Background/Purpose: Sjögren’s Syndrome (SS) is an autoimmune disease with female predominance and frequent perimenopausal onset, indicating a potential pathogenic role for sex hormones.  The goal of this study was to evaluate if cumulative sex hormone exposure impacts the risk of development of SS.

Methods: We performed a case-control study of 2860 women from the Sjögren’s International Collaborative Clinical Alliance registry, including 1320 SS participants, 1106 participants with sicca symptoms but no key objective phenotypic features of SS (“sicca controls”), 371 participants with no sicca symptoms or phenotypic features of SS (“non-sicca controls”), and 63 participants with positive SSA antibody but not meeting criteria for SS (participants were not included in analysis due to low number). Individual reproductive and menstrual factors were used to create composite scores.  Composite estrogen score (CES) was calculated by point assignment for early menarche (≤10 years), high parity, hysterectomy, use of hormone therapy, and late menopause (≥53 years). Cumulative menstrual cycling (CMC) years for premenopausal registrants was calculated as the age of the registrant minus years since first sicca onset, menarche age, and time pregnant. Covariates included age, referral source, race, education level, employment status, smoking status, and recruitment site. Multivariable logistic regression was used for outcomes against the predictors of interest and all results are interpreted in terms of odds ratios (ORs).

Results: Using a regression model adjusting for age, recruitment site, ethnicity, education, employment status, and smoking, we observed a progressive inverse trend between SS and both CES and CMC.  For each stratum of greater cumulative estrogen exposure (CES1-3), there was a progressive and significant decrease in SS risk relative to sicca controls.  The ORs and 95% confidence interval (95% CI) were as follows for the sicca control group: CES1, OR 0.84 [95% CI, 0.7-1.0]; CES 2, OR 0.7 [95% CI, 0.5-0.9]; CES 3, OR 0.43 [95% CI, 0.25-0.75].   Similar trends were seen in the non-sicca control group (Table).  The higher stratum of CES were not significant, but numbers of registrants were small, leading to wide confidence intervals. This finding was corroborated by analysis of the CMC.  At the highest level of CMC within the non-sicca control and sicca control postmenopausal groups there was a 45% and 25% reduction in cumulative sex hormone exposure among SS registrants relative to controls, after adjusting for covariates. 

Conclusion: Women with SS have lower estrogen exposure and cumulative menstrual cycling compared to non-autoimmune sicca and non-sicca control groups. As estrogen exposure and cumulative menstrual cycling increased, there was a trend toward decreased risk of SS. Further longitudinal studies of sex hormone exposure in SS are needed to confirm these findings.