Metformin inhibits estradiol and progesterone-induced decidualization of endometrial stromal cells by regulating expression of progesterone receptor, cytokines and matrix metalloproteinases.

BACKGROUND

Polycystic ovary syndrome (PCOS) is a serious threat for reproductive-aged women. Metformin has been used for the treatment of PCOS. However, its molecular mechanism in decidualization process of PCOS has not been well featured.

METHODS

RT-qPCR analysis was used to detect expression patterns of progesterone receptor (PGR), estradiol receptor alpha (ERα), Cytokeratin 8 and Vimentin in endometrial tissues of PCOS and non-PCOS patients. RT-qPCR assay was also employed to determine mRNA expression of prolactin, Insulin-like growth factor-binding protein 1 (IGFBP-1), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP9). Cytokine secretion were measured by matching ELISA kits. Protein expression of p-ERK1/2, ERK1/2, p-p38 MAPK, p38 MAPK, and PGR (PGRA and PGRB) was tested by western blot assay.

RESULTS

PGR expression was upregulated in PCOS patients. Metformin alleviated estradiol (E2) and progesterone (P4) (EP)-induced decidualization of endometrial stromal cells. Abnormal cytokine secretion was observed in EP-stimulated endometrial stromal cells in the absence or presence of metfromin. Metformin suppressed EP-induced MMP-2 and MMP-9 upregulation. Metformin alleviated EP-triggered p38 MAPK inactivation and PGR (PGRA and PGRB) expression. Metfromin had no effect on ERK1/2 signaling in EP-stimulated endometrial stromal cells.

CONCLUSION

Metformin alleviated EP-induced decidualization of endometrial stromal cells by modulating secretion of multiple cytokines, inhibiting expression of MMP-2 and MMP-9, activating p38-MAPK signaling and reducing PGR expression, providing a deep insight into the molecular basis of metfromin therapy for PCOS patients.