As the understanding of the human immune system evolves, it becomes clear that the rigid map research once relied on is missing novel routes and territories. Traditionally, biological sex acted as a fixed coordinate to explain distinct patterns in infection susceptibility, vaccine efficacy, and autoimmune diseases. While this framework highlights population trends, it fails to address genetic, hormonal, and environmental factors that also shape immunity. Most notably, this static blueprint leaves critical gaps in care for transgender communities, whose medical needs are frequently disregarded by outdated models. As access to gender-affirming hormone therapy (GAHT) increases, deciphering the immune adaptation triggered by exogenous hormones becomes essential to tailor clinical care, manage disease risks for trans patients, and ultimately help redraw a comprehensive map of human health.
THE COORDINATES OF IMMUNITY
Before navigating the map, the fundamental guides must be established. Immune responses all emerge from several overlapping coordinates. Genetics give us the first and most familiar coordinate, which provides the reference point from which initial sex differences in immunity first emerge. One of the two sex chromosomes of humans, the X chromosome, contains the instructions to make numerous proteins that have essential roles in the immune system. This introduces a bias in the ability of the immune system to mount responses. If we think of the immune system like a security alarm, cis-males require multiple signals to trigger the alarm, making them more susceptible to infection and cancer. On the other hand, cis-females tend to have an overly sensitive alarm, reacting quickly to threats, but also being prone to false alarms leading the body to attack itself.
Hormones form the second coordinate, acting as dynamic signals that amplify, suppress, or redirect immune responses as their concentrations fluctuate throughout our lives. Their precise mechanisms and downstream effects on immune cells will be explored in subsequent sections. The third coordinate encompasses both environmental exposure and lived experience. These include factors like nutrition, stress, or even sleep, but also socioeconomic conditions, such as access to healthcare. Beyond these major coordinates, we have other navigational stars that further reshape our position on the map. Age, the microbiome, medication record, or previous infections are all factors that guide each individual within their immune map, not as isolated entities, but intersecting with our initial coordinates and continuously altering our position. The resulting plot is therefore dynamic rather than fixed, making biological sex an important reference point, but not a complete guide to how any individual immune system will work.
WHEN HORMONES SPEAK, IMMUNE CELLS LISTEN
Hormones and the immune system are interwoven in continuous conversation, exchanging signals that help determine how strongly the body responds to infection and whether immune tolerance is maintained. Immune cells carry receptors for sex hormones such as estrogen, testosterone, and progesterone. These hormones can change how immune cells develop, become activated, and communicate with one another. The conversation also runs in the opposite direction; inflammatory signals from the body can affect hormone production and metabolism, which means that changes in one system may reshape the behavior of the other. Yet hormones do not issue simple commands. Their effects depend on their concentration, the type of receptors present on a particular cell, and the broader physiological context. For example, estrogen may strengthen some immune responses, like antibody production and allergy. In contrast, testosterone is often associated with the development of regulatory immune cells that attenuate the inflammatory function of others. Estrogen and testosterone are present in cis-females and cis-males but display different concentrations. Ultimately, what immune cells hear depends not only on which hormone is speaking, but also on the biological setting in which the conversation takes place. During pregnancy, for instance, elevated levels of estrogen and progesterone promote immune tolerance rather than hyperactivation.
CHANGING THE SIGNAL
Gender-affirming hormone therapy (GAHT) changes the signals circulating within the body’s hormonal conversation by altering the concentration, balance, and duration of exposure to estrogen, testosterone, and other sex hormones. GAHT helps individuals develop secondary sex characteristics that align with their gender identity, which is achieved by either introducing exogenous hormones or blocking the effect of hormones produced by the body. While there is a variety of treatment options, feminizing hormone therapy typically offers estrogen administration alongside medication that reduces androgen activity. Masculinizing hormone therapy commonly involves testosterone. The result is not a uniform increase or decrease in immunity, but a context-dependent reorganization of immune dynamics, a shift that researchers are only beginning to understand.
MAPPING NOVEL NAVIGATIONS
One of the first traces of this shift emerged from a longitudinal study of twenty-three trans men, in which testosterone treatment reduced the activity of immune cells involved in antiviral defenses in only three months. Researchers have also detected changes during gender-affirming testosterone treatment in another immune cell population called T cells, which may differentiate into distinct subtypes with unique functions. In a separate cohort of twenty-five trans men, six months of testosterone treatment appeared to shift some T-cell populations from a pro-inflammatory state to a regulatory profile. Interestingly, the trends observed in both studies were similar to those present in cis-males.
Evidence for feminizing GAHT is newer and less detailed at the cellular level, but it points to a comparable recalibration of immune dynamics. Six months of estradiol administration with testosterone suppression altered numerous circulating immune-related proteins and cytokines, with some changes detectable after three months. Importantly, the pattern differed between cyproterone acetate and spironolactone, which are different androgen-blocking drugs, suggesting that the route taken across the hormonal map depends not only on estrogen exposure but also on how testosterone is suppressed. Trans women undergoing feminizing therapy show similar trends in immune profiles to cis-females rather than trans men or cis-males, highlighting a unique role of hormones independent of biological sex.
BLANK SPACES AND THE MAP OF MARKERS
Together, these findings suggest that hormones change who is speaking, which signals are amplified, and how particular immune cells listen. For now, however, the map contains molecular landmarks rather than clinical destinations. Previous studies cannot inform whether patients are more or less susceptible to infection or respond differently to vaccines, nor should an increase in an inflammatory marker automatically be interpreted as harmful, since the same signal may be protective in one biological setting and damaging in another. An initial study looking at the levels of immune proteins circulating in the blood of individuals undergoing feminizing GAHT detected molecules associated with asthma and autoimmunity. Recent findings link an increased risk of sex-associated reproductive cancers and autoimmune diseases like systemic lupus erythematosus to GAHT. Nevertheless, for other cancer treatments and chronic inflammatory conditions, GAHT may even have a therapeutic role. While disease development depends on additional factors, changes in clinically relevant biomarkers should be carefully considered for individuals with an underlying susceptibility.
Drawing clinical conclusions is further complicated by differences in hormone dose, route of administration, treatment duration, and accompanying medications, as well as limited information about participants’ baseline health and the many other factors that shape immunity. The available evidence therefore provides early coordinates rather than reliable clinical directions: researchers can see that the immune map is shifting, but they cannot yet determine where those shifts ultimately lead. Understanding how hormones actively shape immune dynamics will help us move toward an inclusive map of human health that should offer life-saving care for transgender communities. While the map will continue to evolve, filling the blank spaces with robust data will allow us to move past rigid coordinates to a comprehensive model of human immunity.
Ana Sofia Mendoza Viruega