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Metformin Promotes Regeneration of the Injured Endometrium Via Inhibition of Endoplasmic Reticulum Stress-Induced Apoptosis

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Abstract

Intrauterine adhesion (IUA) is now recognized as one of the most common diseases in reproductive-age women. Metformin, a well-known frontline oral antidiabetic drug, has been found effective in numerous different diseases. The aim of this study was to determine the effect of metformin on reducing adhesions in an animal model of IUA. Sprague-Dawley rats were randomized into 4 groups: sham operation, control, metformin-treated for 7 days, and metformin-treated for 14 days. To establish the IUA model, mechanical injury to the endometria of rats was induced with a mini curette. Metformin was injected intraperitoneally after surgery. A significant amelioration in both the number of glands and the fibrotic area, compared to those of the control group, was detected 14 days after metformin intervention. The expression levels of antigen KI-67 and vascular endothelial growth factor were increased at 7 and 14 days after treatment. However, the transforming growth factor-β expression was decreased at 14 days after treatment. Endoplasmic reticulum stress-related apoptosis proteins (glucose-regulated protein 78, caspase-12, and CCAAT/enhancer binding protein (EBP) homologous protein) were downregulated after metformin treatment. Moreover, we determined that the effect of metformin was related to the inhibition of endoplasmic reticulum stress-induced apoptosis via the Phosphatidylinositol 3 kinase (PI3K)/Protein kinase B (AKT) and Extracellular regulated protein kinases1/2 pathways. In conclusion, metformin can attenuate the adhesion and promote the regeneration of the endometrium of the IUA rat, and metformin may serve as a novel therapeutic strategy for IUA patients.

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Author notes

  1. These authors contributed equally to this work

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, Zhejiang, 325000, China

    Xin-Xin Xu MD, Hui-Long Lin MD, Qi Lin MD, Lai-En Shen MD, Emmanuel Ansong MD & Xue-Qing Wu MD, PhD

  2. Department of Obstetrics and Gynecology, The University of Hong Kong, Pokfulam, Hong Kong, China

    Si-Si Zhang MD

  3. Department of Obstetrics and Gynecology, Shenzhen University General Hospital, Guangdong, China

    Xue-Qing Wu MD, PhD

  4. Clinical Medical Academy, Shenzhen University, Guangdong, China

    Xue-Qing Wu MD, PhD

Authors
  1. Xin-Xin Xu MD
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  2. Si-Si Zhang MD
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  3. Hui-Long Lin MD
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  4. Qi Lin MD
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  5. Lai-En Shen MD
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  7. Xue-Qing Wu MD, PhD
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Corresponding author

Correspondence to Xue-Qing Wu MD, PhD.

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Authors’ Note

Xin-Xin Xu and Si-Si Zhang contributed equally to this work. The experiments were carried out according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. This study was approved by the Animal Care and Use Committee of Wenzhou Medical University.

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Xu, XX., Zhang, SS., Lin, HL. et al. Metformin Promotes Regeneration of the Injured Endometrium Via Inhibition of Endoplasmic Reticulum Stress-Induced Apoptosis. Reprod. Sci. 26, 560–568 (2019). https://doi.org/10.1177/1933719118804424

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