Dr. Ron’s Research Review – September 4, 2013

© 2013

This week’s research review focuses on testosterone and the immune system.

It has been shown that testosterone acts directly on CD4+ T lymphocytes to increase Interleukin-10 (IL-10) production. IL-10 is an anti-inflammatory cytokine that suppresses the immune system. A recent meta-analysis shows the reverse: immune activation suppresses plasma testosterone level. (Boonekamp, Ros et al. 2008) (Liva and Voskuhl 2001)

The Immunocompetence Handicap Hypothesis

The immunocompetence handicap hypothesis proposes a trade-off in men between testosterone and immune function. Unfortunately, the high levels of testosterone required for the full expression of sexual signals also increase the risk of mortality due to its immunosuppressive action. The high cost of these signals may prevent cheating.  (Alonso-Alvarez, Perez-Rodriguez et al. 2009) (Boonekamp, Ros et al. 2008)

Dr. Ron


Testosterone-mediated trade-offs in the old age: a new approach to the immunocompetence handicap and carotenoid-based sexual signalling

         (Alonso-Alvarez, Perez-Rodriguez et al. 2009) Download

The immunocompetence handicap hypothesis proposes that testosterone mediates a trade-off between sexual signalling and immunocompetence in males. Such a trade-off could favour the reliability of sexual signals on the basis that testosterone required for signal expression also promotes immunosuppression. However, the immunosuppressive activity of testosterone has not been convincingly demonstrated. We propose that the optimal solution to the testosterone-mediated trade-off should change with age, explaining ambiguous results in the past. Testosterone and ageing would promote two simultaneous immunosuppressive challenges unaffordable for low-quality males. Oxidative stress, as intimately related to ageing and immunosenescence, could contribute to enhance signal reliability. In this context, traits coloured by carotenoids (yellow-red traits) could play a crucial role due to the immunostimulatory and antioxidant properties of these pigments. Here, old and middle-aged male red-legged partridges were treated with testosterone or manipulated as controls. In the presence of high-testosterone levels, middle-aged males increased both circulating carotenoid levels and colour expression, whereas their cell-mediated immunity was not significantly altered. However, in old males, neither circulating carotenoids nor sexual signalling increased when treated with testosterone, but immunosuppression was detected. The link between testosterone and carotenoids could favour the reliability of sexual signals throughout the life.

Immune activation suppresses plasma testosterone level: a meta-analysis

         (Boonekamp, Ros et al. 2008) Download

Females often select mates on the basis of sexual signals, which can be reliable indicators of male quality when the costliness of these signals prevents cheating. The immunocompetence handicap hypothesis (ICHH) provides a mechanistic explanation of these costs, by proposing a trade-off between immune function and sexual displays. This trade-off arises because testosterone enhances sexual signals, but suppresses immune function. Many studies have investigated the ICHH by administrating testosterone, and a recent meta-analysis found little evidence that testosterone suppressed immune function. However, another component of the ICHH, which has received less empirical interest, suggests that there may also be an interaction in the other direction, with immune activation suppressing testosterone levels. We present a meta-analysis to test for this effect. Overall, there was a strong suppressive effect of experimental immune activation on testosterone levels (r=-0.52), regardless of whether live pathogens or non-pathogenic antigens were used to challenge the immune system. The latter is important because it shows that immune activation per se suppresses testosterone levels. Thus, a trade-off between immunocompetence and sexual displays may primarily be generated by the effect of immune activation on testosterone, rather than the opposite effect that has received most attention.

Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production

         (Liva and Voskuhl 2001) Download

Males are less susceptible than females to experimental autoimmune encephalomyelitis and many other autoimmune diseases. Gender differences in cytokine production have been observed in splenocytes of experimental autoimmune encephalomyelitis mice stimulated with myelin proteins and may underlie gender differences in susceptibility. As these differences should not be limited to responses specific for myelin proteins, gender differences in cytokine production upon stimulation with Ab to CD3 were examined, and the mechanisms were delineated. Splenocytes from male mice stimulated with Ab to CD3 produced more IL-10 and IL-4 and less IL-12 than those from female mice. Furthermore, splenocytes from dihydrotestosterone (DHT)-treated female mice produced more IL-10 and less IL-12 than those from placebo-treated female mice, whereas there was no difference in IL-4. IL-12 knockout mice were then used to determine whether changes in IL-10 production were mediated directly by testosterone vs indirectly by changes in IL-12. The results of these experiments favored the first hypothesis, because DHT treatment of female IL-12 knockout mice increased IL-10 production. To begin to delineate the mechanism by which DHT may be acting, the cellular source of IL-10 was determined. At both the RNA and protein levels, IL-10 was produced primarily by CD4+ T lymphocytes. CD4+ T lymphocytes were then shown to express the androgen receptor, raising the possibility that testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. In vitro experiments demonstrated increased IL-10 production following treatment of CD4+ T lymphocytes with DHT. Thus, testosterone can act directly via androgen receptors on CD4+ T lymphocytes to increase IL-10 gene expression.


Alonso-Alvarez, C., L. Perez-Rodriguez, et al. (2009). "Testosterone-mediated trade-offs in the old age: a new approach to the immunocompetence handicap and carotenoid-based sexual signalling." Proc Biol Sci 276(1664): 2093-101. [PMID: 19324780]

Boonekamp, J. J., A. H. Ros, et al. (2008). "Immune activation suppresses plasma testosterone level: a meta-analysis." Biol Lett 4(6): 741-4. [PMID: 18700197]

Liva, S. M. and R. R. Voskuhl (2001). "Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production." J Immunol 167(4): 2060-7. [PMID: 11489988]