title: Dienogest, a synthetic progestin, down-regulates expression of CYP19A1 and inflammatory and neuroangiogenesis factors through progesterone receptor isoforms A and B in endometriotic cells.
abstract: Dienogest (DNG) is a selective progesterone receptor (PR) agonist and oral administration of DNG is used for the treatment of endometriosis. DNG is considered to act on PR to down-regulate pathophysiological factors associated with endometriosis. PR exists as two major isoforms, PR-A and PR-B, and their physiological functions are mostly distinct. It was suggested that PR isoform expression patterns are altered in endometriosis, but it is unknown whether the pharmacological effects of DNG are exerted through PR-A, PR-B or both. In the present study, we investigated the pharmacological effects of DNG through these PR isoforms on the expression of CYP19A1 which encodes aromatase and inflammatory and neuroangiogenesis factors associated with the pain and progression of endometriosis. We used immortalized human endometriotic epithelial cell lines that specifically express PR-A or PR-B in a spheroid cell culture system, and treated them with DNG. We evaluated messenger RNA (mRNA) expression of CYP19A1, prostaglandin (PG)E2 synthase (cyclooxygenase (COX)-2 and microsomal PGE2 synthase (mPGES)-1), inflammatory cytokines (interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1) and neuroangiogenesis factors (vascular endothelial growth factor (VEGF) and nerve growth factor (NGF)) using real-time polymerase chain reaction. In addition, PGE2 production was measured by enzyme immunoassay. We found that DNG down-regulated mRNA expression of CYP19A1, COX-2, mPGES-1, IL-6, IL-8, MCP-1, NGF and VEGF, and PGE2 production in human endometriotic epithelial cell lines that specifically express either PR-A or PR-B. These results demonstrate that DNG activates both PR-A and PR-B and down-regulates the expression of pathophysiological factors associated with pain and progression of endometriosis. Our results suggest that DNG exerts therapeutic efficacy against the pain and progression of endometriosis regardless of PR isoform expression patterns.
authors.affiliation: Development Research, Mochida Pharmaceutical Co., Ltd., 722, Jimba, Gotemba, Shizuoka 412-8524, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ichioka
authors.affiliation: Development Research, Mochida Pharmaceutical Co., Ltd., 722, Jimba, Gotemba, Shizuoka 412-8524, Japan. Electronic address: shizuka.mita@mochida.co.jp.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Mita
authors.affiliation: Development Research, Mochida Pharmaceutical Co., Ltd., 722, Jimba, Gotemba, Shizuoka 412-8524, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Development Research, Mochida Pharmaceutical Co., Ltd., 722, Jimba, Gotemba, Shizuoka 412-8524, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imada
authors.affiliation: Division of Virology, National Cancer Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Bono
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kyo
mesh_terms: D001141:Aromatase / Q000235:genetics*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D004715:Endometriosis / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000235:genetics; D045167:Progesterone Congeners / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000235:genetics; D011980:Receptors, Progesterone / Q000819:agonists* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D016207:Cytokines; D045167:Progesterone Congeners; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D042461:Vascular Endothelial Growth Factor A; C101118:progesterone receptor A; C097314:progesterone receptor B; C023635:dienogest; D009277:Nandrolone; D020932:Nerve Growth Factor; D001141:Aromatase; C561410:CYP19A1 protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
keywords: Dienogest; Endometriosis; Progesterone receptor isoforms