Endometrial molecular genetic phenotypes and histological endometrial phase in women with reproductive failure

During endometrial decidualization, a "window of implantation" is established, which is critical for successful embryo implantation. Histopathological evaluation for endometrial dating, however, was reported to be unreliable for infertility evaluation. Recently, the decidualization score (DS) test was developed to evaluate the endometrial molecular landscape. It collectively assesses the endometrial gene expression of immune regulatory factors, progesterone signaling, and tissue homeostasis. In this study, we aim to investigate the relationship between the histological endometrial phase and molecular genetic phenotypes of the endometrium by examining DS and other potential gene expressions in women with reproductive failures. 29.2 % of reproductive failure patients had normal DS, while 70.8 % had abnormal scores. In reproductive failure patients with normal DS, 76.2 % were in-phase by histopathological evaluation, while 23.8 % were out-of-phase. A similar distribution was observed in patients with abnormal DS, with 78.4 % in-phase and 21.6 % out-of-phase. A significant difference in the distribution of DSs was observed between in-phase and out-of-phase endometrial samples (p = 0.042). Notably, in-phase endometrial samples did not correlate with normal DS, indicating a possible discrepancy between histological dating and functional endometrial status. When comparing endometrial gene expression between the two histological phases, out-of-phase samples exhibited significantly lower expression of IL-15, SLC2A1, and RORC, and higher expression of HOXA10 genes, than in-phase samples. These findings suggest that molecular genetic evaluation should be interpreted in the context of histological changes. An integrated approach combining molecular phenotyping with histological assessment may provide a more accurate characterization of gene expression profiles associated with implantation competence, surpassing the diagnostic value of histology or molecular phenotyping alone.