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Greater cumulative estrogen exposure was inversely associated with risk for primary Sjögren's syndrome, suggesting that more extensive sex hormone exposure might be protective against the development of this autoimmune disease.

In a large case-control study of women enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA), women who had the greatest overall exposure to estrogen because of factors such as early menarche had only half the risk of developing full-blown Sjögren's syndrome despite having some sicca-type symptoms, with an odds ratio of 0.5 (95% CI 0.30-0.86), according to Sara McCoy, MD, of the University of Wisconsin in Madison, and colleagues.

And among those sicca controls, women with the highest cumulative menstrual cycling scores at menopause had a 24% reduction in sex hormone exposure, the researchers reported in .

Sex hormones are thought to play a role in the pathogenesis of Sjögren's syndrome, 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, with the rapid decline in female sex hormones.

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 Sjögren's syndrome from 2003 to 2012.

Patients who met the criteria established by the American College of Rheumatology/European League Against Rheumatism for Sjögren's syndrome were compared 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 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 referred to as sicca controls.

Composite estrogen scores were calculated from variables including early menarche, high parity, hysterectomy, use of hormone therapy, and late menopause, with scores ranging from 0 to 5.

Cumulative menstrual cycling for premenopausal women was calculated as the age of the woman minus the number of years since sicca symptom onset, menarche age, and time spent pregnant, while for postmenopausal women it was calculated as age at menopause or onset of sicca symptoms minus age at menarche and time spent pregnant.

The analysis included 1,320 women with confirmed Sjögren' syndrome and 1,360 sicca controls, whose mean ages were 52 and 54 years, respectively.

The risk reduction for Sjögren's syndrome 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.

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), had 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 typical features 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."

However, she is not suggesting that women be given estrogen-replacement therapy in this context, McCoy told MedPage Today.

"Those women with full-blown Sjögren's syndrome had less exposure than those without. So you might abstract 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," she said.

"I am not endorsing the use of estrogen-replacement therapy," she cautioned.

A limitation of the study, the team said, was its case-control design, and further longitudinal studies will be needed to confirm these observations.

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