Comparative Proteomic Analysis Reveals Metformin Improves the Expression of Biomarkers of Endometrial Receptivity in Infertile Women with Minimal/Mild Endometriosis

The prevalence of endometriosis is approximately 10% in women of reproductive age, and 30–50% of women with endometriosis are infertile. Metformin has been reported to inhibit the growth of ectopic lesions in endometriosis. However, its effect on the eutopic endometrium of endometriosis is unknown. This study aimed to identify whether metformin affects endometrial receptivity in infertile women with minimal/mild endometriosis. We enrolled 10 infertile women who were diagnosed with minimal/mild endometriosis through laparoscopy. Paired endometrial tissues of the secretory phase from participants were collected during surgery and after 2 months of metformin treatment (n = 5) or no medical treatment (n = 5). Protein expression profiles of the paired endometrium were detected by proteomics and compared using the self-control method (2 months later vs. in surgery). Proteomics data revealed six proteins associated with endometrial receptivity among the significantly upregulated proteins after metformin treatment (fold change > 1.5, P < 0.05). Insulin-like growth factor binding protein 7 (IGFBP-7) showed the most robust increase in these six endometrial receptivity-related proteins (fold change: 8.668, P 0.05). The upregulation of IGFBP-7 has been validated through target proteomics, immunohistochemistry, and further demonstrated in endometriosis mouse models induced by autotransplantation. This study revealed that metformin upregulated the expression of IGFBP-7 in the endometrium of human and mouse models of endometriosis. Metformin potentially affects endometrial receptivity of minimal/mild endometriosis by improving the expression of the endometrial receptivity marker IGFBP-7. Similar content being viewed by others Availability of Data and Material The datasets generated and analyzed during the current study are available in the ProteomeXchange repository (accession number: PXD027648) [http://proteomecentral.proteomexchange.org/cgi/GetDataset]. Code Availability Not applicable. Change history 03 February 2022 A Correction to this paper has been published: https://doi.org/10.1007/s43032-022-00873-7

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Mol Reprod Dev. 2021(online). https://doi.org/10.1002/mrd.23537 Huang Y, Yu Y, Gao J, Li R, Zhang C, Zhao H, et al. Impaired oocyte quality induced by dehydroepiandrosterone is partially rescued by metformin treatment. Plos One 2015;10(3): e0122370. https://doi.org/10.1371/journal.pone.012237 Funding This study was funded by the National Key R&D Program of China (Grant number: 2017YCF1001200), Fundamental Research Funds for the Central Universities (SCU2019C4198), and International Science and Technology Cooperation Project of Chengdu (2017-GH02-000060-HZ). Author information Authors and Affiliations Contributions XH implemented human research and analyzed data, drafted the manuscript; LX designed the research and revised the manuscript; YL performed animal experiments and analyzed data; TP assisted with experiments and revised the manuscript, BL, TL, and YL collected and prepared samples; HZ and YO made the concept and supervised the research; WH designed the research, revised the manuscript, and approved the final vision. Corresponding author Ethics declarations Ethics Approval The study was approved by the Ethics Committee of Sichuan University (Grant number: K2017042-1 and K2017042-2). Consent to Participate Written informed consents were obtained from all participants. Consent for Publication Not applicable. Competing Interests The authors declare no competing interests. Additional information This article was updated to include the article note: Xin Huang, Li Xiao and Ying Long have contributed equally to this work and share first authorship. Rights and permissions About this article Cite this article Huang, X., Xiao, L., Long, Y. et al. Comparative Proteomic Analysis Reveals Metformin Improves the Expression of Biomarkers of Endometrial Receptivity in Infertile Women with Minimal/Mild Endometriosis. Reprod. Sci. 29, 2593–2606 (2022). https://doi.org/10.1007/s43032-022-00869-3 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-022-00869-3