Men are known to experience more severe infections than women, and men typically mount weaker immune responses vaccinations. These differences, while well recognized, are poorly understood. Why should men prove less capable of fending off microbes than the so-called fair sex?
After exploring the sex differences observed in the human immune system, a new study has concluded that the answer is, at least in part, testosterone. This study has identified a link between certain genes affected by testosterone and antibody responses to an influenza vaccine.
Published December 23 in the Proceedings of the National Academy of Sciences, this study, entitled “Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination,” also found that men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to trivalent inactivated seasonal influenza vaccine (TIV).
The study was led by researchers at Stanford University who analyzed the neutralizing antibody response to TIV and “a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli.” The antibody responses of 53 females and 34 males of different ages were analyzed.
The researchers found no connection between circulating levels of pro-inflammatory proteins and responsiveness to the flu vaccine. Nor did they find any indication that testosterone suppresses the immune response in any direct way. Instead, the researchers noticed that testosterone seems to interact with a set of genes in a way that dampens the immune response, said the study’s senior author, Mark Davis, Ph.D., a professor of microbiology and immunology and director of Stanford's Institute for Immunity, Transplantation, and Infection.
“This is the first study to show an explicit correlation between testosterone levels, gene expression, and immune responsiveness in humans," said Dr. Davis. “It could be food for thought to all the testosterone-supplement takers out there.”
By investigating patterns in gene expression, the researchers showed that, in men, elevated activity of a particular set of genes (specifically, Module 52 genes) that tend to turn on and off at the same time was associated with a weakened antibody response to the vaccine. The same gene cluster’s activity levels didn't track closely with antibody response in women.
Following up on this finding, the researchers separated the 34 men into two groups—those with above-median and below-median levels of circulating testosterone. In the high-testosterone men, high-activation levels of Module 52 genes correlated with reduced post-vaccination antibody levels. In the low-testosterone men, as in women, activation levels of Module 52 genes bore no significant relationship to the amount of antibodies produced as a result of the influenza vaccine.
Additional analyses showed that testosterone reduces levels of certain transcription factors that ordinarily prevent Module 52 genes from “turning on.” In other words, higher testosterone levels result in more Module 52 expression. Several Module 52 genes have known immune-system connections; activation of one of these genes, for example, results in the accelerated differentiation of cells whose job it is to suppress, rather than foster, immune response. These connections make the interactions of the genes with testosterone an intriguing target of further exploration by immunologists, physiologists, and drug researchers, said Dr. Davis.
But perhaps more intriguing, to many, is this: Why would evolution have designed a hormone that not only enhances classic male secondary sexual characteristics, such as muscle strength, beard growth, and risk-taking propensity, but also restrains the immune system?
In their study, the researchers noted that from an evolutionary perspective, “the immunosuppressive effects of testosterone could be advantageous as a possible homeostatic mechanism to turn off the immune response.” Possible advantages, wrote the authors, include ameliorated immunopathology and the ability to avoid uncontrolled, deadly cytokine storms: “Because males of many species are more likely to experience trauma than females, this positive effect of testosterone may also help to balance out the consequences of reduced immunity to infection.”
“Ask yourself which sex is more likely to clash violently with, and do grievous bodily harm to, others of their own sex,” said Dr. Davis. Men are prone to suffer wounds from their competitive encounters, not to mention from their traditional roles in hunting, defending kin, and hauling things around, increasing their infection risk.
While it’s good to have a decent immune response to pathogens, an overreaction to them can be more damaging than the pathogen itself. Women, with their robust immune responses, are twice as susceptible as men to death from the systemic inflammatory overdrive called sepsis. So perhaps, Dr. Davis suggests, having a somewhat weakened (but not too weak) immune system can prove more lifesaving than life-threatening for a dominant male in the prime of life.