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.