title: Drospirenone reduces inflammatory cytokines, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) expression in human endometriotic stromal cells.
abstract: Drospirenone has been used as a progestin in oral contraceptives with ethinyl estradiol (DRSP/EE) and is expected to regulate endometriosis, however, the direct effects of drospirenone on endometriosis have not been clarified. The aim of this study was to evaluate the anti-inflammatory, anti-angiogenic and anti-neurogenic effects of drospirenone on endometriotic stromal cells (ESC). ESC isolated from endometriotic tissues were obtained from patients during laparoscopic surgery for ovarian endometriosis. ESC were exposed to IL-1β and cultured in the absence or presence of drospirenone. mRNA expression was evaluated using quantitative RT-PCR, and protein was measured using ELISAs. To evaluate the effect of drospirenone on progesterone receptor (PR) and mineralocorticoid receptor (MR), ESC were transfected with siRNA against PR (siPR) and MR (siMR), and cultured in the presence or absence of drospirenone. Drospirenone significantly decreased IL-6, IL-8, VEGF and NGF mRNA expression by ESC. Drospirenone (10-5M) significantly decreased IL-6 secretion and 10-7M drospirenone decreased IL-8 and VEGF secretion. Knockdown of PR, but not MR, negated the effects of drospirenone. In summary, this study demonstrates that drospirenone has anti-inflammatory, anti-angiogenic and anti-neurogenic effects on ESC and these effects are mediated by PR. These drospirenone effects may contribute to the regulatory effects of drospirenone-containing oral contraceptives on endometriosis.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Makabe
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan. Electronic address: kawotan-tky@umin.ac.jp.
authors.forename: Kaori
authors.initials: K
authors.lastname: Koga
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Miyashita
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Fusako
authors.initials: F
authors.lastname: Sue
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Urata
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Gentaro
authors.initials: G
authors.lastname: Izumi
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takamura
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hirata
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hirota
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada-Hiraike
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
mesh_terms: D000328:Adult; D000736:Androstenes / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D003276:Contraceptives, Oral / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004715:Endometriosis / Q000188:drug therapy*; D004717:Endometrium / Q000473:pathology*; D004997:Ethinyl Estradiol / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects* / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000736:Androstenes; D000893:Anti-Inflammatory Agents; D003276:Contraceptives, Oral; D016207:Cytokines; D034741:RNA, Small Interfering; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D042461:Vascular Endothelial Growth Factor A; D004997:Ethinyl Estradiol; D020932:Nerve Growth Factor; C035144:drospirenone
keywords: Drospirenone; Endometriosis; Inflammatory cytokines; Oral contraceptives