase on P4 metabolism and P4/db-cAMP-induced decidual markers (IGFBP-1 and prolactin) expression were examined. The expression of SRD5A1 and SRD5A3 (encoding 5α-reductases type 1 and type 3, respectively) was determined by quantitative RT-PCR.
Results: The level of intact P4 was significantly high in media of P4/db-cAMP-stimulated decidual cells compared with that in undifferentiated control cells. Conversely, allopregnanolone level in decidual cells was less than in control cells. Inhibitors of 5α-reductase, dutasteride and finasteride repressed P4 metabolism in ESC. The P4/db-cAMP-stimulated IGFBP1 and prolactin expression was markedly enhanced by the treatment with dutasteride and finasteride. Furthermore, the expression of SRD5A1 but not SRD5A3 was decreased in P4/db-cAMP-induced decidual cells.
Conclusion: These results suggest that P4 is metabolized by 5α-reductase in ESC and the enzymes-mediated P4 metabolism may be negatively regulated to increase local P4 contents for promoting decidualization.
