Systemic Inflammation and Semen Quality: Associations of Inflammatory Markers With Sperm Parameters Based on the STARR EHR Database

BACKGROUND: Systemic inflammation has been implicated in impaired spermatogenesis, but real-world evidence linking blood-based inflammatory indices to semen quality is limited. OBJECTIVES: To assess associations between systemic inflammatory markers and semen parameters across biologically relevant time windows. MATERIALS AND METHODS: We performed a retrospective cohort study using the Stanford Research Repository (STARR). The cohort included 7172 semen analyses from 925 adult men paired inflammatory testing. Markers included C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-eosinophil ratio (MER) and red cell distribution width (RDW)-to-platelet ratio (RPR). Outcomes were total motile sperm count (TMSC), concentration, motility, morphology, and volume. Spearman correlations and Wilcoxon rank-sum tests were calculated across same day and ±30-, 60-, 90-, 180-, and 365-day windows. Generalized estimating equation models estimated odds of "high" semen parameters (WHO thresholds). RESULTS: Novel indices showed consistent inverse associations that were strongest at 30-90 days. For motility at 60 days, NLR (r = -0.062, p < 0.0001), PLR (r = -0.055, p < 0.0001), and RPR (r = -0.052, p < 0.0001) were significant. For concentration, RPR was inversely associated across all windows (e.g., 1-year r = -0.029, p = 0.0001); NLR was significant at 30 days (r = -0.057, p = 0.0003). TMSC showed negative correlations with NLR, PLR, RPR, and MER in shorter windows. Volume and morphology did not exhibit consistent inverse correlations. CRP and ESR lacked consistent negative associations across windows. In odds-ratio analyses, MER predicted lower odds of high concentration at 180 days (OR 0.9945, 95% CI, 0.9893-0.9997) and 90 days (OR 0.990, 95% CI, 0.981-0.999); PLR predicted lower odds of high motility at 60 days (OR 0.9997, 95% CI, 0.9994-0.9999) and 30 days (OR 0.9993, 95% CI, 0.9990-0.9995). DISCUSSION: Effect sizes were modest but temporally coherent with spermatogenesis, supporting biological plausibility. Traditional markers (CRP/ESR) were less informative. CONCLUSION: CBC-derived inflammatory indices, particularly NLR, RPR, PLR, and MER, are associated with lower semen quality, most notably when testing occurs within 30-90 days of semen analysis. Prospective studies are warranted to test causality and clinical utility.