The selective progesterone receptor modulator-promegestone-delays term parturition and prevents systemic inflammation-mediated preterm birth in mice.
The selective progesterone receptor modulator-promegestone-delays term parturition and prevents systemic inflammation-mediated preterm birth in mice.
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DOI：
10.1016/j.ajog.2021.08.013
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发表时间：
2022-03
影响因子：
9.8
通讯作者：
Lye SJ
中科院分区：
文献类型：
--
作者：
Shynlova O;Nadeem L;Dorogin A;Mesiano S;Lye SJ
孕酮通过其核受体（孕酮受体）起作用，在怀孕期间促进子宫肌层松弛，这种活动的暂停会引发分娩。我们之前发现，20α-羟基类固醇脱氢酶在孕激素进入孕激素受体之前将孕激素转化为非活性形式，从而导致孕激素在足月和早产子宫肌层的局部退出。我们假设一种不被20α-羟基类固醇脱氢酶代谢的选择性孕激素受体调节剂——孕酮，可以维持孕酮受体信号传导，并预防/延迟小鼠足月分娩和早产。在足月分娩小鼠模型中，在妊娠第15、16和17天（足月妊娠天数19.5天），给期妊娠CD-1小鼠皮下注射progestone （0.2 mg/dam）或载药。在炎症性早产模型中，孕鼠在妊娠第15、16、17天分别于24小时前、24小时前、24小时前、24小时后全身性给药细菌内毒素（50 μg腹腔注射；脂多糖组）或给药体（生理盐水）。于脂多糖±孕酮注射后的妊娠第16 ~ 6 h和足月妊娠第18.75天采集母胎组织。采用多重免疫分析法测定孕妇血浆和羊水中10种细胞因子的蛋白水平。通过实时聚合酶链反应评估子宫内膜、蜕膜和胎盘中多种细胞因子和促收缩蛋白的信使RNA水平，并通过免疫印迹法确认。孕前期石可预防足月分娩，维持小鼠妊娠24小时。产仔数和胎重与对照组无显著差异。孕石能100%预防全身性细菌内毒素诱导的早产，阻断子宫收缩，显著抑制所有全身性炎症诱导的子宫内膜细胞因子，部分抑制蜕膜和胎盘炎症。孕酮不能预防细菌内毒素引起的胎儿毒性。孕酮是一种高亲和力结合孕酮受体的选择性孕酮受体调节剂，不被20α-羟基类固醇脱氢酶代谢，可以完全抑制小鼠足月分娩和全身性细菌内毒素诱导的早产。我们认为，这种选择性孕酮受体调节剂可能代表了预防高危早产妇女早产的潜在治疗方法。
Progesterone, acting via its nuclear receptors called progesterone receptors, promotes myometrial relaxation during pregnancy, and suspension of this activity triggers labor. We previously found that 20α-hydroxysteroid dehydrogenase causes a local withdrawal of progesterone in the term and preterm myometrium by converting the progesterone into an inactive form before it accesses the progesterone receptors. We hypothesized that a selective progesterone receptor modulator called promegestone, which is not metabolized by 20α-hydroxysteroid dehydrogenase, would sustain progesterone receptor signaling and prevent/delay term labor and preterm labor in mice. In the term labor mouse model, promegestone (0.2 mg/dam) or a vehicle were administered subcutaneously in timed-pregnant CD-1 mice at gestational days 15, 16, and 17 (term gestational days, 19.5). In the inflammation preterm labor model, pregnant mice received promegestone or a vehicle on gestational days 15, 16, and 17, which was 24 hours before, immediately before, and 24 hours after systemic bacterial endotoxin (50 μg intraperitoneal; lipopolysaccharide group) or vehicle (saline) administration. The maternal and fetal tissues were collected on gestational day 16 6 hours after lipopolysaccharide±promegestone injection and at term gestational day 18.75. The protein levels of 10 cytokines were measured by multiplex immunoassay in maternal plasma and amniotic fluid. Myometrial, decidual, and placental messenger RNA levels of multiple cytokines and procontractile proteins were evaluated by real-time polymerase chain reaction and confirmed by immunoblotting. Promegestone prevented term labor and maintained mice pregnancy postterm >24 hours. The litter size and fetal weights were not different from the controls. Promegestone prevented systemic bacterial-endotoxin-induced preterm labor in 100% of the mice, blocked uterine contractions, significantly inhibited all systemic inflammation-induced myometrial cytokines, and partially inhibited decidual and placental inflammation. Promegestone did not prevent bacterial-endotoxin-induced fetal toxicity. Promegestone a selective progesterone receptor modulator that binds progesterone receptors with high affinity and is not metabolized by 20α-hydroxysteroid dehydrogenase could completely suppress term parturition and systemic bacterial-endotoxin-induced preterm birth in mice. We suggest that such selective progesterone receptor modulators may represent a potential therapeutic approach to the prevention of preterm labor in women at high risk of preterm birth.
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