Behavioral Ecology Vol. 10 No. 3: 345-350
© 1999 International Society for Behavioral Ecology
Forum |
Stress, testosterone, and the immunoredistribution hypothesis
a International Center for Tropical Ecology, University of Missouri-St. Louis, and Department of Biology, Washington University, St. Louis, MO 63130, USA b Department of Biology c Department of Psychology, University of Missouri-St. Louis, St. Louis, MO, USA
Address correspondence to S. Braude, Department of Biology, Box 1137, Washington University, One Brookings Drive, St. Louis, MO 63130, USA. E-mail: braude{at}wustlb.wustl.edu
Received 22 April 1998; revised 28 November 1998; accepted 17 December 1998.
Recent interest in parasites and sexual selection has focused attention on
the paradox that the sexual displays which indicate parasite resistance in
male vertebrates are triggered by testosterone, an apparently
immunosuppressive hormone. We question the underlying assumption that
testosterone is immunosuppressive and offer here the alternative of
immunoredistribution to explain the changes in circulating leukocytes
associated with male displays and elevated testosterone. First, we briefly
examine three hypotheses that have attempted to resolve the testosterone
immunosuppression paradox (Folstad and
Karter, 1992
; Hillgarth et
al., 1997; Wedekind and
Folstad, 1994). Although the immunoredistribution hypothesis
undermines the premise of these hypotheses, there are other problems intrinsic
to each one.
The immunocompetence handicap hypothesis
Folstad and Karter (1992)
proposed the immunocompetence handicap hypothesis as an extension of Zahavi's
(1975) handicap hypothesis for
the evolution of secondary sexual characteristics. While Folstad and Karter's
hypothesis offered an explanation for higher parasite loads in males than in
females, it has been used to explain both correlation and lack of correlation
between testosterone and reduction in indices of immunity. Specifically, if
males with high levels of testosterone have higher indices of immunity or
lower parasite loads, the interpretation would be that those males have such
high-quality immune systems that they can overcome the immunosuppression of
testosterone (Zuk, 1996). On
the other hand, if high-testosterone males have higher parasite loads, the
interpretation would be that those males are of such high quality overall that
they can display and attract females despite higher infection due to
immunosuppression (Salvador et al.,
1996; Weatherhead et al.,
1993). And if no relationship is found between testosterone and
parasite loads, the argument is that the high-quality males "are
reliably signaling their resistance to parasites since they are still able to
fend off parasites in the presence of high circulating levels of
androgens" (Saino and Moller,
1994:1331). The invocation of the immunocompetence handicap to
support such contradictory trends undermines the utility of the
hypothesis.
The resource allocation hypothesis
Wedekind and Folstad (1994)
suggested that testosterone suppresses the immune system so that essential
resources can be allocated instead to produce secondary sexual characteristics
such as horns, songs, or stamina in repeatedly performing a display
(Enstrom et al., 1997;
Hunt et al., 1997). Although
this would explain the adaptive trade-off underlying the immunocompetence
handicap, it could also stand alone as an explanation for testosterone
immunosuppression. However, Hillgarth and Wingfield
(1997) pointed out that this
explanation is unlikely to account for immunosuppression because the metabolic
resources saved by suppressing immunity would be trivial compared to the
associated risk of infection.
The sperm protection hypothesis
Hillgarth et al. (1997)
offered the alternative hypothesis that the immunosuppressive effect of
testosterone protects haploid spermatozoa, which are antigenic because they
are formed long after the development of the immune system. Despite the
partial protection of spermatocytes by Sertoli cells and the blood-testis
barrier, some lymphocytes can pass into the seminiferous tubule
(Turek and Lipshultz, 1994).
Hillgarth et al. (1997)
suggest that testosterone suppresses antibody production in order to protect
antigenic sperm. Thus, testosterone could pleiotropically reduce antibody
production in general when it is in the systemic circulation to regulate other
secondary sexual characteristics. Penn and Potts
(1998) question the likelihood
of this hypothesis because there would be strong selection against sensitivity
of immune cells to testosterone outside the testes. Although the sperm
protection hypothesis might account for some reduced antibody-mediated
immunity in high-testosterone males
(Folstad and Skarstein, 1997),
it still does not explain the change in numbers of circulating leukocytes
associated with elevated testosterone.
