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There are two questions masquerading as one here. The first one is about the theoretical basis for why testosterone could be immunosuppressive and the second one is whether testosterone is indeed immunosuppressive. Since this story is based on the theory, let’s start with that.

Theoretical Basis for Why Testosterone Could Be Immunosuppressive

This story starts in 1975 with evolutionary biologist Amotz Zahavi‘s Handicap principle (1). According to the Handicap principle, females should assess the quality of a potential mate. In turn, this should confer a survival handicap on the selected individuals.

1. In Amotz Zahavi‘s own words, “An individual with a well developed secondary sexual character, is an individual which has survived a test. A female which could discriminate a male possessing a sexually selected character, from one without it, can discriminate between a male which has passed a test and one which has not been tested. The more developed the character the more severe was the test. Females which select males with the most developed characters can be sure that they have selected from among the best genotypes of the male population”(1).

2. Amotz Zahavi then goes on to explicate the Handicap principle using the example of the peacock saying, “The excessive tail plumes of the peacock which seem to attract the females are obviously deletorious (sic) to the survival of the individual. The more brilliant the plumes the more conspicuous the male to predators, and the longer the plumes the more difficult it may be for the male to escape predators or to move about during everyday activity. Hence, only the best males would be able to sustain the handicap. Therefore, if females select for males handicapped by long plumes, they select for quality. It would certainly be better for females to choose high quality males which were not handicapped by the plumes. Therefore we have to assume that a discrimination for quality is more difficult without the test of the plumes”(1). We should not forget here the precedent of the late great evolutionary biologist John Maynard Smith who wrote in 1958 that “sexual selection will have evolutionary consequences only if those individuals which have characteristics which make them successful, in the components for a mate, are also fitter than the average as parents” (2).

3. According to Amotz Zahavi‘s Handicap principle then, “the marker of quality should evolve to handicap the selected sex in a character which is important to the selecting sex, since the selecting sex tests, through the handicap, the quality of its potential mate in characters which are of importance. Hence the attracting character which evolved through mate preference should be related to the special ecological problems of the species. The adaptive significance of the attracting character should lower the fitness of the selected sex in relation to the main ecological problems of the species. The selecting sex should be attracted by a marker only when the handicap it imposes on its mate and its offspring is smaller than the advantage gained by securing a better (tested) mate” (1).

The story expands in 1982 to include disease resistance when the late great evolutionary biologist W. D. Hamilton in collaboration with Marlene Zuk proposed the “Good Genes” hypothesis (3) which proposes that animals should be under selection pressure to evolve preference for mates which can reliably demonstrate health, i.e. reliably display disease resistance or the ability to resist pathogens.

1. In W. D. Hamilton and Marlene Zuk‘s own words, “How could animals choose resistant mates? The methods used should have much in common with those of a physician checking eligibility for life insurance. Following this metaphor, the choosing animals should unclothe the subject, weigh, listen, observe vital capacity, and take blood, urine and fecal samples. General good health and freedom from parasites are often strikingly indicated in plumage and fur, particularly when these are bright rather than dull and cryptic” (3).

2. “Vigor is also conveyed by success in fights and by the frequently exhausting athletic performances of many displaying animals. If susceptibility to parasites is as important in sexual selection as this idea suggests, animals that show more strongly developed epigamic characters should be subject to a wider variety of parasites (except for purely acute pathogens)” (3).

3. “Whichever sex does the choosing picks individuals with the fewest parasites and the highest resistance; the point is that such choice by one sex and advertisement of good health by the other is needed most in species where chronic parasites are common to begin with. Our hypothesis is contradicted if within a species preferred mates have most parasites; it is supported if among species those with most evident sexual selection are most subject to attack by debilitating parasites”(3) .

Finally in 1992 the story culminates with a grand synthesis of sorts when Ivar Forstad and Andrew John Karter proposed the Immunocompetence Handicap Hypothesis (ICHH) (4), which essentially incorporates elements of Amotz Zahavi‘s Handicap principle (1) and W. D. Hamilton and Marlene Zuk‘s “Good Genes” hypothesis (3).

1. The ICHH proposes that “androgen-dependent signal intensity is a plastic response, adjusted according to the potential costs of parasite pathogenicity versus the benefits of increased reproductive success afforded by signal exaggeration(4).

