Decidual senescence in recurrent pregnancy loss: forkhead box M1-targeted progesterone treatment

RESEARCH QUESTION: What is the role of FOXM1 in the pathogenesis of recurrent pregnancy loss (RPL) characterized by increased decidual senescence, and how do two progesterone analogues (medroxyprogesterone acetate [MPA] and dydrogesterone [DYD]) modulate FOXM1 expression and associated senescence markers in an in-vitro decidualization model? DESIGN: Primary decidual cells were isolated from decidual tissue samples collected from women with clinically healthy pregnancies that were terminated voluntarily (control pregnancy group, n = 10) and women with RPL (RPL group, n = 10). Cells were treated with MPA and DYD, and PRL and IGFBP-1 concentrations were analysed by ELISA. FOXO1, FOXM1, phospho-FOXM1 (p-FOXM1), DIO2 and β-GAL expression was examined by immunofluorescence. Co-culture experiments with AC-1M88 trophoblast-like cells assessed spheroid expansion and migration. RESULTS: MPA and DYD treatments significantly ameliorated PRL (P = 0.006 and P = 0.015, respectively) and IGFBP-1 (both P < 0.001) concentrations, and FOXO1, FOXM1 and p-FOXM1 expression (all P < 0.001), in the RPL group. DYD treatment was more effective than MPA treatment in restoring FOXM1 and p-FOXM1 expression (both P < 0.001). MPA and DYD did not affect spheroid expansion in the RPL group but increased cell migration (p=0.009 and p<0.001, respectively); however, neither treatment significantly reduced DIO2 or β-GAL expression. CONCLUSIONS: Decidual cells from women with RPL exhibited reduced FOXM1 expression and increased senescence-associated markers. MPA and DYD restored FOXM1 expression and improved decidual function, but did not reverse senescence marker expression. These findings suggest that combining senomorphic agents with progesterone analogues may represent a promising avenue for future mechanistic and translational research.