Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system

Prostaglandin E2 (PGE2) is a major mediator in the pathophysiology, and pathogenesis of gynecological diseases associated with abnormal endometrial disease with proliferation and inflammation, such as endometriosis. In this study, we investigated the effect of dienogest, a selective progesterone receptor agonist, on PGE2 production and the expression of aromatase, an estrogen synthase, in human immortalized endometrial epithelial cells. Compared with monolayer culture, the cells showed enhanced PGE2 production and expression of the PGE2 synthases cyclooxygenase-2 (COX-2), and microsomal prostaglandin E2 synthase-1 (mPGES-1) in a spheroid culture system. Dienogest inhibited PGE2 production and this effect was reversed by RU486, a progesterone receptor antagonist. Dienogest inhibited the PGE2 synthases mRNA and protein expression, and the nuclear factor-κB activation. Moreover, the suppressive effect of dienogest on PGE2 production was sustained 24 h after the drug was withdrawn. Dienogest but not COX inhibitors inhibited aromatase expression. These results suggest that progesterone receptor activation reduces the gene expressions of COX-2, mPGES-1, and aromatase. Our findings suggest that the pharmacological mechanism of dienogest includes the direct inhibition of PGE2 synthase and aromatase expression and may contribute to the therapeutic effect on the progression of endometriosis.