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Abstract
Background As rheumatoid arthritis (RA) occurs more often in women than in men, it has been suggested that reproductive hormones may play an important role in the pathogenesis.
Methods Between 1991 and 1996, 30 447 subjects (18 326 women) were included in a community-based health survey. Information on female hormonal changes and stress-related factors was obtained using a self-administered questionnaire. This population was linked to four different local and national RA registers. The medical records for patients with a diagnosis of RA were subjected to a structured review and all women with incident RA according to the 1987 American College of Rheumatology criteria after inclusion in the health survey were included in a nested case–control study. Matched controls (1:4) were selected from the health survey population.
Results Early age at menopause (≤45 years) was associated with the subsequent development of RA (OR 2.42, 95% CI 1.32 to 4.45). The effect of early menopause remained significant after adjusting for smoking, level of education and length of breastfeeding (OR 1.92, 95% CI 1.02 to 3.64)
Conclusion RA was predicted by an early age at menopause. This implicates an influence of hormonal changes during the fertile period on the development of RA in postmenopausal women.
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Throughout the reproductive years, the incidence of rheumatoid arthritis (RA) in women is more than twofold the incidence in men.1 2 Based on this and on observations of amelioration of RA during pregnancy, an important role of reproductive hormones has been implicated in the pathophysiology. There are conflicting data on the impact of age at menopause3 4 and age at menarche5 6 on the risk of RA.
The relation between reproductive factors, the hypothalamic–pituitary–adrenal (HPA) axis and inflammation is complex and not fully understood. The HPA axis may be altered in individuals who later develop RA in the uterus7 8 or it may be secondarily modified by later hormonal events, for instance breast-feeding or pregnancy.9 Furthermore, stress-related factors may strongly influence breastfeeding habits,10 and hypothetically, stress-related elevation of proinflammatory cytokines11 could lead to increased RA susceptibility.
The aim of this study was to examine the impact of age at menopause, age at menarche and a set of stress-related factors on the risk of RA with peri or postmenopausal onset and to explore further the effect of long-term breast-feeding in this context.
Patients and methods
The Malmö Diet and Cancer Study (MDCS), a community-based health survey performed in Malmö, Sweden, between 1991 and 1996, included 30 477 subjects (18 326 women) aged 44–74 years.12 Information on lifestyle factors, such as smoking, level of education, reproductive factors and previous and current health status was obtained using a self-administered questionnaire.
As previously described,13 incident cases of RA were identified by linking the MDCS cohort to several local and national registers, followed by a structured review of these cases. All women diagnosed with RA who fulfilled the 1987 American College of Rheumatology criteria for RA14 after inclusion in the MDCS were included in this nested case–control study. Four female controls for every case, matched according to age and year of screening, who were alive and free of RA diagnosis when the index person was diagnosed with RA, were selected from the MDCS survey population.
The women were stratified into two groups, early (≤45 years) or normal to late (>45 years) menopausal age.15 As all cases and controls were 45 years or older when answering the questionnaire, those who reported that they had not yet reached menopause were classified in the later group but were excluded when analysing the total number of fertile years. Early menarche was defined as menarche before the age of 12 years. Breast-feeding history was stratified as previously described.13 The stress-related factors and the definition of smoking history and level of formal education are described in the supplementary text, available online only.
Non-responders to each question were excluded from the corresponding analysis. Data on rheumatoid factor (RF) and anti-cyclic citrullinated peptide status at RA diagnosis or later were extracted in a structured review of all medical records.
Potential predictors were examined in conditional logistic regression models. Each case and the corresponding controls were assigned a group number, which was entered into the logistic regression models as a categorical variable. Multivariate models were used to adjust for potential confounders. Bivariate analyses were stratified by RF status (positive/negative) after RA diagnosis among the cases. The regional research ethics committee for southern Sweden approved the study.
Results
One hundred and thirty-six women with incident RA were compared with 544 age-matched female controls (table 1). The median duration from enrolment in the health survey to RA diagnosis was 5.5 years. The estimated crude incidence was 72/100 000 persons-years, based on the 188 969 person-years follow-up of the cohort. There was missing data on menopause for 45 women (6.6%; seven cases, 38 controls). Those with normal/late menopause were more likely to report breast-feeding more than 12 months compared with those with early menopause (21.4% vs 12.5%; p=0.007).
Characteristics and baseline exposure information on RA cases and matched controls
Bivariate analyses
Early age at menopause (≤45 years) was a predictor of the subsequent development of RA (table 2). Early menopause was significantly associated with RF-negative RA, whereas there was a trend for RF-positive RA that did not reach significance (table 2). Early menarche, at less than 12 years, was significantly associated with a reduced risk of RA, with similar patterns for RF-positive and RF-negative RA when analysed separately (table 2). In accordance with these results, a longer fertile period was protective against developing RA (OR 0.92 per year, 95% CI 0.87 to 0.97).
