Pre-Diagnostic Plasma Endogenous Steroids and the Risk of Exfoliation Glaucoma

Purpose: Exfoliation glaucoma (XFG) is the most common secondary glaucoma. Prior studies suggest a higher incidence in women and links to reproductive history, implying estrogen-related pathways. Metabolomic data also indicated inverse associations with steroid-related plasma metabolites, suggesting steroid involvement in XFG pathogenesis. Methods: We conducted a nested case-control study within the Nurses' Health Study (NHS; 1980-2018), NHSII (1989-2019), and Health Professionals Follow-up Study (1986-2018), with 217 XFG/XFG suspect (XFGS) cases and 217 matched controls (62 men and 372 women). We evaluated 18 endogenous steroids and 5 steroid classes using conditional logistic regression. Secondary analyses examined effect modifications by age and residential latitude, and heterogeneity by disease severity (XFGS versus XFG). Metabolite set enrichment analysis (MSEA) was used for class-level associations. Multiple comparisons were addressed using the number of effective (NEF) tests for individual steroids and the false discovery rate (FDR) for steroid classes. Results: No individual steroid or steroid class met NEF- or FDR-adjusted significance thresholds, overall or by sex. Nonetheless, across both sexes, MSEA demonstrated a nonsignificant inverse trend between androgen levels and XFG/XFGS risk (FDR = 0.22), with 11-ketotestosterone showing a nominal inverse association (odds ratio [OR] = 0.54, 95% confidence interval [CI] = 0.31-0.93, P = 0.03). Progestogen enrichment scores showed an adverse trend (FDR = 0.31), featuring a borderline adverse association between progesterone and XFG/XFGS (OR = 2.21, 95% CI = 1.00-4.87, P = 0.05). Conclusions: Although we observed no statistically significant associations with steroids after correction for multiple testing, the suggestive patterns for androgens and progestogens support the possibility of steroid-related pathways in XFG etiology and support further evaluation in larger studies.