2. “We suggest a plasticity in signaling amplitude that optimizes the trade-off costs and benefits. This trade-off, between parasite-induced pathogenicity (cost) and increased mating success resulting from trait development (benefits), depends on genetic quality. An individual with “good genes” for resistance would pay less in the form of parasite-induced pathogenicity relative to an individual with low genetic resistance for a given signal quality. Thus, genetic quality in terms of parasite resistance modifies expression of secondary sexual characteristics” (4).

3. To account for cheaters, the ICHH proposes, “In summation, this honest (i.e., costly) signaling system for genetic parasite resistance is evolutionarily stable because genotypes coding for cheaters or nondiscriminating receivers would have reduced inclusive fitness because of the detrimental effects of parasitism on future generations relative to those that share an honest signaling system” (4).

4. Thus, the ICHH proposes that the endocrine system regulates life history trade-offs and as such testosterone serves to balance the competing demands of male reproductive function and immune function. A trade-off in this biological context means either a direct or indirect antagonistic interaction between two physiological processes which could have long-term fitness consequence for a given organism (5).

Extant Data Does not Support the notion that Testosterone is Indeed Immunosuppressive

Twenty years and counting, how well does the ICHH hold up to scrutiny? Already in 2004, a careful and thorough meta-analysis of extant studies by Roberts et al (6) concluded that causal linkage between testosterone and immunosuppression was weak at best. In fact, Roberts et al conclude, “The results of many studies attempting to find evidence for the supposed immunosuppressive qualities of testosterone are difficult to interpret since they are observational rather than experimental. Of the experimental studies, the data obtained are ambiguous, and this is reflected in the result of the meta-analysis” (6).

One year later, in 2005, a study (7) published by Muehlenbein and Bribiescas also performed a careful comparative analysis of extant studies, and concluded that

1. Different studies are difficult to compare because they used different methods (e.g. parasite loads or antibody levels) to assess immune function.
2. Different studies used different species with different body sizes, metabolic rates, and physiology, any or all of which could have contributed to the inconsistent results.
3. Many studies did not use optimal sampling procedures to accurately measure prevalence and intensity of parasitic infection.
4. Measurement of a single immune parameter such as leukocyte count or antibody level is not an accurate measure of the entire immune function.
5. Measurement of testosterone level and immune function in a non-disease state cannot accurately assess the influence of the former on the latter since said relationship may be unrelated to what happens during disease.
6. Whether the parasite being examined causes a latent or benign infection versus a virulent one may influence the nature of the association between testosterone and immune function.
7. The genetic “quality” of the hosts may influence the association in that a negative association may only become apparent in lower quality individuals.
8. Few studies concomitantly examined the effect of other potentially immunoregulatory hormones such as cortisol which might mask or augment testosterone‘s effects.
9. Labeling any biochemical substance as globally immunosuppressive may be inappropriate because there is no reason to a priori assume that testosterone should affect all aspects of immune function equally.

Obviously gender differences in immune responses are to be expected and are indeed well documented (8, 9, 10, 11, 12, 13, 14, 15, 16, 17). In fact, one of the earliest reports of a connection between male reproductive function and the immune system was Calzolari‘s observation in 1898 (18) that the thymus, the site of T cell development, of male rabbits castrated before sexual maturity is larger than those in non-castrated male rabbits. However, gender based differences in immune responses are one thing and immunosuppression by a sex hormone is another thing entirely.

In addition to several confounding factors proposed by scientists like Roberts et al (6) and by Muehlenbein and Bribiescas (7), high testosterone levels also influence changes in behavior which remain largely unaccounted for in published studies that have attempted to elucidate the testosterone’s immunosuppressive function, if any.

1. High testosterone levels could lead to dominance over subordinates leading to better access to food. Such a situation would lead to immunoenhancement since better nutrition leads to improved immune function (19).
2. Gender differences in body size mediated by differences in testosterone levels could itself explain some sex biases in infection since larger body size could simply offer a larger surface area for parasitization (20).
3. Testosterone induced change in behavior could be something as simple as increased forage activity which would increase exposure of said male to parasites (21).
4. Sex hormone differences could influence the type of immune response (22, 23, 24). For example, one study found that mucosal wound healing is faster in men than in women suggesting that testosterone or other male associated differences could positively influence the type of immune response necessary and optimal for mucosal wound healing (22).