None of the current explanations for immunosuppression by testosterone is
particularly satisfying because of the huge selective cost of any significant
impairment of immunity to pathogens. If immunity to parasites and disease is
as important as Hamilton and Zuk's
(1982) model suggests,
suppression of immunity should be a rare and limited phenomenon. This has led
us to question the underlying assumption that testosterone actually causes
immunosuppression.
The immunoredistribution alternative
New insights into the immune response to stress offer an alternative explanation for the correlation between high levels of testosterone and changes in the immune system. We propose that leukocytes are temporarily shunted to different compartments of the immune system in response to testosterone, as they are in response to other steroids. This process, called immunoredistribution, would be easy to confuse with immunosuppression if immunity is assessed by leukocyte counts or if the measure of immunity is sampled at only one time or in only one tissue.
Unlike immunosuppression, redistribution is a temporary shifting of immune cells to compartments where they are likely to be more useful. This is far more than a semantic distinction. Immunosuppression implies that there is a single immune system which is inhibited from acting throughout the body and that lower cell counts result from elimination or reduced production of immune cells. Immunoredistribution is a quickly reversible relocation of immune cells to sites where they are most likely to be useful but perhaps less likely to be detected by researchers. Immunoredistribution is a well-documented response to stress and the associated elevation in circulating corticosteroids.
Stress and immunosuppression
Although stress-induced immunosuppression is assumed to be a common
phenomenon, there are a number of systematic problems with the evidence and
interpretation of it. First, Keller et al.
(1992) point out that few of
the studies that describe inhibition of immune cell function controlled for
changes in the proportions of different types of immune cells, and thus may
not have been measuring inhibition at all. Equally important is the empirical
evidence that the endocrine and immune responses to stress are complex and
depend on a number of factors, including the sex ratio and social composition
of the group under study (Sapolsky,
1986; Taylor et al.,
1987). These factors are typically not controlled or taken into
account. When they have been controlled, no suppression of immune cell
activity was found (Klein et al.,
1992). In addition, acute and chronic triggers are often lumped
together. Despite these problems and the fact that responses may differ in
different species, we do not question the evidence of suppression of immune
cell activity under pharmacological doses of steroids. However, these examples
only demonstrate that the activity of immune cells can be artificially
suppressed, not that suppression is a normal physiological response to
corticosteroids or testosterone.
Stress and immunoredistribution
Immunoredistribution is an alternative explanation for the apparent
immunosuppressive effect of stress. Environmental stress and social stress are
both known to increase the level of circulating corticosteroids which in turn
affect the immune system (Harbuz and
Lightman, 1992; Morrow-Tesch
et al., 1994; Taylor et al.,
1987). This common mechanism is due to activation of the
hypothalamus-hypophysis-adrenal axis. In response to the elevated
corticosteroid levels, leukocytes exit peripheral blood circulation and enter
lymph nodes, skin, and other tissues where they are well positioned to combat
challenges from new trauma (Dhabhar,
1998; Dhabhar and McEwen,
1996). Circulating leukocytes then return to normal levels within
a few hours after the stress ceases
(Dhabhar et al., 1995).
Dhabhar has provided the clearest demonstration that temporary
immunoredistribution associated with stress is triggered by corticosteroids
(Dhabhar, 1998;
Dhabhar and McEwen, 1996,
1997;
Dhabhar et al., 1994,
1995,
1996), but the phenomenon of
immunoredistribution has been recognized as an important trade-off response
for at least the past 25 years. Fauci
(1975) had already shown that
corticosteroid treatment in guinea pigs leads to a temporary lowering of
lymphocytes in peripheral circulation as they migrate to bone marrow. Chung et
al. (1986) further showed that
glucocorticosteroids in mice cause lymphocytes to migrate to peripheral lymph
nodes and bone marrow. In fact, the temporary redistribution of various
leukocytes in response to hormone stimulation is well documented
(Claman, 1972;
Cohen, 1972;
Dhabhar, 1998;
Dhabhar and McEwen, 1996,
1997;
Dhabhar et al., 1994,
1995,
1996;
Fauci and Dale, 1974;
Gross, 1990;
Landmann et al., 1984;
Lundin and Hedman, 1978;
Moorhead and Claman, 1972;
Schedlowski et al., 1993;
Spry, 1972) and can even be
traced back to Dougherty and White
(1944).
