Hypogonadism and the risk of rheumatic autoimmune disease

Abstract

Testosterone deficiency has been linked with autoimmune disease and an increase in inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor, and interleukin-6 (IL-6). However, no large-scale longitudinal studies have examined this association. We examined whether untreated hypogonadism was associated with an increased risk of rheumatic autoimmune disease in a large nationally representative cohort. Using one of the nation’s largest commercial insurance databases, we 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. All patients were followed until December 31, 2014 or until they lost insurance coverage or were diagnosed with a rheumatic autoimmune disease. Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHRs). Untreated hypogonadism was associated with an increased risk of developing any rheumatic autoimmune disease (HR = 1.33, 95 % CI = 1.28, 1.38), rheumatoid arthritis (HR = 1.31, 95 % CI = 1.22, 1.44), and lupus (HR = 1.58, 95 % CI = 1.28, 1.94). These findings persisted using latency periods of 1 and 2 years. Hypogonadism was not associated with the control outcome, epilepsy (HR = 1.04, 95 % CI = 0.96, 1.15). Patients diagnosed with hypogonadism who were not treated with testosterone had an increased risk of developing any rheumatic autoimmune disease, rheumatoid arthritis, and lupus. Future research should further examine this association, with particular attention to underlying mechanisms.

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism

“…The pituitary–gonadal axis plays key roles in growth, sex development, metabolism, musculoskeletal build-up, strength, mood, energy, immune system, libido, and reproduction ( 22 – 24 ). Fluctuations in or impaired fine-tuning of the axis can result in a wide range of endocrine disorders that may be local but severe, e.g., infertility ( 25 ), or affect the entire body, as seen with adverse outcomes involving this axis such as sexual symptoms ( 4 ), depression ( 26 ), coronary heart disease/heart attack ( 27 ), autoimmune diseases such as arthritis ( 28 ), and diabetes ( 29 , 30 ). Testosterone forms a negative feedback loop that inhibits the production of both LH and gonadotropin-releasing hormone (GnRH) in the hypothalamus ( 31 ).…”

Androgen-Induced Immunosuppression

“…Both sex hormones and genes expressed on the X or Y chromosomes have been proposed to drive this bias, as exemplified by the fact that Klinefelter’s patients (XXY karyotype) express not only two X chromosomes but also reduced levels of androgens, and present with an increased risk for most of these disorders ( 114 ). Many patients of either sex with autoimmune disorders that predominantly affect women also demonstrated lower serum concentrations of androgens ( 76 , 115 , 116 ). Here, we will discuss the influence of androgens on the development and severity of RA, MS, and SLE.…”

“…A number of reports have suggested that androgens are protective in SLE. Although many male lupus patients have normal levels of androgens ( 194 ), men with hypogonadism are at increased risk of developing SLE ( 114 , 116 , 195 ) and testosterone supplementation of male lupus patients with genetic hypogonadism (Klinefelter’s syndrome) has, in two cases, been beneficial in treating lupus ( 196 , 197 ). However, no large-scale studies involving testosterone supplementation in male lupus patients have been reported ( 198 ).…”

Dihydrotestosterone levels at birth associate positively with higher proportions of circulating immature/naïve CD5+ B cells in boys

“…Therefore, a lot of emphasis have been placed on the role of female sex hormones on immune responses and on different immune cell subsets, reviewed in 15 , 16 . Less is known about the impact of androgens on the immune system, but androgen deficiency in men is associated with increased risk for autoimmune disease 17 , 18 . In male mice, castration induces expansion of both the bone marrow and the splenic B-cell population 19 , 20 , which can be reversed by replacement with testosterone or dihydrotestosterone (DHT) 20 .…”