The effects of endometrial injury on endometrial receptivity in recurrent implantation failure

Recurrent implantation failure (RIF) represents a major challenge in assisted reproduction and is frequently associated with impaired endometrial receptivity and alterations in the local endometrial microenvironment. Endometrial injury induced by Pipelle biopsy has been proposed as a potential approach associated with modulation of receptivity; however, the underlying biological mechanisms remain incompletely understood. In this prospective exploratory study, endometrial samples were obtained from 19 women with RIF on cycle days 19-21 before and after Pipelle biopsy-induced injury and were compared with samples from fertile women serving as a reference for physiological endometrial receptivity. Endometrial ultrastructure was examined using transmission electron microscopy, and immunohistochemical expression of estrogen receptor alpha (ER-α), leukemia inhibitory factor (LIF), integrin αvβ3, and immune-related markers including CD56, CD68, and inducible nitric oxide synthase (iNOS) was evaluated. Before biopsy, endometrial tissues from RIF patients exhibited abnormal epithelial morphology, reduced numbers of pinopodes, and altered expression of selected receptivity markers compared with fertile controls. Increased intraepithelial lymphocyte infiltration and changes in immune cell distribution were also observed, which may reflect disturbances in the endometrial immune microenvironment. In the cycle following biopsy-induced injury, ultrastructural organization showed partial resemblance to the reference endometrium with increased pinopode formation and enhanced LIF expression showed partial resemblance to the levels observed in the fertile reference endometrium. In contrast, ER-α and integrin αvβ3 expression showed limited or no significant change. Evaluation of immune markers indicated persistent but altered stromal distribution of CD56⁺ uterine natural killer cells and CD68⁺ macrophages together with increased iNOS expression, which may be associated with local immune activation and inflammatory signaling processes involved in tissue remodeling These findings are consistent with the presence of detectable ultrastructural, molecular, and immunological changes in the endometrium of women with RIF following Pipelle biopsy-induced injury and may reflect alterations in local receptivity-related mechanisms. However, given the exploratory design, relatively small sample size, and the limited panel of molecular and immune markers examined, the findings should be interpreted with caution and considered hypothesis-generating rather than definitive. Further controlled studies integrating broader immune profiling and clinical outcome measures are required to clarify the role of endometrial injury in biological processes related to implantation competence.