Dienogest reduces HSD17β1 expression and activity in endometriosis

Abstract

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, 17b-hydroxysteroid dehydrogenase 1 (HSD17b1), HSD17b2, HSD17b7, HSD17b12, steroid sulfatase (STS), and estrogen sulfotransferase (EST) was evaluated by real-time quantitative PCR. The activity and protein level of HSD17b1 were measured with an enzyme assay using radiolabeled estrogens and immunohistochemistry respectively. OESCs showed increased expression of aromatase, HSD17b1, STS, and EST, along with decreased HSD17b2 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 HSD17b1 expression and enzyme activity at 10 K7 M (P!0.01). Results of immunohistochemical analysis displayed reduced HSD17b1 staining intensity in OE w/D (P!0.05). In conclusion, DNG exerts comprehensive inhibition of abnormal estrogen production through inhibition of aromatase and HSD17b1, contributing to a therapeutic effect of DNG on endometriosis.

E2‐mediated EMT by activation of β‐catenin/Snail signalling during the development of ovarian endometriosis

“…The detailed immunostaining score for E‐cadherin, vimentin, β‐catenin and Snail is shown in Table , respectively. 17β‐hydroxysteroid dehydrogenase 1 (17β‐HSD1) is a predominant enzyme that catalyse the estrone to oestradiol (E 2 ) . In Figure B, we also detected 17β‐HSD1 mRNA levels were higher in OC compared with EU and NC.…”

“…is a predominant enzyme that catalyse the estrone to oestradiol (E 2 ). 33,34 In Figure 1B, we also detected 17β-HSD1 mRNA levels were higher in OC compared with EU and NC.…”

Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer

“…In the strongly progesterone receptor (PgR) positive breast cancer cell line T-47D, progesterone, levonorgestrel, and medroxyprogesterone acetate were shown to up-regulate HSD17B1 and HSD17B5 expression and down-regulate HSD17B2 expression, with smaller effects seen on HSD17B1 expression in the moderately positive MCF7 [79]. Recently the progestin Dienogest was shown to down-regulate both HSD17B1 and aromatase expression in endometriosis patients, if this is also applicable in breast cancer remains to be seen [80]. In addition, HSD17B1 has long been known to be under the positive stimulatory influence of growth factors like insulin-like growth factors Types I and II and retinoic acid and immunological factors like interleukin 1 (IL-1), IL-6 and tumor necrosis factor α (TNFα) and it is possible that the cells of the immune system are an important source of the factors that modulate the expression and activity of HSD17B1 is breast tumors [53].…”

Aromatase as a target for treating endometriosis

“…Accumulating evidence showed that dienogest directly inhibited progesterone receptor‐mediated cell proliferation and the production of inflammatory cytokines, toll‐like receptor 4 and nerve growth factor . Our group showed, using spheroid cultures of endometriotic stroma cells, that dienogest reduced the expression of aromatase and the expression and enzyme activity of 17ß‐HSD1, which catalyze the conversion of less potent E 1 to the more potent E 2 form in tissues . These findings suggest that dienogest comprehensively inhibits abnormal estrogen production in endometriosis.…”