The steroid hormone dydrogesterone inhibits myometrial contraction independently of the progesterone/progesterone receptor pathway

Abstract

AimsIn this study, we aimed to investigate the direct effects of steroid hormones on pregnant myometrial contraction. Main methodsThe effect of steroids on oxytocin-induced contraction was examined in vitro using pregnant rat or human myometrium. Subsequently, we evaluated whether RU486, a potent progesterone antagonist, influenced the effects of progestin on myometrial contraction. Additionally, we evaluated the effects of progestin on high-concentration KCl-induced contraction caused by voltage-dependent calcium channels in order to investigate the mechanisms involved in this process. Key findingsOf the natural steroids examined, 17β-estradiol, progesterone, testosterone, cortisol, and aldosterone did not influence oxytocin-induced contraction at concentrations <10−6 M. Of the tested progestins, medroxyprogesterone acetate, norethisterone, chlormadinone acetate, levonorgesterol, 17α-hydroxyprogesterone capronate, and dienogest had no effect on contraction at <10−6 M. However, dydrogesterone showed rapid and direct inhibition of contraction at 10−6 M, and this inhibitory effect was dependent on dose and time. RU486 did not block the inhibitory effects of dydrogesterone on contraction. High-concentration KCl-induced contraction was also inhibited by dydrogesterone, and the inhibitory effects of dydrogesterone were observed at concentrations as low as 10−7 M. Additionally, oxytocin-induced contraction in pregnant human myometrium was inhibited by 10−6 M dydrogesterone. SignificanceThese results suggested that the rapid and direct effects of dydrogesterone on myometrial contraction were caused by a nongenomic pathway and that the progesterone receptor was not required for dydrogesterone action. Additionally, the mechanism of dydrogesterone action may involve voltage-dependent calcium channels.