Lipid remodeling and circulating semaphorin 3A in diminished ovarian reserve

Diminished ovarian reserve (DOR) lacks strong plasma biomarkers, and recent studies have implicated lipid remodeling in its pathophysiology. In our previous study, we noted elevated circulating levels of semaphorin 3A (SEMA3A) in women with DOR, especially among those who achieved beta-human chorionic gonadotropin (β-hCG) positivity following in vitro fertilization. In this study, we explored whether there are correlations between increased SEMA3A levels and the lipid profile in DOR compared to healthy controls. We performed integrated untargeted metabolomics of plasma lipid and amide classes in women with DOR and healthy controls. Group differences and associations with SEMA3A and reproductive hormones were analyzed using ANCOVA or partial Spearman correlations adjusted for age, body mass index (BMI), and group, with multiple testing controlled by the two-stage Benjamini-Krieger-Yekutieli false discovery rate (BKY FDR) (q ≤ 0.05). Discrimination was evaluated using the area under the receiver operating characteristic curve (ROC AUC) with DeLong's test and FDR correction. Multiple lipid species, particularly glycerophospholipids and ether lipids, varied between groups and demonstrated fair to good discrimination, confirming lipid profile alterations consistent with lipid remodeling. Circulating SEMA3A showed no significant correlation with individual lipid species after adjusting for covariates and controlling for FDR. In contrast, reproductive hormones, including anti Müllerian hormone (AMH), follicle-stimulating hormone (FSH), prolactin (PRL), and tyroid-stimulating hormone (TSH), exibited coherent association with lipid species, particularly within triacylglycerol pathways. Plasma lipidomics in DOR revealed a reproducible remodeling signature; however, SEMA3A did not align with these systemic lipid changes, suggesting context-dependent, likely local ovarian or vascular signaling. Larger, prospective studies with harmonized sampling and complementary matrices (e.g., follicular fluid) are needed to clarify the role of SEMA3A and validate lipid-based signatures relevant to DOR.