High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction

Abstract

Our goal in the present work was to determine whether male patients with untreated hypogonadism have an increased risk of developing rheumatic/autoimmune disease (RAD), and, if so, whether there is a relation to the type of hypogonadism. We carried out neuroendocrine, genetic, and rheumatologic investigations in 13 such patients and 10 healthy male 46,XY normogonadic control subjects. Age and body mass index were similar in the two groups. Nine of the 13 patients had hypergonadotropic hypogonadism (five of whom had Klinefelter's syndrome [karyotype 47,XXY]) and 4 of the 13 had hypogonadotropic hypogonadism (46,XY). Of these last four, two had Kallmann's syndrome and two had idiopathic cryptorchidism. Eight (61%) of the 13 patients studied had RADs unrelated to the etiology of their hypogonadism. Of these, four had ankylosing spondylitis and histocompatibility B27 antigen, two had systemic lupus erythematosus (in one case associated with antiphospholipids), one had juvenile rheumatoid arthritis, and one had juvenile dermatomyositis. In comparison with the low frequencies of RADs in the general population (about 0.83%, including systemic lupus erythematosus, 0.03%; dermatomyositis, 0.04%; juvenile rheumatoid arthritis, 0.03%; ankylosing spondylitis, 0.01%; rheumatoid arthritis, 0.62%; and other RAD, 0.1%), there were surprisingly high frequencies of such disorders in this small group of patients with untreated hypogonadism ( P < 0.001) and very low serum testosterone levels ( P = 0.0005). The presence of RADs in these patients was independent of the etiology of their hypogonadism and was associated with marked gonadal failure with very low testosterone levels.

Autoimmune diseases and reproductive aging

“…In men, a higher prevalence of autoimmune diseases has been suggested in patients with hypogonadism [13]. In fact, relative androgen deficiency has been noted in some, but not all, studies of men with SL [14–23], RA [24–34] and MS [35–38] (Table 1).…”

Hypogonadism and the risk of rheumatic autoimmune disease

“…The mechanisms that underlie this difference are unclear but evidence points to the modulatory roles of sex hormones in the pathogenesis of autoimmune disease. Testosterone deficiency has been linked with autoimmune disease [2–5] and an increase in inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor, and interleukin-6 (IL-6) [6–8]. Notably, testosterone is reported to have anti-inflammatory functions via suppression of both the cellular and humoral immune system [9].…”

Expression of Humoral Autoimmunity is Related to Androgen Receptor CAG Repeat Length in Men with Systemic Lupus Erythematosus

“…Klinefelter’s syndrome (the most common form of male hypogonadism) has been repeatedly found in association with lupus [4], and in isolated case reports, restoration of normal testosterone levels has been accompanied by remission of features of the autoimmune process [4–8]. Other forms of male hypogonadism, including hypogonadotrophic hypogonadism, have also been noted in association with lupus [4, 6], suggesting that androgen deficiency, not the chromosomal abnormalities or pituitary hormone changes present in Klinefelter’s hypogonadism, is the main factor that affects the development of autoimmune phenomena in hypogonadal men.…”