Elevated plasma glucose links intrafollicular bile acids to altered embryological outcomes in IVF patients

Human reproduction is intricately linked to systemic metabolic regulation, with disturbances in glucose metabolism adversely affecting fertility outcomes. Beyond their classical role in lipid digestion, bile acids (BAs), cholesterol-derived catabolites, have emerged as bioactive signaling molecules influencing glucose homeostasis and reproductive physiology. Notably, enhanced glycemic control observed after bariatric surgery, BA administration, or BA sequestrant therapy underscores the potential of BAs as regulators of glucose metabolism and as promising biomarkers or therapeutic targets in metabolic disorders. However, most existing studies investigating the endocrine function of BAs within the follicular environment have been limited to animal models, and the relationship between female metabolic status and the intrafollicular BA milieu in humans remains poorly understood. This study investigates whether systemic metabolic states modulate intrafollicular BA composition and examines how these changes may impact reproductive potential and in vitro fertilization outcomes. Comparative analysis of matched serum and follicular fluid (FF) samples revealed that the primary glycine-conjugated BA, glycochenodeoxycholic acid, was significantly elevated in FF, while the secondary BAs, deoxycholic acid and ursodeoxycholic acid, exhibited marked decreases in FF compared to serum (p < 0.001). K-means clustering of intrafollicular BA concentrations identified two distinct groups characterized by significantly different BA levels in both FF and serum (p ≤ 0.0001 and p < 0.05, respectively). Among the glucometabolic parameters assessed, glucose emerged as a critical determinant of cluster separation, exhibiting the strongest positive correlation with PC1 (r = 0.43, p < 0.01). A linear regression model further substantiated that intrafollicular BA concentrations were dependent on fasting plasma glucose levels (p ≤ 0.01). Elevated plasma glucose also correlated significantly with markers of insulin resistance and metabolic syndrome risk, including HOMA-IR (r = 0.39, p = 0.01), triglyceride/HDL cholesterol ratio (r = 0.33, p = 0.04) and leptin/adiponectin ratio (r = 0.37, p = 0.02). Interestingly, women with higher intrafollicular BA levels showed fewer follicles, zygotes, and blastocysts but experienced higher clinical pregnancy rates following frozen embryo transfer (p < 0.05). These findings reveal a novel link between systemic glucose metabolism and intrafollicular BA homeostasis, suggesting that subtle metabolic imbalances may impair oocyte maturation and embryo development, while potentially enhancing endometrial receptivity or embryo competence in frozen cycles.