Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway.
Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway.
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DOI：
10.3892/etm.2017.5650
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发表时间：
2017-12
影响因子：
2.7
通讯作者：
Yuanyuan Wu;Peng-fen Li;Dan Zhang;Ying-pu Sun
中科院分区：
文献类型：
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作者：
Yuanyuan Wu;Peng-fen Li;Dan Zhang;Ying-pu Sun
多囊卵巢综合征（PCOS）是一种常见的妇科内分泌疾病，可导致月经紊乱、高雄激素血症和持续性无排卵等健康问题。高雄激素血症和胰岛素抵抗是PCOS的基本特征。为探讨二甲双胍和吡格列酮联合应用对PCOS的治疗作用及其可能机制，采用肌注戊酸雌二醇（EV）建立PCOS大鼠模型。观察二甲双胍和吡格列酮单药或联合用药对正常大鼠和PCOS大鼠睾酮水平、卵泡发育和胰岛素抵抗的影响。通过使用5 '腺苷一磷酸激活的蛋白激酶（AMPK）/磷酸肌醇-3激酶（PI 3 K）/c-Jun N-末端激酶（JNK）途径的三种抑制剂（化合物C、Wortmannin和SP 600125）来探索二甲双胍和吡格列酮对POCS的治疗作用的潜在机制。结果表明，EV诱导的PCOS大鼠表现为高雄激素血症、高胰岛素血症和卵泡发育不良。二甲双胍或吡格列酮单药治疗可显著抑制PCOS大鼠的高睾酮水平，降低囊状卵泡和初级卵泡的比例，促进早期窦状卵泡的数量，显著降低高空腹胰岛素浓度和稳态模型评估的胰岛素抵抗指数。此外，二甲双胍和吡格列酮联合治疗的疗效高于其单个组分。此外，二甲双胍和吡格列酮单独或联合治疗影响PCOS大鼠JNK磷酸化水平。化合物C和渥曼青霉素消除了二甲双胍和吡格列酮联合治疗对改善PCOS大鼠卵泡生长的作用，而SP 600125治疗增强了这种联合治疗作用。这些数据表明，二甲双胍和吡格列酮联合治疗通过调节AMPK/PI 3 K/JNK通路在改善PCOS方面表现出显著的疗效。
Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogenism and insulin resistance are the basic characteristics of PCOS. To investigate the combined effect of metformin and pioglitazone on POCS and the potential mechanisms, a rat model of PCOS was established by intramuscular injection of estradiol valerate (EV). The effect of metformin and pioglitazone monotherapy or combination therapy in control rats and PCOS rats was evaluated, involving the testosterone level, follicular development and insulin resistance. The potential mechanism for the therapeutic effect of metformin and pioglitazone on POCS was explored through using three inhibitors of the 5'adenosine monophosphate-activated protein kinase (AMPK)/phosphoinositide-3 kinase (PI3K)/c-Jun N-terminal kinase (JNK) pathway (Compound C, Wortmannin and SP600125). The results showed that EV-induced PCOS rats demonstrated hyperandrogenemia, hyperinsulinemia and follicular dysplasia. Metformin or pioglitazone monotherapy significantly suppressed the high level of testosterone, reduced the raised percentage of cystic follicles and primary follicles, promoted the number of early antral follicles, and markedly decreased the high concentration of fasting insulin and homeostatic model assessment for insulin resistance index in PCOS rats. In addition, metformin and pioglitazone combination therapy demonstrated greater efficacy than its individual components. Furthermore, individual or joint treatment with metformin and pioglitazone affected the phosphorylation level of JNK in PCOS rats. Compound C and Wortmannin eliminated the effect of metformin and pioglitazone combination therapy on improving the follicular growth in PCOS rats, whereas SP600125 treatment enhanced this combination therapy effect. These data suggested that metformin and pioglitazone combination therapy demonstrated great efficacy in ameliorating PCOS through regulating the AMPK/PI3K/JNK pathway.