Metformin sensitizes endometriosis to medroxyprogesterone acetate treatment through MIG-6 mediated signaling.

Abstract

This study evaluates the synergistic therapeutic effect of metformin (MET) combined with medroxyprogesterone acetate (MPA) on endometriosis (EM) and investigates the involvement of the steroid receptor coactivator-1 (SRC-1) and mitogen-inducible gene 6 (MIG-6). Immunohistochemical analysis revealed significantly decreased SRC-1, progesterone receptor (PGR), and MIG-6 protein expression in human ectopic EM lesions compared to normal eutopic endometrium. In an EM mouse model, the combination of metformin (MET) and MPA resulted in the greatest reduction of ectopic lesion size and weight compared to either treatment alone. This combination therapy also uniquely increased serum Eotaxin and decreased interleukin-12p40 levels. Transcriptome analysis demonstrated specific enrichment of immune activation pathways only in the combination treatment group. In vitro, using the human endometriosis epithelial cell line 12Z, the MET and MPA combination significantly suppressed cell proliferation and migration, concomitant with an upregulation of SRC-1, PGR, and MIG-6 messenger RNA expression. We conclude that MET enhances the therapeutic efficacy of MPA against EM. This effect may be mediated through MIG-6 signaling and involves the upregulation of SRC-1, inhibiting ectopic cell proliferation and migration, and inhibiting endometriotic lesion progression, representing a novel strategy to overcome progesterone resistance. KEY MESSAGES: SRC-1, MIG-6, and PGR are downregulated in human endometriotic lesions. MET and MPA act cooperatively to suppress lesion growth in a murine model. Combination therapy increases Eotaxin levels while decreasing IL-12p40 in mice. MET and MPA activate immune surveillance pathways within lesions. MET and MPA synergistically inhibit endometriotic cell growth and migration.