Sex hormones like estrogen and testosterone don’t just affect things like body shape or voice—they also play a role in how the immune system works. This is especially important for transgender people who take these hormones as part of their gender-affirming care. However, there’s not much research on how these hormone treatments affect the immune system, especially in young transgender people.
Introduction
Sex hormones such as estrogen and testosterone are well-known for their profound effects on the human body, extending beyond reproductive health to influence the immune system. These immunomodulatory properties have been extensively studied in cisgender populations, revealing notable sex-based differences in immune responses, disease susceptibility, and outcomes. However, the immunological impact of gender-affirming hormone (GAH) therapy—a cornerstone of medical transition for transgender individuals—remains underexplored, particularly in young people.
A recent study, “Plasma testosterone concentration is correlated with circulating immune cell abundance in transgender young people on gender-affirming hormone treatment,” provisionally accepted in Frontiers in Immunology, addresses this critical gap by examining how GAH, specifically testosterone and estrogen therapy, modulates immune cell populations in transgender youth[1]. This article provides a comprehensive analysis of the study's methodology, findings, and broader implications, placing them within the context of current immunological and transgender health research.
Background: Sex Hormones and Immune Modulation
Sex differences in immune function are well documented. Females typically mount stronger immune responses, resulting in better outcomes following certain infections and vaccinations, but also a higher incidence of autoimmune diseases. Males, on the other hand, are more susceptible to some infections and tend to have more muted immune responses[2]. These differences are attributed to a combination of genetic, hormonal, and environmental factors.
Sex hormones exert their influence through various mechanisms:
Estrogen generally enhances immune responses, increasing the activity and abundance of both innate and adaptive immune cells.
Testosterone is considered immunosuppressive, tending to dampen immune responses and reduce certain immune cell populations[2].
Understanding how these hormones shape immunity is particularly relevant for transgender individuals undergoing GAH, as therapy induces hormone levels that align with their gender identity, potentially shifting their immune profile toward that of their affirmed gender.
Study Design and Methods
The study recruited 100 participants: 47 transgender youth on GAH (testosterone or estrogen for at least six months) and 53 age-matched controls not taking GAH[1]. The participants were part of the Gender and IMmunity (GIM) study, which sought to characterize immune changes associated with hormone therapy in young people.
Key methodological features included:
Immune Profiling: Peripheral blood samples were analyzed using an 18-color flow cytometry panel to assess a broad range of immune cell types. For a subset of 36 samples, a more detailed 37-parameter MaxPar panel was used with mass cytometry (CyTOF), enabling high-dimensional analysis of immune cell subsets.
Hormone Measurement: Plasma concentrations of testosterone and estrogen were measured and correlated with immune cell abundances.
Statistical Analysis: Multiple regression models were used to compare immune cell populations across groups and to assess correlations with hormone levels, controlling for relevant covariates.
Participants were grouped by birth-registered sex and current hormone treatment: trans males (assigned female at birth, on testosterone), trans females (assigned male at birth, on estrogen), and their respective control groups.
Key Findings
1. Testosterone and Immune Cell Abundance in Transgender Males
The study found that testosterone treatment in trans males was associated with significant changes in specific immune cell populations compared to control females (cisgender females not on GAH)[1]:
Lower numbers of CD11c+ B cells: CD11c+ B cells are a subset of B cells implicated in immune regulation and autoimmunity. Their reduction may reflect a shift toward a more “male-typical” immune profile, which generally exhibits lower B cell activity.
Higher numbers of CD4+ regulatory T cells (Tregs): Tregs are crucial for maintaining immune tolerance and preventing autoimmunity. An increase in Tregs suggests enhanced immune regulation, potentially contributing to the lower incidence of autoimmune diseases observed in males.
Higher frequency of naïve B cells: Naïve B cells are unexposed to antigens and represent the “reserve” of the adaptive immune system. Their increased abundance in trans males correlated with plasma testosterone levels.
2. T Cell Subset Changes
The study also identified alterations in T cell subsets:
Decrease in CD161+ T effector memory cells in trans males: This subset is involved in rapid immune responses and tissue surveillance. The decrease was associated with lower testosterone levels, suggesting a direct hormonal influence.
Other T cell subset differences in both trans males and trans females: While several differences were noted, only those in trans males showed a clear correlation with testosterone concentration.
