Guo Sili, Li Xiaohan, Liu Mei, Feng Meiqi, Wang Xi, Xue Haibo, Zhang Lei
Department of Endocrinology and Metabolism, The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medicial University, Binzhou, Shandong, People's Republic of China.
Drug Des Devel Ther. 2025 May 23;19:4297-4310. doi: 10.2147/DDDT.S522730. eCollection 2025.
Polycystic ovary syndrome (PCOS) is a typical reproductive endocrine system disease with high incidence rate among childbearing age women. Several clinical data show that glucagon-like peptide-1 receptor agonists (GLP-1RAs) might have therapeutic effects on PCOS, but the mechanisms are still unclear. Here, we aim to assess the effects of semaglutide (a weekly preparation of GLP-1RAs) on PCOS in vivo.
C57BL/6J female mice aged 3 weeks were subcutaneously injected with dehydroepiandrosterone and fed high-fat diet for 3 weeks to establish PCOS model. Then, we randomly divided the modeled mice into PCOS group (n=6), S-Low group (n=6), and S-High group (n=6). Additionally, six normal mice served as controls. Mice in S-Low and S-High group were intraperitoneally injected with corresponding dose of semaglutide every week for 4 weeks. The estrus cycle was observed daily. At the end of the experiment, body weight, blood glucose, and serum hormone levels were measured. Ovarian morphology was also observed. Then, the oxidative stress markers, autophagy-related proteins and CYP19A1, StAR, and CYP17A1 expression in ovarian tissue were measured. Finally, we used Western blot to detect the expression of PI3K/AKT/mTOR and downstream proteins.
After treatment with semaglutide, the estrous rhythm of PCOS mice was restored, the number of ovarian vesicles decreased, serum hormone imbalance corrected, and glucose tolerance improved. The relative expression of CYP17A1, StAR, Beclin-1, and LC3B, as well as MDA, were significantly reduced, while CYP19A1, p62, GSH, and SOD were significantly increased. Finally, semaglutide alleviates ovarian oxidative stress and autophagy via the PI3K/AKT/mTOR pathway.
Semaglutide alleviates autophagy and ovarian oxidative stress via the PI3K/AKT/mTOR pathway in mice with PCOS.
多囊卵巢综合征（PCOS）是一种典型的生殖内分泌系统疾病，在育龄妇女中发病率较高。多项临床数据表明，胰高血糖素样肽-1受体激动剂（GLP-1RAs）可能对PCOS具有治疗作用，但其机制仍不清楚。在此，我们旨在评估司美格鲁肽（一种每周一次的GLP-1RAs制剂）对PCOS的体内作用。
对3周龄的C57BL/6J雌性小鼠皮下注射脱氢表雄酮，并给予高脂饮食3周以建立PCOS模型。然后，我们将建模小鼠随机分为PCOS组（n=6）、S-低剂量组（n=6）和S-高剂量组（n=6）。此外，六只正常小鼠作为对照。S-低剂量组和S-高剂量组的小鼠每周腹腔注射相应剂量的司美格鲁肽，共4周。每天观察发情周期。实验结束时，测量体重、血糖和血清激素水平。同时观察卵巢形态。然后，测量卵巢组织中氧化应激标志物、自噬相关蛋白以及CYP19A1, StAR和CYP17A1的表达。最后，我们使用蛋白质免疫印迹法检测PI3K/AKT/mTOR及其下游蛋白的表达。
用司美格鲁肽治疗后，PCOS小鼠的发情节律恢复正常；卵巢卵泡数量减少；血清激素失衡得到纠正；糖耐量得到改善。CYP17A1、StAR、Beclin-1和LC3B的相对表达以及丙二醛（MDA）显著降低，而CYP19A1、p62、谷胱甘肽（GSH）和超氧化物歧化酶（SOD）显著增加。最后，司美格鲁肽通过PI3K/AKT/mTOR途径减轻卵巢氧化应激和自噬。
司美格鲁肽通过PI3K/AKT/mTOR途径减轻PCOS小鼠的自噬和卵巢氧化应激。
