Triglycerides and ovarian response in diminished ovarian reserve: a two-sample mendelian randomization and clinical mediation study

Background Diminished ovarian reserve (DOR) impairs assisted reproduction. Whether triglyceride (TG) plays a causal role in ovarian reserve remains unclear. Methods We performed a bidirectional two-sample Mendelian randomization (MR) analysis using female-specific GWAS data to assess causality between metabolic traits and ovarian reserve markers (AMH, FSH). Findings were validated in a retrospective cohort of 8,851 DOR women undergoing their first IVF/ICSI cycle, using mediation analysis to elucidate pathways to oocyte yield. Results MR revealed that genetically predicted TG was causally associated with lower FSH (IVW β=-0.096, FDR = 5.28×10 -5 ), with no evidence of reverse causation. Clinical validation confirmed this association. Mediation analysis uncovered that TG exerted a direct negative effect on oocyte yield, but concurrently lowered FSH, creating a suppression effect that partially counteracted this detriment (indirect effect: β = 0.0073, 95% CI: 0.0029 to 0.0117, p = 0.0021; suppression proportion: 23.6%). TG did not show a causal effect on AMH in MR (IVW OR = 1.035, 95% CI: 0.965-1.111, p = 0.338), and clinical mediation through AMH was not robust. Despite impacting oocyte yield, TG did not independently predict clinical pregnancy or live birth; age and AMH remained dominant. Conclusion This study provides genetic evidence for a causal role of TG in lowering FSH and identifies a suppression pathway through which TG affects oocyte yield. These findings provide additional insight into the relationship between lipid metabolism and ovarian reserve, and highlight TG as a potential modifiable factor worthy of further investigation.