Scientists at the Stanford University School of
Medicine have linked high testosterone levels in men
to a poor immune response to an influenza vaccine.
In the study, women had a generally stronger
antibody response to the vaccine than men, but the
average response mounted by men with relatively low
testosterone levels was more or less equivalent to
that of women.
It has long been known that, for reasons that are
not clear, men are more susceptible to bacterial,
viral, fungal and parasitic infection than women
are, and that men’s immune systems don’t respond as
strongly as women’s to vaccinations against
influenza, yellow fever, measles, hepatitis and many
Women are known to have, on average, higher blood
levels of signaling proteins that immune cells pass
back and forth to jump-start inflammation, a key
component of immune-system activation.
Furthermore, previous research in animals and in
cell-culture experiments has established that
testosterone has anti-inflammatory properties,
suggesting a possible interaction between the male
sex hormone and immune response.
However, the new study found no connection between
circulating levels of pro-inflammatory proteins and
responsiveness to the flu vaccine.
Nor does testosterone appear to directly chill
immune response; rather, it seems to interact with a
set of genes in a way that damps that response, said
the study’s senior author, Mark Davis, PhD,
professor of microbiology and immunology and
director of Stanford’s Institute for Immunity,
Transplantation and Infection.
The scientists took advantage of ongoing
longitudinal research at Stanford.
Since 2008, the research participants, who span a
broad range of ages, have been getting blood drawn
before and after receiving annual influenza
Many have returned year after year for their annual
flu shots and associated blood draws.
The participants’ samples are analyzed at Stanford’s
Human Immune Monitoring Core, a distributed center
deploying state-of-the-art instrumentation and
expertise, for tens of thousands of variables,
including circulating levels of numerous
immune-signaling proteins; counts of various
blood-cell subtypes; and the degree to which each of
the roughly 22,000 genes in a participant’s
circulating immune cells is active or inactive.
“Most studies don’t report on sex differences, a
major determinant of variation in immune response,”
said the study’s lead author, David Furman, PhD, a
research associate in Davis’ group.
The Stanford team, in collaboration with researchers
at the French governmental research organization
INSERM, aimed at probing those differences.
Analysis of samples from 53 women and 34 men showed
that, on average, women had significantly stronger
antibody responses to the influenza vaccine,
consistent with other studies.
The women also showed higher average pre-vaccination
blood levels of pro-inflammatory immune-signaling
proteins, as earlier studies have found.
But pre-vaccination levels of those proteins in a
particular woman’s blood didn’t significantly
predict the degree of her post-vaccination antibody
In men, elevated activity of a particular set of
genes that tend to turn on and off at the same time
was associated with a weakened antibody response to
The same gene cluster’s activity levels didn’t track
closely with antibody response in women.
Previous studies have shown that some of the
constituent genes of this multi-gene cluster (known
as Module 52) are involved in immune regulation —
and that activation of the module is somehow boosted
Davis and their colleagues separated the 34 men into
two groups — those whose circulating levels of
testosterone in its bioactive form were above the
median level, and those with below-median levels of
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 (regulatory
proteins) 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.
Other Stanford co-authors were Cornelia Dekker, MD,
professor of pediatrics and medical director of the
Stanford-LPCH Vaccine Program; Robert Tibshirani,
PhD, professor of statistics and of health research
and policy; and Noah Simon, PhD, a former
postdoctoral scholar in Tibshirani’s group, now on
the faculty of the University of Washington.
For more information
Systems analysis of sex differences reveals an
immunosuppressive role for testosterone in the
response to influenza vaccination
Stanford School of Medicine
Institut national de la santé et de la recherche