title: 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, 17β-hydroxysteroid dehydrogenase 1 (HSD17β1), HSD17β2, HSD17β7, HSD17β12, steroid sulfatase (STS), and estrogen sulfotransferase (EST) was evaluated by real-time quantitative PCR. The activity and protein level of HSD17β1 were measured with an enzyme assay using radiolabeled estrogens and immunohistochemistry respectively. OESCs showed increased expression of aromatase, HSD17β1, STS, and EST, along with decreased HSD17β2 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 HSD17β1 expression and enzyme activity at 10(-7) M (P<0.01). Results of immunohistochemical analysis displayed reduced HSD17β1 staining intensity in OE w/D (P<0.05). In conclusion, DNG exerts comprehensive inhibition of abnormal estrogen production through inhibition of aromatase and HSD17β1, contributing to a therapeutic effect of DNG on endometriosis.
authors.affiliation: Department of Obstetrics and Gynecology Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan moriman@koto.kpu-m.ac.jp.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Obstetrics and Gynecology Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Fumitake
authors.initials: F
authors.lastname: Ito
authors.affiliation: Department of Obstetrics and Gynecology Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsushima
authors.affiliation: Department of Obstetrics and Gynecology Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takaoka
authors.affiliation: Department of Obstetrics and Gynecology Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Koshiba
authors.affiliation: Department of Obstetrics and Gynecology Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Obstetrics and Gynecology Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Kusuki
authors.affiliation: Department of Obstetrics and Gynecology Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Jo
authors.initials: J
authors.lastname: Kitawaki
mesh_terms: D000328:Adult; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004715:Endometriosis / Q000201:enzymology* / Q000235:genetics; D004717:Endometrium / Q000187:drug effects / Q000201:enzymology; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
chemical_list: C023635:dienogest; D009277:Nandrolone; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; D001141:Aromatase
keywords: 17β-hydroxysteroid dehydrogenase 1; dienogest; endometriosis; ovarian endometrioma; spheroid culture