Glucocorticoid Therapy in Recurrent Implantation Failure: From Empirical Use Toward a Proposed Precision Approach

Implantation failure remains a major challenge in assisted reproductive technology (ART) and is increasingly recognized as a heterogeneous phenomenon arising from the complex interplay between embryo competence, endometrial receptivity, and maternal factors. Immune alterations have been reported in subsets of women with recurrent implantation failure (RIF), including differences in uterine natural killer cell phenotype and function, T-cell responses, cytokine signaling, and autoimmune markers. However, their causal significance and clinical utility remain uncertain, and RIF itself should not be considered evidence of an immune-mediated disorder. Glucocorticoids can modulate innate and adaptive immune responses and inflammatory pathways involved in implantation, providing a biological rationale for their investigation as an adjunctive therapy in ART. Nevertheless, clinical studies have not demonstrated consistent improvements in reproductive outcomes, particularly in unselected ART populations or women selected solely based on a history of RIF. Although positive findings have been reported in selected populations and immune-profile-guided approaches, their interpretation is limited by heterogeneity in patient selection, treatment regimens, and immune-stratification methods. Furthermore, currently proposed immunological biomarkers lack sufficient validation to reliably identify patients who may benefit from treatment. This narrative review examines the immunological mechanisms involved in implantation, critically evaluates the evidence linking immune dysregulation with RIF, and assesses the biological rationale, clinical evidence, and maternal- and pregnancy-related safety considerations surrounding glucocorticoid therapy. Particular emphasis is placed on the limitations of current immune testing and the potential transition from empirical glucocorticoid use toward a proposed precision approach. Future progress will require reproducible immune endotypes, prospectively validated treatment-predictive biomarkers, and adequately powered biomarker-stratified randomized controlled trials using standardized glucocorticoid regimens and prioritizing live birth alongside maternal, pregnancy, and neonatal safety outcomes. Until such evidence is available, immune-guided glucocorticoid therapy should be considered investigational rather than an established treatment strategy for RIF.