Testosterone Replacement Effectively Inhibits the Development of Experimental Autoimmune Orchitis in Rats: Evidence for a Direct Role of Testosterone on Regulatory T Cell Expansion

Abstract

Despite the immune-privileged status of the male genital tract, infection and inflammation of the male genital tract are important etiological factors in male infertility. A common observation in clinical and experimental orchitis as well as in systemic infection and inflammation are decreased levels of testosterone. Emerging data point to an immunosuppressive role of testosterone. In our study, we substituted testosterone levels in experimental autoimmune orchitis (EAO) in rat by s.c. testosterone implants. EAO development was reduced to 17% when animals were treated with low-dose testosterone implants (3 cm long, EAO+T3) and to 33% when rats were supplied with high-dose testosterone implants (24 cm, EAO+T24) compared with 80% of animals developing disease in the EAO control group. In the testis, testosterone replacement in EAO animals prevented the accumulation of macrophages and significantly reduced the number of CD4+ T cells with a strong concomitant increase in the number of regulatory T cells (CD4+CD25+Foxp3+) compared with EAO control. In vitro testosterone treatment of naive T cells led to an expansion of the regulatory T cell subset with suppressive activity and ameliorated MCP-1–stimulated chemotaxis of T lymphocytes in a Transwell assay. Moreover, expression of proinflammatory mediators such as MCP-1, TNF-α, and IL-6 in the testis and secretion of Th1 cytokines such as IFN-γ and IL-2 by mononuclear cells isolated from testicular draining lymph nodes were decreased in the EAO+T3 and EAO+T24 groups. Thus, our study shows an immunomodulatory and protective effect of testosterone substitution in the pathogenesis of EAO and suggests androgens as a new factor in the differentiation of regulatory T cells.

Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit

“…An anti-inflammatory effect of testosterone in castration-induced prostate inflammation was previously reported (Robinette 1988, Tangbanluekal & Robinette 1993, Quintar et al 2006, Yatkin et al 2009). Androgens therefore act as endogenous inhibitors of immune responses, even in the prostate, as already reported for other autoimmune processes (Ansar Ahmed et al 1986, Fox 1992, Harbuz et al 1995, Fijak et al 2011. Although our data showing that testosterone supplementation reduces the expression of pro-inflammatory cytokines are consistent with previous studies (Bebo 1999, Liva & Voskhul 2001, Fijak et al 2011), the precise mechanisms of testosteronemediated immunomodulation are still unknown.…”

Testicular defense systems: immune privilege and innate immunity

“…61 Androgens also regulate the testicular immunoprivileged status. [64][65][66] Notably, androgens would not directly affect testicular immune cells because these cells lack the androgen receptor.…”

“…70 Testosterone inhibits EAO induction in rats. 66 Within the testis, the androgens act on SCs that express the androgen receptor. Conditional knockout of the androgen receptor in SCs in mice impairs testicular immune privilege, possibly due to the impairment of BTB permeability.…”

Testosterone Replacement Therapy in Reversing “Andropause”: What Is the Proof-of-Principle?

“…115 To the best of our knowledge and despite the growing interest in the understanding of the role of sex hormones and TRT in the homeostasis of immunity, actual data from studies conducted in healthy older men with late-onset hypogonadism are still lacking. However, by considering the well-demonstrated immune-suppressive activities exerted by androgens, male hormones, and their derivatives have been tested as therapeutic approaches in RA, 116 in other autoimmune disorders, 117 and in patients with Klinefelter syndrome (KS). 118 Paradoxically, the lack of T in patients with KSenhanced cellular and humoral immunity and TRT suppress this both in KS and in autoimmune diseases.…”