The testosterone immunoredistribution hypothesis
We propose, testosterone has a similar effect on the immune system to
corticosteroids (i.e., immunoredistribution rather than suppression). Not only
would suppression of the whole immune system be wasteful and maladaptive, but
redistribution of immune cells would be an extremely valuable adaptive
trade-off (Dhabhar, 1998). Just
as emotional stress is often a good indicator of imminent trauma and
immunochallenge, the testosterone surge in a displaying and competing male is
also a good predictor of potential injury and immunochallenge. Male-male
competitions are often not orderly, ritualized battles that avoid actual
fighting. Rather, males in a wide range of species are often seriously
injured, even killed, in competition over mates
(Clutton-Brock, 1982;
Cox, 1981;
Geist, 1966,
1974;
Silverman and Dunbar, 1980;
Wilkinson and Shank, 1977).
Moreover, courtship interactions are always likely to involve some danger and
stress because of the unpredictability of a potential mate's response
(Hinde 1953,
1954). Therefore, we should
expect immune resources to be temporarily redeployed to sites of potential
injury.
We envision three possible mediating mechanisms for testosterone-mediated
immunoredistribution. First, testosterone may directly activate
immunoredistribution by binding to receptors in leukocytes or endothelium,
thereby triggering migration to specific tissues
(Figure 1a). Such receptors for
steroid hormones have already been identified
(Cupps and Fauci, 1982;
Fox, 1995;
Dhabhar, 1998). Second,
testosterone may enhance corticosteroid levels which, in turn, trigger
immunoredistribution (Figure
1b). Ketterson et al.
(1991) and Ketterson and Nolan
(1992) have demonstrated that
experimentally elevated testosterone in dark-eyed juncos causes elevated
corticosterone levels. Johnsen
(1998) also found that
seasonal elevations of corticosteroids and testosterone were significantly
correlated. Finally, high testosterone levels may merely correlate with high
corticosteroid levels due to the stress associated with male-male competition
or courtship (Figure 1c). For
example, the changes in circulating leukocyte frequencies in high-testosterone
red jungle fowl males reported by Zuk et al.
(1995) are well-known
responses to stress and corticosteroids in domestic chickens
(Gross and Siegel, 1983,
1985).
|
Although there is evidence that stress and cortisol inhibit testosterone
under some situations (Rivier and Vale,
1984), testosterone levels do correlate with corticosteroid levels
under more relevant circumstances, such as in the presence of reproductive
females (McDonald et al.,
1986; Silverin,
1998; Taylor et al.,
1987). In addition, Sapolsky
(1986) suggests that
corticosteroids have different effects on testosterone level depending on a
male's status in the group.
Our model contradicts what many believe to be settled science: that
testosterone is immunosuppressive. The concept of immunosuppression by
testosterone has been broadly accepted in the behavioral ecology literature
and can be traced back to a number of reviews by Grossman
(1984,
1985) and Alexander and
Stimson (1988). These reviews
have been repeatedly cited as the authority for the phenomenon of
immunosuppression by testosterone (Folstad
and Karter, 1992; Galeotti et
al., 1997; Hillgarth and
Wingfield, 1997; Ros et al.,
1997; Saino and Moller,
1994; Saino et al.,
1995; Wedekind and Folstad,
1994; Zuk, 1994;
Zuk and McKean, 1996).
However, Grossman (1984,
1985) and Alexander and
Stimson (1988) discuss the
varying effects of steroids on different components of the immune system and
are careful not to imply that all elements of immunity are stimulated or
suppressed. They also review evidence for enhancement of different measures of
immunity by both androgens and estrogens. The lack of strong evidence for
immunosuppression by testosterone was recently noted by Hilgarth and Wingfield
(1997), but they concluded
that this points to a need for more research, rather than a need to question
whether immunosuppression exists.
The reason for originally suspecting that testosterone is immunosuppressive
appears to have come from the epidemiological finding that males suffer higher
rates of infection and disease than females. However, Zuk
(1990) pointed out that many
incidences of disease and mortality in the males of many species are due to
indirect effects of testosterone on behavior. For example, males often engage
in riskier behaviors and are thereby exposed to different infectious agents
than females. Hence, Zuk and McKean
(1996) distinguish ecological
from physiological causes in the sex differences in infection. In addition, we
suggest that the sex differences in the rates of certain diseases may be due
to the action of testosterone if redistribution leaves respiratory, digestive,
or other systems less protected from infection. For example, Deerenberg et al.
