Endometrial BCL6 Expression and Reproductive Outcomes in Infertile Women: A Systematic Review

Background/Objectives: Endometrial B-cell lymphoma 6 (BCL6) overexpression has been proposed as a marker of progesterone resistance, occult endometriosis, and endometrial dysfunction in infertile women. Its possible association with reproductive outcomes and its potential role in guiding management before embryo transfer have attracted increasing interest. However, the prognostic and clinical significance of BCL6 across infertility settings remains incompletely defined. We systematically reviewed the literature on endometrial BCL6 expression and reproductive outcomes in infertile women. Methods: This systematic review was conducted according to a prospectively registered PROSPERO protocol. Studies evaluating endometrial BCL6 expression on biopsy in infertile women were eligible if they reported reproductive outcomes or clinically relevant comparative data. Two prespecified questions were addressed: whether high or abnormal BCL6 expression is associated with poorer reproductive outcomes than low or normal expression, and whether treatment before embryo transfer improves outcomes in BCL6-positive women. Thirteen studies were included in the review. Because the included studies differed substantially in infertility phenotype, embryo context, hormonal preparation, biopsy timing, and outcome reporting, findings were synthesized narratively. Results: The available evidence suggests that abnormal or elevated endometrial BCL6 expression may be associated with poorer reproductive outcomes in some infertility populations, particularly in women with unexplained infertility undergoing IVF, although this pattern was less evident in selected euploid embryo transfer cohorts. Treatment-oriented studies suggested a possible benefit of pre-transfer medical suppression or surgical management in some BCL6-positive women, but findings were variable across studies. Supportive non-comparative and mechanistic studies further indicated that interpretation of BCL6 is influenced by hormonal preparation, endometrial context, and whether BCL6 is considered in isolation or within a broader biological or multimarker framework. Interpretation of the available evidence was constrained by the limited number of comparative studies, observational study designs, variability in clinical populations, and incomplete standardization of reproductive outcome reporting. Conclusions: Endometrial BCL6 appears biologically and clinically relevant as a marker of endometrial dysfunction in selected infertility settings, but current evidence is insufficient to support routine stand-alone clinical use or strong treatment recommendations. Its apparent prognostic and clinical utility varies across patient populations and reproductive settings. Larger prospective comparative studies with harmonized biopsy protocols, standardized outcome reporting, and independent external validation are needed to clarify the role of BCL6 in reproductive medicine.