Immune Dysregulation and Endometrial Receptivity Impairment in Women With Repeated Implantation Failure and Dyslipidemia

CONTEXT: Dyslipidemia adversely affects reproduction outcomes; however, its relation with repeated implantation failure (RIF) remains unclear. OBJECTIVE: This study aims to analyze the impact of dyslipidemia on assisted reproductive technology (ART) outcomes, endometrial transcriptome, and microbiome of RIF women. DESIGN: A retrospective real-world analysis and prospective study. SETTING: University clinic. PATIENTS: 6499 infertile women, including 5618 non-RIF and 881 RIF. INTERVENTIONS: Dyslipidemia. MAIN OUTCOME MEASURES: Implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR) were compared in RIF women with or without dyslipidemia. Results of endometrial studies, including RNA sequencing (RNA-seq)-based endometrial receptivity test (ERT), 16S rRNA-based microbiome study, next-generation sequencing (NGS)-based gene comparison, and bulk RNA-seq deconvolution analysis were analyzed. RESULTS: The prevalence of dyslipidemia in RIF women was significantly higher. In dyslipidemia women, IR, CPR, and LBR were significantly lower, and the prevalence of nonreceptive ERT and the presence of endometrial pathogenic bacteria were higher than those of controls. After the personalized treatment, CPR 73.3% and LBR 60.0% were achieved in dyslipidemia women. NGS revealed that 176 differentially expressed genes in the endometrium of RIF women with dyslipidemia compared to those without, suggesting highly enriched in cholesterol and steroid biosynthesis and monocyte differentiation processes. An increased endometrial CD56dim natural killer cells and macrophage M1/M2 ratio with dysregulated immune factors were found by bulk RNA-seq deconvolution analysis. CONCLUSION: RIF women with dyslipidemia have significantly poorer ART outcomes. In women with dyslipidemia, immune homeostasis was breached in the luteal phase endometrium, implicating a possible immune mechanism for dyslipidemia-related implantation failure.