3. Estrogen and Immune Cells in Transgender Females
While estrogen treatment in trans females was associated with some differences in immune cell populations compared to control males, these changes were generally not correlated with plasma estrogen levels. This suggests that, at least in young people, estrogen’s immunomodulatory effects may be less pronounced or more complex than those of testosterone in this context[1].
4. Broader Immune System Adaptations
The findings align with other recent research showing that testosterone therapy in trans men suppresses certain immune functions (such as type I interferon responses) while increasing inflammation markers like TNF-α[3][2]. These changes mirror the immune profiles typically seen in cisgender males and may have implications for susceptibility to infections and autoimmune diseases.
Mechanistic Insights: How Do Sex Hormones Modulate Immunity?
Sex hormones influence immune cells through:
Direct receptor-mediated effects: Immune cells express androgen and estrogen receptors, allowing them to respond directly to circulating hormones.
Epigenetic remodeling: Hormone receptors can alter chromatin structure and gene expression, leading to long-term changes in immune cell function and phenotype[4].
Cytokine regulation: Hormones modulate the production of cytokines—key signaling molecules in immune responses—shifting the balance between pro-inflammatory and anti-inflammatory states.
For example, testosterone has been shown to attenuate type I interferon responses in dendritic cells and monocytes while potentiating TNF-α and other inflammatory cytokines in monocytes and natural killer cells[3]. These effects are mediated through complex signaling pathways, including the activation of nuclear factor kappa B (NF-κB) and modulation of chromatin accessibility at immune-related genes[4][3].
Clinical Implications
1. Autoimmunity and Infection Risk
The observed shift toward a more “male-typical” immune profile in trans males on testosterone may have protective effects against autoimmune diseases, which are more prevalent in females. However, it could also increase susceptibility to certain infections or alter vaccine responses, reflecting patterns seen in cisgender males[2].
2. Monitoring and Personalized Care
Given these immunological changes, transgender individuals on GAH may benefit from tailored monitoring of immune function, particularly if they have pre-existing autoimmune conditions or are at risk for infections. Further research is needed to determine whether these cellular changes translate into clinically significant differences in disease risk or outcomes.
3. Implications for Transgender Health Research
This study underscores the importance of including transgender populations in immunological research. GAH provides a unique model to disentangle the effects of sex hormones from genetic sex, offering insights that may benefit not only transgender individuals but also broader efforts to understand sex differences in immunity[4].
Limitations and Future Directions
1. Cross-Sectional Design
The study’s cross-sectional nature limits the ability to infer causality or track changes over time. Longitudinal studies are needed to confirm these findings and assess the long-term impact of GAH on immune function.
2. Functional Outcomes
While the study documents changes in immune cell abundance, it does not directly assess functional immune responses (e.g., to infection or vaccination). Future research should include functional assays to determine the clinical significance of these cellular changes.
3. Age and Developmental Considerations
The study focuses on young people, whose immune systems are still maturing. The effects of GAH may differ in older individuals or those with underlying health conditions.
4. Diversity of Participants
Greater diversity in terms of race, ethnicity, and comorbidities would enhance the generalizability of the findings.
Broader Context: What Do Other Studies Show?
Other recent studies corroborate and extend these findings:
Longitudinal analyses in trans men reveal that testosterone therapy modulates a cross-regulated axis between type-I interferon and TNF, attenuating interferon responses and enhancing inflammatory cytokine production[3].
Epigenetic studies indicate that GAH can remodel the chromatin landscape of immune cells, potentially leading to lasting changes in immune function[4].
Comparative studies in cisgender and transgender populations highlight that the unique interplay between sex hormones and chromosomes shapes immune cell proportions and responses, with GAH providing a model to dissect these effects[4][2].
Conclusion
This study provides important new evidence that testosterone therapy in transgender young people is associated with significant changes in immune cell populations, particularly B and T cell subsets, and that these changes are correlated with plasma testosterone levels[1]. While estrogen therapy in trans females also affects immune cells, the associations with plasma hormone levels are less clear.
These findings have implications for understanding sex differences in immunity, the health of transgender individuals on GAH, and the broader field of immunology. Further research, especially longitudinal and functional studies, is needed to clarify the clinical significance of these changes and to inform personalized care for transgender individuals undergoing hormone therapy.
