Association of Sjögren's Syndrome With Reduced Lifetime Sex Hormone Exposure: A Case–Control Study

Abstract

Objective To test whether cumulative estrogen exposure, as determined by age at menarche, age at menopause, female hormone use, hysterectomy, and parity, have an effect on the development of primary Sjögren's syndrome (SS). Methods We performed a case–control study of 2,680 women from the Sjögren's International Collaborative Clinical Alliance registry, including 1,320 registrants with primary SS and 1,360 with sicca symptoms but no key features of primary SS (sicca controls). The composite estrogen score (CES) was calculated by point assignment for early menarche (age ≤10 years), high parity (>3 pregnancies), hysterectomy, female hormone use, and late menopause (age ≥53 years). Cumulative menstrual cycling (CMC) was calculated as years menstruating minus time pregnant. Results Using a regression model that adjusted for age, recruitment site, ethnicity, education, employment status, and smoking, we observed a progressive inverse trend between primary SS and CES. The odds ratio (OR) and 95% confidence interval (95% CI) were as follows for the sicca control group: CES 1, OR 0.81 (95% CI 0.67–0.99); CES 2, OR 0.74 (95% CI 0.57–0.97); CES 3, OR 0.50 (95% CI 0.30–0.86). This trend was corroborated by analysis of CMC. At the highest level of CMC within the postmenopausal group there was a 24% reduction in cumulative sex hormone exposure among primary SS participants relative to controls. Conclusion Women with primary SS have lower estrogen exposure and CMC compared to sicca controls. Increasing estrogen exposure was negatively associated with development of primary SS. Further longitudinal studies of sex hormone exposure in primary SS are needed to confirm these findings.

Association of the Risk of Primary Sjögren's Syndrome With Fibrocystic Breast Disease: A Nationwide, Population-Based Study

“…We also noted that osteoporosis appeared to be associated with a modestly increased risk of developing pSS, and the finding was consistent with previous studies ( 1 , 31 , 32 ). One Taiwanese study reported that the presence of osteoporosis was associated with a slightly increased risk of developing xerophthalmia (aOR, 1.26; 95% CI, 1.22–1.30) ( 31 ).…”

“…The strong predisposition of post-menopausal women to develop pSS suggests a key role for sex hormones in the pathogenesis of pSS. Notably, McCoy et al recently conducted a case–control study of 2,680 women in the Sjögren's International Collaborative Clinical Alliance registry and found that pSS in women was associated with a lower cumulative estrogen exposure and the menstrual cycling time compared with sicca controls ( 32 ). The aforementioned evidence and the central role of estrogen deficiency in the pathogenesis of osteoporosis suggest that a low estrogen level contributes to the association between osteoporosis and SS in post-menopausal women.…”

Environmental factors in the pathogenesis of primary Sjögren's syndrome

“…Furthermore, sicca controls had a significantly younger age of menarche and a higher proportion of current female hormone therapy. Intriguingly, high compared to low CES was significantly associated with lower ocular staining score and lower prevalence of hypergammaglobulinaemia, RF and anti‐Ro/SSA autoantibodies in the SS patients .…”

“…However, counterintuitively, several studies have suggested a protective role for female sex hormones in SS. McCoy et al reported on female patients with SS ( n = 1320) compared to sicca controls ( n = 1360) with regard to age of menarche, age of menopause, reproductive history, use of female hormone therapy at time of enrolment and hysterectomy history (Table ). Composite oestrogen scores (CES) and cumulative menstrual cycling (CMC) years before onset of sicca symptoms were analysed.…”

Current State of Knowledge on Primary Sjögren’s Syndrome, an Autoimmune Exocrinopathy

“…In a recent case-control study, pSS in women was associated with lower oestrogen exposure and lower cumulative menstrual cycling time compared to sicca controls. Conversely, an increasing oestrogen exposure was negatively associated with development of pSS [ 66 ]. Finally, an effect of X chromosome per se is also evoked since men with Klinefelter’s syndrome have a higher risk of developing pSS—20 times higher—compared to healthy men, despite normal sex hormone levels [ 67 , 68 ].…”