Orchestrating implantation: endometrial receptivity as a convergence point of endocrine, metabolic, and immune signals

Endometrial receptivity is a transient and highly coordinated functional state that enables embryo apposition, adhesion, invasion, and subsequent pregnancy establishment during the window of implantation, and its disruption represents an important contributor to infertility, recurrent implantation failure, and early pregnancy loss. In this review, we integrate current evidence on the molecular and cellular mechanisms governing endometrial receptivity, with particular emphasis on the dynamic interplay among hormonal signaling, intracellular regulatory pathways, metabolic reprogramming, and the immune microenvironment. Estrogen and progesterone orchestrate the transition of the endometrium from proliferation to differentiation and decidualization, while signaling networks including Wnt/β-catenin , PI3K/AKT/mTOR , LIF/JAK/STAT , and TGF-β/BMP coordinate epithelial function, stromal remodeling, angiogenesis, and embryo–endometrial communication. Metabolic pathways involving glucose, lipids, and amino acids provide not only energetic and biosynthetic support but also signaling and epigenetic inputs required for decidualization and implantation, whereas uterine natural killer cells, T cells, macrophages, and dendritic cells establish the finely balanced immune environment necessary for maternal–fetal tolerance. These regulatory layers converge at shared signaling and functional nodes, including PI3K/AKT/mTOR , STAT3 , TGF-β/SMAD , amino-acid–dependent epigenetic regulation, and angiogenic pathways, thereby coupling decidualization, immune tolerance, vascular remodeling, and trophoblast invasion. Importantly, emerging evidence supports a conceptual shift from viewing impaired receptivity as the consequence of isolated molecular defects toward understanding it as a systems-level disruption of interconnected endocrine, metabolic, immune, and cellular networks, a common pathological feature across infertility-associated disorders such as endometriosis, polycystic ovary syndrome, chronic endometritis, and adenomyosis. Defining the temporal and spatial coordination of these networks may facilitate the development of more reliable biomarkers and mechanism-based, personalized strategies for assessing and restoring endometrial receptivity, ultimately improving implantation and reproductive outcomes.