基于多囊卵巢综合征大鼠模型评估二甲双弧对子宫功能障碍的改善作用
文献 Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome. 发表在 EBioMedicine 原文链接
Abstract：
Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS) patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial-stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K-Akt-NFκB network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction.
摘要：
经胰岛素和人绒毛膜促性腺激素处理的成年大鼠，其内分泌、代谢和生殖异常情况与多囊卵巢综合征(PCOS)患者相似。在本研究中，我们采用多囊卵巢综合征大鼠模型评估二甲双胍对PCOS相关子宫功能障碍的影响。二甲双胍不仅可以降低雄激素水平，改善胰岛素敏感性，调节生殖周期，还可引起PCOS患者子宫形态学变化。在分子和细胞水平上，二甲双胍使雄激素受体介导的转录程序正常化，并恢复上皮间质的相互作用。与葡萄糖转运相比，二甲双弧通过PI3K-Akt-NFκB通路抑制子宫炎症基因表达，但不影响细胞凋亡。这些作用似乎与AMPK亚基和自噬相关蛋白调节无关。研究发现当二甲双胍治疗部分恢复着床时，在PCOS大鼠子宫中，数个与着床相关的基因被正常化。研究结果让我们更为清楚地理解二甲双胍改善雄激素过高分泌和胰岛素抗性引起的子宫缺陷所导致的植入中断。本实验数据可能为深入的分子和功能探究提供依据，一定程度上二甲双胍可能成为治疗PCOS患者子宫功能障碍的潜在选择。
使用试剂原文信息：Serum concentrations of gonadotropins (follicle stimulating hormone and luteinizing hormone), steroid hormones (17β-estradiol, progesterone, testosterone, and androstenedione), sex hormone-binding globulin, and insulin were determined using enzyme-linked immunosorbent assay (ELISA) kits (Cloud-Clone Corp., Houston, TX).