What makes men and women different? Some differences are obviously biological, such as anatomy and the genetics of X and Y chromosomes. Other differences are social, the result of culture and history. And sometimes the reason men and women differ isn’t so clear. Disease often affects men and women differently, and in many cases it is difficult to know whether the cause is social, biological, or both—and this poses a challenge to medical researchers who struggle to account for the impact of gender on medical outcomes.
The reasons for differences between men and women in the incidence of some diseases are clear-cut. Lung cancer rates are higher among men for purely social reasons: until recently, men were more likely than women to smoke. On the other hand, the fact that the blood-clotting disorder hemophilia occurs almost exclusively in males is the result of genetics—the disease is caused by a mutation in a gene on the X chromosome. Women, with two X chromosomes, have a back-up version of this gene, while men, with only one X chromosome, don’t.
But other diseases pose more of a mystery. On average, men are affected more often and more severely by infectious diseases like viruses, bacteria, and other pathogenic microbes, and their immune systems respond less effectively to vaccines. While this observation could potentially be explained by social differences—maybe men are less likely to take simple precautions to avoid infection, or perhaps women are more likely to have their immune systems primed by exposure to sick children—researchers have long suspected that the immune systems of males and females are innately different.
ONE KEY PIECE OF evidence for this idea is that women are more likely to suffer from autoimmune diseases like rheumatoid arthritis, when the immune system begins to attack things that it shouldn’t. That women are more susceptible to autoimmune diseases, while men have a higher incidence of infectious diseases suggests that women’s immune systems are much more active than men’s. It’s a neat hypothesis, but scientists have struggled to find any important differences in the detailed biology of the immune system that could explain why these diseases affect men and women so differently.
There is a set of obvious candidates that could be the cause of sex-based differences in immunity: hormones. Sex hormones, like estrogen and testosterone, are not only responsible for the characteristic physical differences between men and women, but they also have the ability to directly influence the many components of the immune system, like the white blood cells that produce antibodies and mount attacks against invading microbes and viruses. Intriguingly, some women experience a remission from some autoimmune diseases during pregnancy, when levels of sex hormones change dramatically. But it’s been difficult to establish any direct link between levels of sex hormones circulating in the blood and the performance of men’s and women’s immune systems.
Recent research is now beginning to firmly establish that link. This month, a team of scientists at Stanford University has reported some of the best evidence yet that testosterone directly influences immune system function in men. The researchers took blood samples from male and female volunteers who were given a flu shot. Women had higher levels of immune system molecules circulating in their blood than men, and they produced more effective antibodies against the flu virus. And there were not only differences between men and women, but there were differences among men—the men with the weakest response to the flu shot had high levels of both testosterone and testosterone-induced enzymes, suggesting that high levels of testosterone can suppress immunity.
This finding that testosterone may dial down the immune system in humans is consistent with the results of studies of other animals, ranging from fish to chimps. But why would an essential male hormone deliberately handicap the immune system?
THE ANSWER MIGHT BE that this is one of those odd outcomes that follow from the perverse incentives of evolutionary logic. In 1992, a pair of biologists at the University of Tromsø in Norway proposed the “immunocompetence handicap hypothesis,” which essentially says that males will perform dumb, dangerous stunts to impress females. The idea behind the immunocompetence handicap hypothesis is that, in order to prove their genetic fitness to potential mates, males make a trade-off between a robust immune system and a set of elaborate, testosterone-driven secondary sex characteristics, like brightly colored plumage in tropical birds. Those males with the best immune system genes will be healthy despite a big testosterone handicap. The males who can tolerate the highest testosterone levels will have the most exaggerated sex characteristics, and therefore, sex characteristics will be a reliable visual indicator of genetic fitness.
The immunocompetence handicap hypothesis has been provocative and controversial. The evidence for it is decidedly mixed, but the idea has spawned more extensive research into the question of what visual cues signal robust health in humans. Is men’s sexual attractiveness related to the performance of their immune systems? In a study published last year, an international team of scientists attempted to answer that question. The authors hypothesized that masculine features in young male volunteers would be rated more attractive by women and signal the possession of good immune system genes. It turns out that the body feature most closely linked to attractiveness and immune system performance is fat—as you might expect, having too much or too little is less attractive and less healthy.
Whether human males handicap their immune systems for the sake of sexual attractiveness is an unresolved question, but the consequences of sex-based differences in immunity are large, for both men and women. Medical researchers hope that a better understanding of the causes will help them tailor vaccines, drugs, and other treatments to the distinct needs of men and women.