Researchers have learned how hormones significantly influence our immune systems, shedding light on the different ways men and women experience diseases.
A team from the Karolinska Institutet in Sweden and Imperial College London has revealed for the first time how sex hormones regulate certain aspects of our immune systems and the effects this has on disease susceptibility and health outcomes in both genders.
It is already known that diseases can manifest differently in men and women due to subtle variations in their immune systems. For instance, women are nine times more likely to develop the autoimmune condition systemic lupus erythematosus (SLE), while men have a greater chance of experiencing severe initial infections from COVID-19, whereas women are at higher risk for long-COVID symptoms.
However, understanding the direct effects of genetics, hormones, and behavior on our immune systems has been challenging, particularly in determining which elements are influenced and how this relates to disease risk.
In a clinical study involving 23 transgender men undergoing hormone therapy, researchers managed to clarify the specific parts of the immune system that are dynamically influenced by sex hormones, distinguishing them from those determined by genetics.
The findings illustrate how elevated testosterone and diminished estrogen levels shift the balance between two vital immune signaling pathways. These pathways have significant implications for the immune system’s response to infections and diseases: antiviral interferon type 1 (IFN-1) and pro-inflammatory signals like tumor necrosis factor alpha (TNF-α).
The study, published today in the journal Nature, offers new insights into the mechanisms that contribute to differences in infection rates, autoimmune diseases, and cancers between men and women. This could pave the way for more precise and targeted treatment options.
The researchers stress the need for ongoing clinical follow-ups for transgender individuals receiving hormone therapy, to better understand how such treatments may affect their immune systems and disease risk over time.
Professor Petter Brodin, who holds the Garfield Weston Chair and is a Professor of Pediatric Immunology at Imperial College London, led this research while he was at the Karolinska Institutet. He stated, “These discoveries are relevant for everyone. For the first time, we’ve pinpointed the immune system components that are directly regulated by sex hormones, rather than just genetic differences. This could significantly change how we understand the differing impact of diseases on males and females, and lead to new treatment possibilities for immune diseases and cancer.”
Testosterone Treatment
In this study, Karolinska Institutet clinical researchers recruited 23 transgender men who were assigned female at birth and were receiving testosterone therapy. Blood samples were obtained from participants at three different times: before hormone treatment, after three months, and after one year of therapy, allowing researchers to examine changes in immune cells and proteins in the bloodstream.
The analysis identified key immune system components that shifted following treatment, particularly concerning pathways related to inflammatory responses to infections and diseases. Notably affected were TNF-α and IFN-1, which are crucial in inflammation, recognizing harmful pathogens, and regulating immune responses to threats and damage.
To determine whether these changes were due to rising testosterone levels or declining estrogen levels, researchers analyzed blood from 11 female donors. They applied receptor blockers to demonstrate that the changes were directly resulting from testosterone signaling rather than the absence of estradiol signal.
These findings are significant for understanding the direct immunological effects of hormone therapy in transgender individuals. The researchers believe the immune regulatory changes seen with hormone therapy may help explain why men and women react differently to infections, and why men are at a higher risk for severe immune responses like ‘cytokine storms’ and increased mortality rates from COVID-19 and other grave infections.
Understanding Sex Differences
Professor Brodin is now continuing this research at the Medical Research Council Laboratory for Medical Science (MRC LMS), based at Imperial’s Hammersmith Campus. Further studies will analyze blood samples to identify which immune system components and pathways could be targeted for potential therapies.
He expressed gratitude towards the participants of the study, noting: “Transgender individuals are often under-represented and underserved in the medical field. Besides the essential immunological insights gained here, their involvement allows for a deeper understanding that may improve the long-term health of transgender individuals globally.”
The research received funding from the Knut and Alice Wallenberg Foundation, the Swedish Society for Medical Research, the Swedish Research Council, Karolinska Institutet, and the European Research Council (ERC).
