Immunity in transgender men illuminates role of testosterone

A new study in Nature examines the role of testosterone in the immune system.

The immune systems of cisgender men and women are often associated with different health outcomes. The rate of autoimmunity is higher in cisgender women, but cisgender men are more likely to die from SARS-CoV-2 infection. The underlying causes of these differences have evaded understanding. They could be caused by differences in sex hormones, genetic factors like X chromosome inactivation, social factors that bias the results, or a combination of factors.

This new study, published on Sept. 4, isolates one of these variables—the presence of testosterone—to try to tease out the effect of the hormone on immunity (DOI: 10.1038/s41586-024-07789-z). The researchers studied the immune systems of 23 transgender men who were receiving gender-affirming hormone therapy (GAHT) with testosterone undecanoate. They collected blood samples over a year, starting at the beginning of GAHT. Then they analyzed how the participants’ immune systems changed during that time, comparing the immune system components with those of cisgender women and cisgender men.

The most dramatic differences after a year of testosterone-based GAHT were observed in the interferon and tumor necrosis factor (TNF) pathways, which have implications for both autoimmunity and fighting acute infections. The type 1 interferon pathway, which is usually upregulated in cisgender women compared to cisgender men, was downregulated in this cohort. Meanwhile, the TNF pathway, an inflammatory pathway, was upregulated in this cohort.

Nils Landegren of Uppsala University, one of the senior authors of the paper, says this makes sense given what is known about the relatively increased risk of death from COVID-19 in cisgender men.

When their immune systems would try to fight the virus, “if the interferon response failed early during the infection, then you would instead see this uncontrolled overactivation of the immune system,” he says. Scientists have noted overactivated immune systems in people who died from COVID-19. “So basically, we’re seeing that testosterone plays a key role in this [immune system overactivation] as well. Testosterone is downregulating the interferon response but upregulating this inflammatory response,” he says.

Autoimmune disorders like lupus often involve overactivation of the interferon pathway, Landegren says. These disorders are less common in cisgender men, so testosterone downregulating the interferon pathway may be part of the explanation.

Co-senior author Petter Brodin, of the Karolinska Institutet and Imperial College London, says that these dramatic effects in the interferon and TNF pathways were caused by the increased presence of testosterone rather than the lack of estradiol (a form of estrogen) that can result from GAHT. The researchers tested whether in vitro blood samples from cisgender women exhibited the differences observed in the transgender group when the cisgender women were deprived of estradiol versus when they were exposed to testosterone; only the testosterone test aligned with the results in transgender men.

This study raises the possibility of developing treatments that take advantage of these hormone-based differences, says Margaret McCarthy, an endocrinologist who wrote an accompanying viewpoint (DOI: 10.1038/d41586-024-02432-3) but was not involved in the research.

TNF and interferons could be therapeutic targets, she says, noting that future therapies for conditions like lupus could increase the amount of TNF in certain tissues, mimicking the protective effect that TNF seems to have in cisgender men.

“It just gives us so many more targets to work with,” she says.