-Not a recommendation for estrogen-replacement therapy, though, researchers caution Questions Addressed: What is the relationship between estrogen levels and the development of pSS in women? Do the data indicate a cause-effect relationship between estrogen levels and pSS? Study Synopsis and Perspective: There is an inverse association between greater cumulative estrogen exposure and risk for pSS, suggesting that more extensive sex hormone exposure might be protective against the development of this autoimmune disease, a large case-control study has shown. Sara McCoy, MD, of the University of Wisconsin in Madison, and colleagues reported that in 2,680 women enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA), those who had the greatest overall exposure to estrogen because of factors such as early menarche had only half the risk of developing full-blown SS despite having some sicca-type symptoms, with an odds ratio of 0.5 (95% CI 0.30-0.86). As the team explained in their study online in Arthritis Care & Research, sex hormones are thought to play a role in the pathogenesis of SS, which is characterized by lymphocytic infiltration of the salivary and lacrimal glands, and other manifestations such as antibody positivity and parotid enlargement. This association with sex hormones has been suspected because women are affected 10 times more often than men, and the usual age of onset is around the time of menopause, when there is a rapid decline in female sex hormones, the researchers explained. However, few studies have examined this association in detail, so McCoy's group analyzed data from SICCA, which is a National Institutes of Health-funded international registry that enrolled patients with suspected or confirmed SS from 2003 to 2012. The analysis included 1,320 women with confirmed Sjögren' syndrome and 1,360 sicca controls; mean ages were 52 and 54 years, respectively. The researchers compared patients who met the criteria established by the American College of Rheumatology/European League Against Rheumatism for SS with those who had at least one objective sicca sign such as unstimulated whole salivary flow of 0.1 mL/min or less, or a Schirmer's test result below 5 mm/5 min, but who did not have anti-Sjögren's-syndrome-related antigen (SSA) antibodies, or a biopsy sialadenitis focus score of 1 or higher; this group of patients were designated as sicca controls. McCoy and co-authors calculated composite estrogen scores from variables including early menarche, high parity, hysterectomy, use of hormone therapy, and late menopause, with scores ranging from 0 to 5. They calculated cumulative menstrual cycling for premenopausal women as the age of the woman minus the number of years since the onset of sicca symptoms, menarche age, and time spent pregnant, while for postmenopausal women, the calculation was age at menopause or onset of sicca symptoms minus age at menarche and time spent pregnant. The researchers found that the risk reduction for SS among the sicca controls was progressive, with odds ratios of 0.81 (95% CI 0.67-0.99) for those with a composite estrogen score of 1, and 0.74 (95% CI 0.57-0.97) for a score of 2, then declining to 0.50 for those with scores of 3 or higher. And among those sicca controls, women with the highest cumulative menstrual cycling scores at menopause had a 24% reduction in sex hormone exposure. The pattern was less clear for cumulative menstrual cycling scores. Among premenopausal women, those in the third quartile for exposure had an odds ratio of 0.49 (95% CI 0.30-0.80) for Sjögren's syndrome, although statistical significance was not seen for those in the top quartile (OR 0.69, 95% CI 0.38-1.26). For postmenopausal women, the lowest risk was in the top quartile (OR 0.76, 95% CI 0.56-1.04). This measure may be less sensitive for the detection of risks for Sjögren's syndrome because it does not reflect factors other than menstruation that can influence hormone exposure, the researchers explained. Regarding the individual reproductive and menstrual factors, sicca controls had a lower likelihood of having had a hysterectomy (OR 0.71, 95% CI 0.57-0.89, P<0.001), a younger age at menarche (12.8 vs 13.1 years, P<0.00001), and more often were using exogenous hormones (21% vs 14%, P<0.001). Further analysis of patients with the highest composite estrogen scores (more than 3) found reduced risks of these features, which are typical of Sjogren's syndrome: Ocular staining score of 5 or higher, OR 0.4 (95% CI 0.2-0.7) Hypergammaglobulinemia, OR 0.3 (95% CI 0.1-0.8) Rheumatoid factor positivity, OR 0.5 (95% CI 0.2-0.9) Anti-SSA positivity, OR 0.5 (95% CI 0.3-0.9) "Our findings suggest that cumulative estrogen exposure may have a modulating effect on factors that predispose women to autoimmune disease," McCoy and colleagues concluded. "In the case of primary Sjögren's syndrome, lower cumulative estrogen exposure appears to augment the clinical expression of disease." McCoy emphasized, however, that she is not suggesting that women be given estrogen-replacement therapy in this context. "Those women with full-blown Sjögren's syndrome had less exposure than those without," she told MedPage Today. "So you might [extract] from that observation that estrogen exposure over the long term might be protective. So what we do next is say, what's the mechanism behind that and is it something we can harness to understand the disease better, and down the road develop new targeted therapies ... I am not endorsing the use of estrogen-replacement therapy." A limitation of the study, the team said, was its case-control design, which confirms an association but not a cause-effect relationship. Another limitation is the dearth of information available from the SICCA registry on details of menstrual cycling and reproductive factors such as menstrual regularity or lactation, which are both known to influence hormone-related results. Another concern is the use of a sicca control group rather than a healthy control group, the researchers stated. "It is possible that the sicca-control group represents an incomplete form of pSS. However, this might actually strengthen our results, as a more similar control group would reduce the chances of the significant findings we report." Source Reference: Arthritis Care & Research 2019; DOI: 10.1002/acr.24014 Study Highlights: Explanation of Findings While SS may affect people of any age, symptoms usually manifest in those from the ages of 45 and 55, and approximately 10 times more women than men are affected. About half of pSS patients also have rheumatoid arthritis or another connective tissue autoimmune disease, such as lupus. McCoy and co-authors said that importantly, while pSS and other autoimmune diseases "share a marked female predominance ... pSS is distinctive in exhibiting a peak onset of symptomatic disease around the age of menopause, despite the presence of autoantibodies up to 20 years earlier." "Environmental exposures such as gut microbiota may help explain sexual dimorphism," the researchers said. For example, in nondiabetic mice, male and females develop type 1 diabetes at different rates, a process dependent on gut microbiota, which regulate sex hormone levels and the risk of autoimmunity. "It is this complex interplay between different genetic, environmental, and estrogen exposures that might contribute to the variable and more severe phenotype of younger onset pSS compared to later onset pSS," McCoy's group wrote. They noted that this was the largest epidemiological study to date to evaluate the association of sex hormone exposure in women with the development of pSS. The team compared 1,320 women with pSS with 1,360 women who did not have pSS from the SICCA registry, and found an inverse association between reproductive and menstrual factors and the prevalence of pSS. "Our findings suggest that cumulative estrogen exposures may have a modulating effect on factors that predispose women to autoimmune disease. In the case of pSS, lower cumulative estrogen exposure appears to augment the clinical expression of disease," the researchers said. "At the highest level of CMC [cumulative menstrual cycle] within the postmenopausal group there was a 24% reduction in cumulative sex hormone exposure among pSS registrants relative to controls." "Female sex hormones might be protective in primary Sjögren's syndrome," McCoy and colleagues continued, explaining that the study results give insight into possible novel mechanisms of the disease's pathogenesis. The team concluded: "Women with pSS have lower estrogen exposure and CMC compared to a sicca control. Increasing estrogen exposure was negatively associated with development of pSS. Further longitudinal studies of sex hormone exposure in pSS are needed to confirm these findings." Source
