Follicular Fluid Amino Acid Alterations in Endometriosis: Evidence for Oxidative Stress and Metabolic Dysregulation

Background/Objectives: Endometriosis (EM) is a chronic gynecological condition associated with infertility, oxidative stress, and altered metabolic regulation. Follicular fluid (FF) reflects the microenvironment of the developing oocyte, and changes in its amino acid composition may affect reproductive outcomes. This study aimed to characterize alterations in the amino acid composition of the FF in EM and to identify potential reproductive outcomes. Methods: Targeted metabolomic analysis of 20 amino acids was performed on FF samples from 56 women undergoing in vitro fertilization (17 with endometriosis, 39 controls). Amino acid concentrations were quantified and compared between groups, adjusting for age and body mass index. Pathway, biomarker, and multivariate analyses were conducted to explore metabolic alterations and potential diagnostic markers. Results: Asparagine, histidine, and glycine concentrations were significantly higher in the EM group after adjustment for age and BMI. Pathway analysis indicated perturbations in glycine/serine metabolism, glutathione metabolism, and porphyrin metabolism, consistent with oxidative stress and mitochondrial dysfunction. Multivariate modeling demonstrated partial separation between groups, while biomarker analysis identified asparagine (AUC = 0.76), along with glycine and histidine, as potential discriminators. Additional enrichment of bile acid and methylation-related pathways suggested broader systemic metabolic changes in EM. Conclusions: EM is associated with distinct amino acid alterations in the FF, particularly elevated asparagine, histidine, and glycine, reflecting oxidative and mitochondrial imbalance in the follicular environment. These metabolites emerged as candidate biomarkers requiring validation for EM-related oocyte quality changes and may help individualize in vitro fertilization approaches.