A recent study by Rebecca Keith and co-workers from the National Jewish Health, Denver, CO, US, published in Arthritis and Rheumatism, provides further experimental evidence that testosterone deficiency might play a role in the development of arthritis.
It is well known that sex hormones are involved in the pathogenesis of rheumatoid arthritis(RA). In addition, a progressive RA associated interstitial lung disease occurs in nearly 10% of RA patients but little is known about its pathogenesis.
Previous research suggests that androgenic deficiencies, particularly of gonadal origin in males, may contribute to RA, while supplemental testosterone has been shown to improve RA symptoms in both postmenopausal women and men with low levels of testosterone.
Previous studies indicate that men with RA have lower levels of serum testosterone (T) than healthy men as well as compared with men with osteoarthritis  and ankylosing spondylitis. These findings have led to the hypothesis that low T levels may have a pathogenic role in RA.
A 2002 study by B. Tengstrand, K. Carlström and I. Hafströms showed that men with RA had lower levels of bioavailable T expressed as NST compared with healthy age‐matched controls and that frank hypogonadism was quite common. Thus, 33 of the 104 examined patients were considered hypogonadal, which was significantly more than in the control population.
Yet, it is not quite clear whether low testosterone levels precede the development of RA. A recent population-based case-control study, however, indicates that low levels of T are predictive of rheumatoid factor (RF)-negative RA (Pikwer M et al., Ann Rheum Dis. 2013 Apr 3. Epub ahead of print).
In the study of Keith et al., a surgical orchiectomy approach was used to prospectively investigate the effects of T on the development of arthritis, interstitial lung disease, and autoantibody formation in SKG mice. The authors report that female SKG mice developed arthritis and interstitial pneumonia with more rapid onset and with increased prevalence and severity as compared to male SKG mice.The removal of T increased both lung and joint disease in male mice, creating a phenotype that is intermediate between that of intact males and that of females.
The authors conclude that T is protective against the development of arthritis and lung inflammatory disease, and that this might be related, at least in part, to the ability of testosterone to modulate the development of antibodies against citrullinated proteins.
In 2014, Mitra Pikwer et al. in a nested case–control study and participants of the Swedish Malmo Preventive Medicine Program (MPMP), which began in 1974 and tracked the health of more than 33,000 people born between 1921 and 1949. The authors identified all those MPMP participants who were subsequently diagnosed with rheumatoid arthritis up to December 2004 by cross checking national and regional registers.
Stored blood samples were available for 104 of the men who subsequently developed rheumatoid arthritis, and for 174 men of the same age who did not develop the disease.
The authors found that lower levels of testosterone were associated with subsequent development of RF-negative RA. This study indicate that low levels of testosterone are predictive of RF-negative RA, suggesting that hormonal changes precede the onset of RA and affect the disease phenotype.
In 2016, Jacques Baillargeon et al. conducted a retrospective cohort study in which we identified 123,460 men diagnosed with hypogonadism between January 1, 2002 and December 31, 2014 and with no prior history of rheumatic autoimmune disease. We matched this cohort to 370,380 men without hypogonadism, at a 1 to 3 ratio, on age and index/diagnosis date.
In this study, the authors found that a diagnosis of hypogonadism was associated with an increased risk of developing any rheumatic autoimmune disease, rheumatoid arthritis, and lupus. To our knowledge, this is the first large-scale, longitudinal, population-based study to examine this association.
In 2022, studying 79 female RA patients and 50 age-matched controls, Xianhui Zhang et al. found that the testosterone level in RA patients was significantly lower than in the control group.
Cover image: Renoir, Pierre-Auguste, by Dornac; from Wikimedia Commons, public domain