Could alternate hypotheses better explain the data and help better synthesize the nature of trade-off between reproductive and immune functions?
Corollary: Absence of a measured response does not mean absence of all response

An interesting and different take on the issue of assessing immunocompetence in the context of trade-offs and resulting life histories is Martin et al’s (5) suggestion that

1. Trade-offs between reproduction and immune defense may either be just that or may represent re-allocations within the immune system itself depending on the species being examined.
2. Such re-allocations may not be detected unless multiple, particular aspects of immune activity are measured.

The latter is indeed an important criticism of many existing studies since the vast majority typically relied on one or few simple tests to assess immune function. Martin et al (5) recommend that ecological immunologists use a broad and comprehensive construct such as the Immune Defence Component Model (IDCM) proposed by Schmid-Hempel and Ebert (25), and conceptualize immune function as being separable into four types of defenses available to animals. Doing so would better elucidate the particular type of immune defense function being studied since immune function is by no means a monolithic entity.

 

 

Martin et al’s critique (5) leads us directly to an alternative hypothesis that could explain extant data on the relationship between testosterone and immune function without needing to resort to immunosuppression. This is the “Immunoredistribution” hypothesis proposed by Braude et al (26). We need to remember here that many studies examine immune function by examining cells and soluble response mediators in circulation, and typically interpret reduction in circulating immune function as reduction in overall immune function. Braude et al (26) propose instead that rather than reduction, “leukocytes are temporarily shunted to different compartments of the immune system in response to testosterone” and that “redistribution is a temporary shifting of immune cells to compartments where they are likely to be more useful“.

 

 

Finally, we have to consider the newest kid on the block when considering factors that could explain gender differences in immune responses, namely microbiota. Several recent studies in mice (27, 28, 29) have shown that microbiota differences between male and female mice could help explain the well-known sex bias in autoimmunity. This scenario would suggest that gender based differences in hormones could lead to establishment and maintenance of different microbiota which in turn could influence both the nature and strength of ensuing immune responses.

1. Page on arizona.edu
2. Maynard-Smith, J. 1958. A Century of Darwin. (S.A. Barnett, ed.). Cambridge: Harvard University Press.
3. Science Magazine: Sign In
4. Page on ucsb.edu
5. Seasonal changes in vertebrate immune activity: mediation by physiological trade-offs
6. Roberts, M. L.; Buchanan, K. L.; Evans, M. R. Testing the immunocompetence handicap hypothesis: a review of the evidence Anim. Behav. 68, 227-239 (2004).
7. Testosterone-mediated immune functions and male life histories
8. Elsevier
9. Gender Difference in the Non-Specific and Specific Immune Response in Humans
10. Page on oxfordjournals.org
11. Sex Hormones and the Genesis of Autoimmunity
12. Gender and autoimmunity
13. Sex Differences in Autoimmune Disease from a Pathological Perspective
14. Page on nature.com
15. Sex-Specific Genetic Architecture of Human Disease
16. http://www.thelancet.com/journal…
17. Genetic and hormonal factors in female-biased autoimmunity
18. Calzolari, A. : Recherches experimentales sur un rapport probable entre la fonction du thymus et celle des testicules. Arch. Ital. de Biol., Turin, xxx, 71-77, 1898-99.
19. Feeding the immune system
20. Parasites as a Viability Cost of Sexual Selection in Natural Populations of Mammals
21. Patterns and processes
22. Mucosal Wound Healing
23. Gonadal Steroids and Immunity
24. In Vivo Effects of Sex Steroids on Lymphocyte Responsiveness and Immunoglobulin Levels in Humans
25. Page on sciencedirect.com
26. Stress, testosterone, and the immunoredistribution hypothesis (scroll down to page 345 after downloading; article starts on page 345).
27. Science Magazine: Sign In
28. http://www.cell.com/immunity/abstract/S1074-7613%2813%2900341-5
29. Page on cell.com

Why is testosterone immunosuppressive?

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