Reproductive factors and the risk of RA for all cases and by RF status at inclusion: bivariate analysis
Parity (table 2) and stress-related factors (see supplementary table S1, available online only) had no significant effect on the risk of RA.
Multivariate analyses
Early menopause (p=0.007) and early menarche (p=0.013) had a similar influence on the risk of RA in models adjusted for parity. In multivariate analysis, long-term breastfeeding (>12 months; OR 0.45, 95% CI 0.22 to 0.92) and early menopause (OR 2.22, 95% CI 1.20 to 4.12) had independent effects on the risk of RA. The association with early menopause remained significant in a model adjusted for the length of breastfeeding, smoking and the level of formal education (OR 1.92, 95% CI 1.02 to 3.64).
In a multivariate model including all three variables related to reproduction as covariates and further adjusted for smoking and level of education, the estimated effects of early menarche, early menopause and the length of breastfeeding were similar to the bivariate analyses, although CI were wider (table 3).
Multivariate analysis, adjusted for all variables in the table
Discussion
In this nested case–control study based on a prospective survey, we found that early menopause was significantly associated with RA. This may suggest a link between hormonal changes and chronic inflammation or factors specifically related to RA (see supplementary text, available online only).
Smoking and a low level of formal education are known predictors of early menopause,16 but adjusting for these did not change our estimates, indicating that they were not confounders in our sample. Our results support the study by Merlino et al,3 who found that women who reached menopause after the age of 51 years had a reduced risk (adjusted RR 0.64) of developing RA compared with women whose menopause occurred before the age of 45 years. In a Swedish case–control study, early menopause was protective against RA.4 The retrospective nature and the limited sample size of that study could explain the discrepancy from our results.
Potential explanations for our findings include endocrine factors such as an insufficient HPA axis with a sluggish response to stress.17 On the pathway to RA development such sluggish HPA axis could possibly manifest itself as a lower frequency of early menarche, a higher frequency of breastfeeding problems and more frequent early menopause. Other mechanisms could hypothetically also be involved including premature ovarian failure (see supplementary text, available online only).
We have previously shown that cumulative breastfeeding of more than 12 months was associated with a significantly reduced risk of developing RA.13 This is in accordance with a previous report,18 although a recent retrospective study reported opposing results.19 As expected, women with early menopause in the present study were less likely to report a history of long-term breastfeeding. However, age at menopause and history of breastfeeding were found to affect the risk of RA independently.
Early menarche (<12 years) was inversely associated with RA, although the number of patients was limited. This is in accordance with a Danish study,5 but an American study reported contradictory results, with an increased risk of RA in subjects with early menarche (<11 years).6 Geographical and ethnic differences, as well as differences in the case mix, may explain these discrepancies.
Hormonal factors may have different effects on disease presenting in the middle-aged/older individuals compared with those with a younger onset, as well as between RF-positive and RF-negative RA. In our material the effect of early menopause was statistically significant for RF-negative RA, although there also was a similar trend for RF-positive RA. This is in contrast to other risk factors for RA, for instance smoking, which is mainly a predictor of RF-positive RA.20
We did not find any association between the risk of RA and a set of stress-related factors, including sleeping disorders and self-reported health. We can not exclude that such factors may have an impact on the risk of RA, as our questions were asked several years before diagnosis. Furthermore, psychosocial aspects not investigated in the present study may be important.
Limitations of the present study include the lack of information on polycystic ovary syndrome, endometriosis or hysterectomy and the low number of subjects with early menarche. It is possible that unmeasured confounders influenced our analysis; in particular as there is a long lag period between some of the exposures (ie, menarche and breast-feeding) and the development of RA. Furthermore, due to the lack of screened subjects aged less than 44 years, our results are only relevant for disease starting after this age.
The strengths of our study consist of the community-based approach and the fact that data on predictors were collected before RA diagnosis. This means that the effect of RA on lifestyle and recall bias could not influence our results.
In conclusion, early age at menopause was one of several hormonal factors that were associated with an increased risk of RA. This suggests an influence of hormonal changes during the fertile period on the development of RA in postmenopausal women.
Acknowledgments
The authors would like to thank Professor Göran Berglund for his contributions to the study design and to the first draft of this paper. The authors also thank Anders Dahlin for excellent help with data extraction from the MDCS database and Per-Olof Östergren for valuable comments on the questionnaire regarding stress-related factors.
References
Supplementary materials
Supplementary Data
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Footnotes
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Competing interest None.
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Ethics approval The regional research ethics committee for southern Sweden approved the study.
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Provenance and peer review Not commissioned; externally peer reviewed.