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Metformin improves polycystic ovary syndrome and activates female germline stem cells in mice

WANG Chun-Hong^1,2, WANG Qiang-Qiang^1,2, SU Ya-Shan¹, SUN Ya-Qun¹, SUN Miao¹, LIU Xin-Rui¹, MA Hui-Ming¹, LI Guang-Yong³, DU Xiao-Li², HE Rui^1,2,*

¹宁夏医科大学基础医学院，生育力保持教育部重点实验室，银川 750004；²College of Traditional Chinese Medicine, Key Laboratory of Hui Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004, China；³Urology Department of General Hospital, Ningxia Medical University, Yinchuan 750004, China

Abstract

Polycystic ovary syndrome (PCOS) is a common disease caused by complex endocrine and metabolic abnormalities in women of childbearing age. Metformin is the most widely used oral hypoglycemic drug in clinic. In recent years, metformin has been used in the treatment of PCOS, but its mechanism is not clear. In this study, we aimed to investigate the effect of metformin on PCOS and its mechanism through PCOS mouse model. Female C57BL/6J mice aged 4–5 weeks were intragastrically given letrozole (1 mg/kg daily) combined with a high-fat diet (HFD) for 21 days to establish the PCOS model. After modeling, metformin (200 mg/kg daily) was intragastrically administered. One month later, the body weight and oral glucose tolerance test (OGTT) were measured. Hematoxylin eosin (H&E) staining was used to detect the pathological changes of ovary. The serum levels of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2 and testosterone (T) were measured by ELISA. The expression of DDX4/MVH was detected by immunohistochemistry. DDX4/MVH and PCNA were co-labeled by immunofluorescence. The protein levels of DDX4/MVH, PCNA, cyclin D2, AMPK and mTOR were detected by Western blot. The results showed that after metformin treatment, the body weights of PCOS mice were gradually returned to normal, glucose tolerance was significantly improved, serum E2 levels were increased, while AMH, LH, T levels and LH/FSH ratio were decreased. Ovarian polycystic lesions were reduced with reduced atresia follicles. Furthermore, the number of proliferative female germline stem cells (FGSCs) and levels of proliferation related proteins (PCNA, cyclin D2) were significantly increased, and the p-mTOR and p-AMPK levels were markedly up-regulated. These results suggest that metformin treatment not only improves hyperandrogenemia, glucose intolerance and polycystic ovarian lesions in PCOS, but also activates the function of FGSCs. The underlying mechanism may be related to the phosphorylation of AMPK and mTOR. These findings provide new evidence to use metformin in the treatment of PCOS and follicular development disorder.

Key words: metformin; polycystic ovary syndrome; female germline stem cells; AMPK/mTOR

Received: 　　Accepted:

Corresponding author: 何瑞　　E-mail: ruihe515@163.com

DOI: 10.13294/j.aps.2021.0090

Citing This Article：

WANG Chun-Hong, WANG Qiang-Qiang, SU Ya-Shan, SUN Ya-Qun, SUN Miao, LIU Xin-Rui, MA Hui-Ming, LI Guang-Yong, DU Xiao-Li, HE Rui. Metformin improves polycystic ovary syndrome and activates female germline stem cells in mice. Acta Physiol Sin 2022; 74 (3): 370-380 (in Chinese with English abstract).