Effects of Progestins and Progesterone Receptor Modulators Used for Emergency Contraception on Endometrial Gene Expression and Implantation

The human endometrium responds to progesterone, including emergency contraception (EC) drugs such as levonorgestrel (LNG), mifepristone, and ulipristal acetate (UPA). Here, we investigated gene expression during the window of implantation (WOI) in mammals and compared it with that of women receiving LNG, UPA, and mifepristone across a wide variety of experimental models and conditions. Evidence from in vivo models, ex vivo endometrial platforms, embryo-endometrium co-cultures, and stem cell-derived trophoblast systems is presented. The findings from single-cell and spatial transcriptomic studies were synthesized narratively. We focused on clinical outcomes and functional implantation-related endpoints, while viewing molecular signatures as supportive mechanistic evidence. The evidence indicates that human endometrial WOI is governed by a progesterone-driven receptivity signature (PAEP, SPP1, LIF, HOXA10/11, IGFBP1) conserved across placental mammals. Post-ovulatory LNG left transcriptomic and receptivity markers unchanged. UPA suppressed progesterone-regulated genes, opposing the ERA receptive signature. Mifepristone suppressed receptivity and exerted embryotoxic effects in preclinical studies. The evidence supports the conclusion that, when administered post-ovulation, LNG, UPA, and mifepristone exert distinct endometrial effects that cannot be reduced to a single mechanism of action. Available evidence indicates that LNG at EC doses has minimal impact on endometrial receptivity. UPA, at EC doses, alters progesterone-regulated endometrial gene expression relevant to endometrial embryo implantation processes. Mifepristone suppresses pathways associated with endometrial receptivity and exhibits direct embryotoxic effects in preclinical models at concentrations exceeding those used clinically. In summary, LNG exerts negligible effects on endometrial molecular processes. In contrast, UPA and mifepristone both meaningfully disrupt progesterone-dependent endometrial processes.