Dienogest reduces HSD17 beta 1 expression and activity in endometriosis

作者：Mori Taisuke^*; Ito Fumitake; Matsushima Hiroshi; Takaoka Osamu; Koshiba Akemi; Tanaka Yukiko; Kusuki Izumi; Kitawaki Jo

来源：Journal of Endocrinology, 2015, 225(2): 69-76.

DOI：10.1530/JOE-15-0052

• 17 beta-hydroxysteroid dehydrogenase 1
• dienogest
• endometriosis
• ovarian endometrioma
• spheroid culture

Endometriosis is an estrogen-dependent disease. Abnormally biosynthesized estrogens in endometriotic tissues induce the growth of the lesion and worsen endometriosis-associated pelvic pain. Dienogest (DNG), a selective progesterone receptor agonist, is widely used to treat endometriosis and efficiently relieves the symptoms. However, its pharmacological action remains unknown. In this study, we elucidated the effect of DNG on enzymes involved in local estrogen metabolism in endometriosis. Surgically obtained specimens of 23 ovarian endometriomas (OE) and their homologous endometrium (EE), ten OE treated with DNG (OE w/D), and 19 normal endometria without endometriosis (NE) were analyzed. Spheroid cultures of stromal cells (SCs) were treated with DNG and progesterone. The expression of aromatase, 17 beta-hydroxysteroid dehydrogenase 1 (HSD17 beta 1), HSD17 beta 2, HSD17 beta 7, HSD17 beta 12, steroid sulfatase (STS), and estrogen sulfotransferase (EST) was evaluated by real-time quantitative PCR. The activity and protein level of HSD17 beta 1 were measured with an enzyme assay using radiolabeled estrogens and immunohistochemistry respectively. OESCs showed increased expression ofaromatase, HSD17 beta 1, STS, and EST, along with decreased HSD17 beta 2 expression, when compared with stromal cells from normal endometria without endometriosis (NESCs) (P<0.01) or stromal cells from homologous endometrium (EESCs) (P<0.01). In OESCs, DNG inhibited HSD17 beta 1 expression and enzyme activity at 10(-7) M (P<0.01). Results of immunohistochemical analysis displayed reduced HSD17 beta 1 staining intensity in OE w/D (P<0.05). In conclusion, DNG exerts comprehensive inhibition of abnormal estrogen production through inhibition of aromatase and HSD17 beta 1, contributing to a therapeutic effect of DNG on endometriosis.

• 出版日期2015-5