Levonorgestrel Inhibits Embryo Attachment by Eliminating Uterine Induction of Leukemia Inhibitory Factor
Levonorgestrel Inhibits Embryo Attachment by Eliminating Uterine Induction of Leukemia Inhibitory Factor
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DOI：
10.1210/endocr/bqz005
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发表时间：
2020-02-01
期刊：
影响因子：
4.8
通讯作者：
Osuga, Yutaka
中科院分区：
文献类型：
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作者：
Matsuo, Mitsunori;Hirota, Yasushi;Osuga, Yutaka
孕激素包括黄体酮（P-4）和左炔诺孕酮（LNG），在临床上用于多种目的，例如避孕和不孕症治疗。孕激素对子宫的影响仍有待阐明。在这里，我们研究了过量孕激素对胚胎植入的影响，重点关注子宫白血病抑制因子（LIF）的功能，LIF是一种由雌激素诱导的细胞因子，对于胚胎附着至关重要。从妊娠第1天到第4天，用赋形剂（对照）、300μg/kg/天剂量的LNG和10mg/天剂量的P-4治疗野生型（WT）雌性小鼠。 LNG 处理和 P-4 处理的小鼠在怀孕第 5 天表现出胚胎附着失败（具有胚胎附着位点的小鼠率 [%MAS] 分别为 11% 和 13%），而所有对照小鼠均具有正常的附着位点。 LNG 处理和 P-4 处理的小鼠在第 4 天晚上的子宫 LIF 表达显着降低。第 4 天以 24 微克/天的剂量施用重组 LIF (rLIF) 显着挽救了 LNG 治疗和 P-4 治疗小鼠的胚胎附着失败（%MAS，分别为 80% 和 75%）。雌二醇 (E-2) 给药还可挽救 LNG 治疗小鼠的胚胎附着失败（%MAS，83%）。此外，植入前过量的 P-4 治疗会降低蜕膜 P-4 受体 (PGR) 的表达，并诱导蜕膜化缺陷（除了 LIF 下调）。这些发现表明，孕激素通过下调子宫 LIF 表达来抑制胚胎附着，并通过下调 PGR（独立于 LIF 减少）来损害蜕膜化。这项研究可能有助于更好地了解孕激素的避孕作用。
Progestogens including progesterone (P-4) and levonorgestrel (LNG) are clinically used for multiple purposes such as contraception and infertility treatment. The effects of progestogens on the uterus remains to be elucidated. Here we examine the effect of excessive progestogen administration on embryo implantation focusing on the function of uterine leukemia inhibitory factor (LIF), a cytokine that is induced by estrogen and essential for embryo attachment. Treatment of wildtype (WT) female mice with vehicle (control), LNG at the dose of 300 mu g/kg/day and P-4 at the dose of 10 mg/day from day 1 to day 4 of pregnancy was conducted. LNG-treated and P-4-treated mice showed embryo attachment failure on day 5 of pregnancy (The rate of mice with embryo attachment sites [%MAS], 11% and 13%, respectively), while all the control mice had normal attachment sites. Uterine LIF expression was significantly reduced in LNG-treated and P-4-treated mice on day 4 evening. Administration of recombinant LIF (rLIF) at the dose of 24 mu g/day on day 4 significantly rescued embryo attachment failure in LNG-treated and P-4-treated mice (%MAS, 80% and 75%, respectively). Estradiol (E-2) administration also rescued embryo attachment failure in LNG-treated mice (%MAS, 83%). Furthermore, excess P-4 treatment before implantation decreased decidual P-4 receptor (PGR) expression and induced decidualization defect apart from LIF downregulation. These findings indicate that progestogens cause embryo attachment inhibition through downregulation of uterine LIF expression and compromised decidualization through downregulation of PGR independently of LIF reduction. This study may contribute to a better understanding of contraceptive action of progestogens.