New research explains differences between men's and women's immune systems

Now, three Swedish research groups led by Karolinska Institutet and Uppsala University has conducted a unique study analysing the regulation and adaptation of the immune system over time in 23 trans men who have undergone gender-affirming testosterone treatment.  

“We have followed individuals who were assigned female sex at birth and later received testosterone treatment in adulthood. Their genetic profile remains unchanged, while their hormone profile shifts entirely from typically female to male hormone levels,” says Petter Brodin, paediatrician and professor of paediatric immunology at the Department of Women's and Children's Health, Karolinska Institutet, who led the study together with Nils Landegren, assistant professor at Uppsala University, and Olle Kämpe, Professor at the Department of Medicine, Solna, Karolinska Institutet. “This unique change allows us, for the first time, to identify which parts of a person's immune system are directly regulated by sex hormones rather than genetic sex differences.” 

The researchers can now demonstrate that increased testosterone levels and the accompanying reduction in estrogen particularly affect the balance between two crucial immune signaling systems: antiviral interferon type 1 (IFN-1) and proinflammatory signals such as tumour necrosis factor alpha (TNFα).  

The immune system changes throughout life

They also have a hypothesis about why the immune system needs to be dynamically regulated by hormones throughout life. 

“All individuals must be able to adjust their immune systems over the course of their lives to be optimally regulated for the conditions and challenges we face. During puberty and sexual maturation, new demands arise, and the immune system must be regulated differently to enable pregnancy in women and muscle growth in men,” says Petter Brodin. 

By regulating these key functions via sex hormones, this can be achieved, and in women, it is dynamically controlled even during a menstrual cycle,” he adds. 

The results of the study open an entirely new field of research, according to Nils Landegren. 

“The newfound knowledge will help us better influence people's immune systems even without using sex hormones. For example, new drugs can be developed to impact these regulatory mechanisms and thus rebalance the immune response, especially for women with the autoimmune rheumatic disease SLE,” he explains. 

However, the results also have a more direct implications for transgender individuals. 

“This research is also of crucial for transgender individuals undergoing gender-affirming hormone therapy, and I believe that this group deserves significantly more scientific attention and follow-up to ensure their long-term health,” says Petter Brodin. 

The research was funded by the Knut and Alice Wallenberg Foundation, the Swedish Society for Medical Research, the Swedish Research Council, Karolinska Institutet and the European Research Council (ERC).