Hormonal transitions across the lifespan shape susceptibility to Sjogren’s disease

Objectives Sjogren’s disease (SjD) shows a strong female predominance, but the contribution of age-related hormone changes to this sex bias remains uncertain. We investigated whether natural hormonal transitions across the lifespan align with variation in male and female prevalence of SjD. Methods Electronic health records from 101 856 SjD patients and 1.33 million controls were analyzed. Sex-specific prevalence was compared with serum testosterone, estradiol, and sex hormone-binding globulin (SHBG) levels. Population-level hormone distributions from the National Health and Nutrition Examination Survey (NHANES) were incorporated using imputation. Generalized linear models evaluated associations between hormone fluctuations and sex prevalence across age groups. Results Male prevalence among SjD patients peaked during early childhood (30.1% [95% CI: 26.2–34.1]), declining sharply in late puberty into adulthood (9.8% [95% CI: 9.5–10.2]), and rose again in older adults (13.5% [95% CI: 13.3–13.8]). These non-linear shifts paralleled age-dependent trajectories of testosterone and estradiol. Hormone concentrations did not differ significantly between SjD patients and controls, indicating that physiological transitions, rather than abnormal levels, align with disease risk. Conclusion Age-dependent hormonal changes correspond with evolving sex bias in SjD, challenging the static 9:1 female-to-male paradigm. These findings highlight the role of age-related hormonal dynamics in shaping autoimmune susceptibility.