(1997) found that there was a
lower immune response to an antigenic agent injected into the abdominal
cavities of zebra finches during work or brooding stress. Similar reduced
protection of the abdominal and thoracic organs due to immunoredistribution is
also likely to result from increased testosterone. However, this would be a
secondary effect of testosterone and not immunosuppression.
Mounting evidence against testosterone immunosuppression
There is a wide array of published data on enhancement of immunity
correlated with testosterone. For example, Dunlap and Schall
(1995) found that uninfected
male fence lizards had unexpectedly higher levels of testosterone than
infected males; Zuk et al.
(1995) found that monocytes,
heterophils and eosinophils all increased with increasing testosterone in red
jungle fowl. Klein and Nelson
(1998) found that testosterone
correlated with higher specific immune response in volves. Ros et al.
(1997) found that
testosterone-treated male gulls had increased antibody titers. Although these
are confounding results for any immunosuppression model, they are consistent
with an immune system that temporarily redistributes its immune resources.
Predictions and tests
The suppression and redistribution models offer different explanations for
phenomena such as reduction in circulating leukocytes and a wide range of
different predictions follows from each hypothesis
(Table 1). On the other hand,
we share the prediction of the suppression model in expecting a priori to find
similar effects of chronic and acute elevation of testosterone. Our
expectation follows from the idea that testosterone would be a reliable
predictor of potential trauma, whether acute or chronic. However, the immune
response to chronic and acute stress may differ
(Dhabhar, 1998;
Dhabhar and McEwen, 1997).
Therefore, if the effect of testosterone on immunoredistribution is mediated
by corticosteroids (Figure 1b)
or is correlated with stress (Figure
1c), there may be differences in the response to chronic and acute
elevations of testosterone.
|
To determine whether acute changes in testosterone levels result in males
suffering from immunosuppression or benefiting from temporary
immunoredistribution, one must time sample the indices of immune response.
Dhabhar et al. (1995) found
that a variety of leukocytes returned to baseline levels 3 h after stress
treatments ended. Therefore, it would be crucial to test whether testosterone
and circulating leukocytes experience parallel changes over time in displaying
and competing males.
More specifically, we expect that some leukocytes are differentially
locating to potential sources of injury and that peripheral immunity should
increase with testosterone. Resistance to cutaneous infection should increase
with testosterone, perhaps by the migration of macrophages and neutrophils
which would best enhance defense against bacterial infection of a wound. Thus,
we expect an enhanced dermal response in high-testosterone males similar to
that found in stressed individuals
(Dhabhar and McEwen,
1996).
Although the redistribution hypothesis specifically predicts changes in
circulating leukocyte populations, it is founded on a general expectation that
suppression is extremely maladaptive and should not be a common phenomenon
(outside of normal negative feedback regulation of immunostimulation).
Consequently, we would also expect enhancement of antibody-mediated immunity
in response to elevated testosterone as has been found in response to stress
(Dhabhar and McEwen,
1996).
We look forward to testing these predictions experimentally in the immediate future. Until then, we believe that this hypothesis will offer a useful framework for interpreting the apparently confounding data collected by others who are currently examining the interactions between testosterone, immunity, and sexual selection.
ACKNOWLEDGEMENTS
We thank Nancy Berg, Godfrey Bourne, Harvey Friedman, Dan Hanson, Manuel Leal, and four anonymous reviewers for helpful comments on earlier versions of the manuscript. We are also grateful to Charlotte Ellis and Ruth Lewis for their generous help in the library. Finally, we thank Marlene Zuk, Charles Grossman, and Ivar Folstad for reviewing the manuscript in May 1997.
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A. Roulin, C. Riols, C. Dijkstra, and A.-L. Ducrest Female plumage spottiness signals parasite resistance in the barn owl (Tyto alba) Behav. Ecol., January 1, 2001; 12(1): 103 - 110. [Abstract] [Full Text] [PDF]
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D. L. Duffy, G. E. Bentley, D. L. Drazen, and G. F. Ball Effects of testosterone on cell-mediated and humoral immunity in non-breeding adult European starlings Behav. Ecol., November 1, 2000; 11(6): 654 - 662. [Abstract] [Full Text] [PDF]
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