Uterine factor infertility-current understanding and limitations

Uterine factor infertility (UFI) is an underrecognized cause of implantation failure, contributing to 10-15% of recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). Although current diagnostic tools, such as ultrasonography, hysteroscopy, and the endometrial receptivity array (ERA), effectively identify structural uterine pathology and timing-based receptivity deficits, they fail to capture the molecular and cellular dysfunction in the endometrium. The endometrium is a highly dynamic mucosal tissue that undergoes cyclical remodeling throughout the menstrual cycle under the coordinated influence of estrogen (E2) and progesterone (P4). During each menstrual cycle, the endometrium proliferates under the influence of E2; differentiates and becomes receptive to implantation during P4 dominance in the midluteal phase and is shed in the absence of implantation. Thus, optimal endometrial development is critical for successful implantation and maintenance of pregnancy, even in the presence of a competent oocyte. The current review highlights the roles of hormones (mainly E2 and P4) and cytokine signaling networks in regulating endometrial receptivity, as well as their disruption in RIF and RPL. The review also emphasizes existing diagnostics and unexplored emerging molecular and spatial profiling technologies as future strategies for precise assessment of endometrial competence.