Authors Pikwer M, Giwercman A, Bergström U, Nilsson J, Jacobsson LTH, Turesson C
Review Date April 2013
Citation Ann Rheum Dis 2013 Published Online First (3 April 2013): doi:10.1136/annrheumdis-2012-202781
Rheumatoid arthritis (RA) is less common among men than women, and sex hormones have been suggested to play a part in the pathogenesis. Lower levels of testosterone have been demonstrated in men with RA, but it is not known if these changes precede the disease – to date there is only one small prospective study reported. Testosterone has been proposed to have anti-inflammatory functions, by suppressing both the cellular and humoral immune system. Male sex has been found to be an independent predictor of remission in early RA. This has led to the hypothesis that androgen supplementation may be useful in the management of RA; however, testosterone as a treatment for RA has so far been investigated in limited only samples, with varying results.
The purpose of this nested case-control study was to explore the hormone levels in men before RA diagnosis, by analysing reproductive hormone levels in serum samples of incident cases of RA and comparing them to levels in matched controls who did not develop RA.
The Malmö Preventive Medicine Program (MPMP) was conducted in Malmö, Sweden (population 235,000 in 1974) between 1974 and 1992m (n=22,444 males born 1921-1949; 10,902 females born 1925-1938. The overall attendance rate was 71.2%. The participants (mostly Caucasian of Scandinavian origin) underwent physical examination including height and weight measurements and laboratory tests, completed a self-administered questionnaire on health and lifestyle factors and were invited to leave fasting blood samples.
In a nested case–control study, using information and blood samples from the MPMP, incident cases of RA were identified by linking the cohort to local and national RA registers. Two controls for each validated case, matched for age, sex and year of screening, were selected from the MPMP. Stored blood samples were analysed for levels of testosterone and other reproductive hormones.
The effect of baseline hormone levels on the risk of RA was examined by bivariate conditional logistic regression analysis. Multivariate logistic regression analysis was used to adjust for potential confounders. Analyses were stratified by rheumatoid factor (RF) status at diagnosis or later (ever positive vs negative) and also by time from screening to RA diagnosis (above vs below the median).
151 male cases of incident RA were identified, of which serum was available for 104 (median time from screening to RA diagnosis = 12.7 years (range 1–28); 73% rheumatoid factor (RF) positive at diagnosis or later) and 174 matched controls. In conditional logistic regression models, adjusted for smoking and body mass index, lower levels of testosterone were associated with subsequent development of RF-negative RA (odds ratio [OR]=0.31 per SD, 95% confidence interval [CI]=0.12 to 0.85), with a less strong association with RF-positive RA (OR=0.87 per SD; 95% CI=0.53 to 1.43). Restricting cases to those with an RA diagnosis > 5 years after screening did not change the results.
Levels of follicle-stimulating hormone were significantly increased in pre-RF-negative RA (p=0.02), but decreased in pre-RF-positive RA (p=0.02).
Lower levels of testosterone were predictive of RF-negative RA, suggesting that hormonal changes precede the onset of RA and affect the disease phenotype.
Points to Note
- There are limited data on the importance of androgen levels for the development of RA, particularly in men.
- Low testosterone could be a consequence of primary testicular dysfunction, could be due to a relationship with the hypothalamus–pituitary–gonadal axis, or also a result of inflammation causing a reduction in testosterone production. However, the lack of difference in serum indicators of inflammation or self-reported health status between pre-RA cases and controls, does not indicate inflammation due to early arthritis as the main explanation for the observed differences.
- Low testosterone levels might be a consequence of RA. Alternatively, low testosterone levels may reflect a role for androgens in the pathogenesis of RA. This is supported by the age-related sex differences in the epidemiology of RA. More research regarding this hypothesis could greatly improve the clarity of this relationship.
- A strength of this study was the ability to stratify by RF-status. However, there was only a small number of cases in the RF-negative group (n=22), impacting on the precision of estimates.
- Due to the limitations of the population examined (largely of Scandinavian and Caucasian descent) the generalisability of results is limited. To confirm these findings in other populations, further research into the relationship of testosterone and other reproductive hormones with RA incidence is warranted.