Yadav Shubhi, Dadge Shailesh, Garg Richa, Goand Umesh K, Agarwal Arun, Chauhan Divya, Gayen Jiaur R
Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India.
Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India.
Steroids. 2025 Feb;214:109558. doi: 10.1016/j.steroids.2024.109558. Epub 2024 Dec 30.
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder associated with insulin resistance (IR) and hyperandrogenism. IR plays a crucial role in the etiology of PCOS. An insulin-sensitizing agent like metformin is most commonly used as an off-label drug for the treatment of PCOS. PSTi8 (a pancreastatin inhibitor) is known as a promising therapeutic insulin-sensitizing agent for the treatment of IR in metabolic diseases. Thus, this study evaluates the insulin-sensitizing effects of PSTi8 compared to metformin on IR, hyperandrogenism, ovarian, and metabolic dysfunction in a PCOS model. To induce PCOS, rats were administered letrozole at a dose of 2 mg/kg via oral administration and fed a 60 % high-fat diet. Metformin and PSTi8 lowered serum insulin, testosterone, luteinizing hormone (LH) levels, and the LH/follicle-stimulating hormone ratio in the blood serum and improved steroidogenic gene expression in the PCOS ovaries. Both treatments increased the levels of sex hormone-binding globulin and estrogen hormone. Metformin and PSTi8 restore ovarian and uterine histomorphometry and improve the estrous cycle in PCOS rats. Metformin and PSTi8 treatments also improve blood glucose level and increase insulin sensitivity, inflammation, reactive oxygen species accumulation, lipid parameters, body weight, and fat mass in PCOS rats. This study revealed that PSTi8 is as helpful as metformin in decreasing hyperandrogenism by improving insulin sensitivity, free testosterone level and restoring disturbed reproductive and metabolic parameters in PCOS rats. PSTi8 has potential to serve as a therapeutic molecule for preventing IR induced by a western diet in PCOS.
多囊卵巢综合征（PCOS）是一种与胰岛素抵抗（IR）和高雄激素血症相关的异质性内分泌和代谢紊乱疾病。IR在PCOS的病因中起关键作用。像二甲双胍这样的胰岛素增敏剂最常作为治疗PCOS的非标签药物使用。PSTi8（一种胰抑制素抑制剂）是一种有望用于治疗代谢疾病中IR的治疗性胰岛素增敏剂。因此，本研究评估了与二甲双胍相比，PSTi8对PCOS模型中IR、高雄激素血症、卵巢和代谢功能障碍的胰岛素增敏作用。为诱导PCOS，给大鼠经口给予剂量为2mg/kg的来曲唑，并喂食60%的高脂饮食。二甲双胍和PSTi8降低了血清胰岛素、睾酮、黄体生成素（LH）水平以及血清中的LH/促卵泡激素比值，并改善了PCOS卵巢中类固醇生成基因的表达。两种治疗均提高了性激素结合球蛋白和雌激素的水平。二甲双胍和PSTi8恢复了PCOS大鼠的卵巢和子宫组织形态学，并改善了发情周期。二甲双胍和PSTi8治疗还改善了PCOS大鼠的血糖水平，提高了胰岛素敏感性、炎症、活性氧积累、脂质参数、体重和脂肪量。本研究表明，PSTi8在改善胰岛素敏感性、游离睾酮水平以及恢复PCOS大鼠紊乱的生殖和代谢参数方面，与二甲双胍一样有助于降低高雄激素血症。PSTi8有潜力作为一种治疗分子，用于预防PCOS中西方饮食诱导的IR。
