A unique collection of fasting morning blood samples obtained from 104 men who subsequently developed rheumatoid arthritis (RA) showed that those with lower testosterone levels were more likely to develop rheumatoid factor (RF)-negative RA, which suggests that hormonal changes both precede disease onset and affect disease phenotype.
Mitra Pikwer, MD, a rheumatology fellow at Lund University Faculty of Medicine, Malmö, Sweden, and colleagues also report in their article, published online in the Annals of the Rheumatic Diseases, that the men who developed RF-negative RA also had increased levels of follicle-stimulating hormone (FSH).
"The results on testosterone confirmed our hypothesis, since low testosterone levels have been noted in men who already have developed the disease. The results on [FSH] were a bit surprising. Men who would later develop RF-positive disease seemed to have a less responsive hypothalamus–pituitary–gonadal (HPG) axis with a lesser FSH response considering a relatively low testosterone level. Men who would later develop RF-negative RA had a good HPG-axis response. This suggests different hormonal pathways in the development of RF-positive and RF-negative RA," Dr. Pikwer told Medscape Medical News.
The researchers conducted a nested case-control study using information and blood samples from the Malmö Preventive Medicine Program, a preventive case-finding program conducted in Malmö, Sweden, between 1974 and 1992. The database included 22,444 men and 10,902 women. Incident cases of RA were identified by linking the cohort to local and national RA registers, and each case was compared with two age- and sex-matched control patients.
Conditional logistic regression models adjusted for smoking and body mass index (BMI) showed that lower levels of testosterone were associated with an increased risk for development of RF-negative RA, and that FSH levels were significantly increased in men who developed RF-negative RA (P = .02) but decreased in those who developed RF-positive RA (P = .02).
Proinflammatory cytokines stimulate the hypothalamic–pituitary–adrenal axis but suppress the HPG axis, so low testosterone levels might have been a consequence of the underlying inflammatory disease, according to the authors. However, they found no significant differences in erythrocyte sedimentation rate between case and control patients.
"Based on the available data, it is unlikely that the low testosterone levels in men who later developed RA are explained by inflammation. We believe that testicular dysfunction is a primary risk factor for RF-negative RA. In addition, testosterone levels may be further affected by inflammation in the time period around and after the clinical disease onset," Dr. Pikwer said.
The men who developed RA were leaner than the control patients, and there was a negative correlation between BMI and both testosterone and free testosterone levels (P < .001). There was no correlation between BMI and FSH, luteinizing hormone, or sex-hormone binding globulin. All of the hormone levels were higher in smokers than in nonsmokers. Smoking was associated with increased risk for RF-positive RA in bivariate logistic regression analysis.
"As we move to more personalized medicine, we are no longer going to be able to ignore the impact of sex hormones on inflammation. Understanding how sex hormones regulate disease will be critical to develop better therapies and breakthroughs in our understanding of disease pathogenesis," DeLisa Fairweather, PhD, told Medscape Medical News. Dr. Fairweather, who was not involved in the study, is assistant professor in the Division of Molecular and Translational Toxicology at Johns Hopkins University's Bloomberg School of Public Health in Baltimore, Maryland. She recently reported on the role of sex hormones in cardiovascular disease.
Testosterone supplements are aggressively marketed, but neither Dr. Pikwer nor Dr. Fairweather would recommend them for men trying to avoid RA.
"There is an increasing literature demonstrating the importance of sex hormones in regulating inflammatory cells, which drive disease. Estrogen is a strong driver of rheumatoid arthritis by increasing antibody-mediated damage. Testosterone and estrogen influence large groups of genes through estrogen response elements and androgen response elements. The key is that testosterone has opposite effects to estrogen on immune cells. If testosterone levels drop, the protective effects of testosterone in reducing RA would decrease, and estrogen levels would likely increase. The increase in estrogen...would promote RA in men," Dr. Fairweather said.
"Testosterone supplementation is not a good strategy because it is likely to have unpredictable consequences, such as increased cardiovascular disease/atherosclerosis in men. A recent clinical trial of testosterone supplementation in older men had to be stopped early because of increased [cardiovascular disease]. A better approach would be to gain an understanding of the target genes that testosterone [suppresses] or that estrogen [stimulates] that lead to RA. Therapies to those target genes would likely have fewer bad side effects."
This study was supported by the Swedish Research Council, the Swedish Rheumatism Association, Lund University and the County of Skåne. The authors and Dr. Fairweather have disclosed no relevant financial relationships.
Ann Rheum Dis. Published online April 3, 2013. Abstract
Janis C. Kelly • Medscape Medical News © 2013 WebMD, LLC