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 (AS). 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 with participants of the Swedish Malmo Preventive Medicine Program (MPMP), began in 1974, 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.
A 2020 systematic review found that male patients with rheumatic diseases have a high prevalence of sexual dysfunction (SD) and this was statistically significant in many studies when comparing patients to age-matched healthy controls. In addition, SD seems to occur at a younger age in patients with rheumatic diseases. The authors reported that hypogonadism and testicular dysfunction is a common finding, especially in patients with RA and systemic lupus erythematosus (SLE) and this is associated with disease activity.
Of note, when comparing the androgenic status of men with RA and ankylosing spondylitis (AS), a rheumatic disease that is more prevalent in men than women, it was found that only RA had a detrimental effect on testicular function.
Infertility affects 10–15% of men but semen quality in men with rheumatic diseases can be impaired in patients with SLE, spondyloarthropathies (SpA), sarcoidosis and Muckle-Wells syndrome (MWS). Sperm count and motility were the most common semen quality parameters affected.
In conclusion, male sexual and reproductive health is affected by rheumatic diseases, but the degree and extent of this is still unknown and varies per disease. The authors of this systematic review encourage rheumatologists and other clinicians to consider male sexual health in their clinical practice. Timely detection and treatment of SD and fertility problems can have a big impact on the quality of life of patients and avoid the use of expensive medical care.
Lipid mediators (LM), produced from polyunsaturated fatty acids, represent a class of bioactive small molecules with pivotal roles in the onset, maintenance and resolution of inflammation. LM encompass pro-inflammatory eicosanoids and specialized pro-resolving mediators (SPM) that coexist in a tightly regulated balance necessary for the return to homeostasis. Whereas, most of the AA-derived prostaglandins (PG) and leukotrienes (LT) formed by the COX and 5-lipoxygenase (5-LOX) pathway, respectively, exhibit rather pro-inflammatory properties, the so-called specialized pro-resolving mediators (SPM) including lipoxins (LX), protectins (PD), resolvins (Rv), and maresins (MaR) promote resolution of inflammation.
It appears that the biosynthesis of inflammation-related LM is sex-biased with superior LT levels in females, and there are clear indications for throughout suppressive effects of androgens on LT formation in neutrophils, monocytes and macrophages. Androgens reduce LT biosynthesis in various inflammation models related to LT in vivo which can translate into impaired efficiency of anti-LTs.
Sex specific differences in PG biosynthesis and the impact of androgens may depend on the organ/tissue but also on the presence or absence of inflammatory status: under healthy conditions, androgens may increase PG formation along with elevated COX-2 induction, while in presence of an inflammatory stimulus androgens may repress PG biosynthesis. Overall, it seems that androgens significantly impact pro-inflammatory LM formation in innate immune cells with direct consequences for pathophysiology but also for the pharmacotherapy of inflammation.
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
Pierre-Auguste Renoir and rheumatoid arthritis: Pierre-Auguste Renoir suffered from rheumatoid arthritis for most of his life. His symptoms developed when he was in his 50s and led to almost complete disability when he was 70 years old. Although the deformities he suffered because of the rheumatoid arthritis were disabling, Renoir never stopped painting nor decreased the quality of his work. The most popular French impressionist painter Renoir used his creativity to develop his own exercises and assistive equipment for painting despite his disability. Thus, Renoir exemplifies an artistic life altered by RA over more than 25 years that he dedicated entirely to his art and the depiction of beauty and happiness testified by his own words: “The pain passes, but the beauty remains.”