Key Takeaways
Testosterone treatment in trans males is linked to lower CD11c+ B cells, higher Tregs, and increased naïve B cells, with these changes correlating with plasma testosterone levels[1].
Estrogen treatment in trans females leads to some immune cell changes, but these are not consistently correlated with estrogen levels[1].
The immunomodulatory effects of GAH mirror known sex differences in immunity and may influence disease risk and treatment responses in transgender individuals[3][2].
Further research is essential to determine the functional and clinical implications of these immune changes and to optimize care for transgender populations.
By advancing our understanding of how sex hormones shape the immune system, studies like this not only improve transgender health care but also shed light on fundamental principles of human immunology.
References:
Introduction
Sex hormones such as estrogen and testosterone are well-known for their profound effects on the human body, extending beyond reproductive health to influence the immune system. These immunomodulatory properties have been extensively studied in cisgender populations, revealing notable sex-based differences in immune responses, disease susceptibility, and outcomes. However, the immunological impact of gender-affirming hormone (GAH) therapy—a cornerstone of medical transition for transgender individuals—remains underexplored, particularly in young people.
A recent study, “Plasma testosterone concentration is correlated with circulating immune cell abundance in transgender young people on gender-affirming hormone treatment,” provisionally accepted in Frontiers in Immunology, addresses this critical gap by examining how GAH, specifically testosterone and estrogen therapy, modulates immune cell populations in transgender youth[1]. This article provides a comprehensive analysis of the study's methodology, findings, and broader implications, placing them within the context of current immunological and transgender health research.
Background: Sex Hormones and Immune Modulation
Sex differences in immune function are well documented. Females typically mount stronger immune responses, resulting in better outcomes following certain infections and vaccinations, but also a higher incidence of autoimmune diseases. Males, on the other hand, are more susceptible to some infections and tend to have more muted immune responses[2]. These differences are attributed to a combination of genetic, hormonal, and environmental factors.
Sex hormones exert their influence through various mechanisms:
Estrogen generally enhances immune responses, increasing the activity and abundance of both innate and adaptive immune cells.
Testosterone is considered immunosuppressive, tending to dampen immune responses and reduce certain immune cell populations[2].
Understanding how these hormones shape immunity is particularly relevant for transgender individuals undergoing GAH, as therapy induces hormone levels that align with their gender identity, potentially shifting their immune profile toward that of their affirmed gender.
Study Design and Methods
The study recruited 100 participants: 47 transgender youth on GAH (testosterone or estrogen for at least six months) and 53 age-matched controls not taking GAH[1]. The participants were part of the Gender and IMmunity (GIM) study, which sought to characterize immune changes associated with hormone therapy in young people.
Key methodological features included:
Immune Profiling: Peripheral blood samples were analyzed using an 18-color flow cytometry panel to assess a broad range of immune cell types. For a subset of 36 samples, a more detailed 37-parameter MaxPar panel was used with mass cytometry (CyTOF), enabling high-dimensional analysis of immune cell subsets.
Hormone Measurement: Plasma concentrations of testosterone and estrogen were measured and correlated with immune cell abundances.
Statistical Analysis: Multiple regression models were used to compare immune cell populations across groups and to assess correlations with hormone levels, controlling for relevant covariates.
Participants were grouped by birth-registered sex and current hormone treatment: trans males (assigned female at birth, on testosterone), trans females (assigned male at birth, on estrogen), and their respective control groups.
Key Findings
1. Testosterone and Immune Cell Abundance in Transgender Males
The study found that testosterone treatment in trans males was associated with significant changes in specific immune cell populations compared to control females (cisgender females not on GAH)[1]:
Lower numbers of CD11c+ B cells: CD11c+ B cells are a subset of B cells implicated in immune regulation and autoimmunity. Their reduction may reflect a shift toward a more “male-typical” immune profile, which generally exhibits lower B cell activity.
Higher numbers of CD4+ regulatory T cells (Tregs): Tregs are crucial for maintaining immune tolerance and preventing autoimmunity. An increase in Tregs suggests enhanced immune regulation, potentially contributing to the lower incidence of autoimmune diseases observed in males.
Higher frequency of naïve B cells: Naïve B cells are unexposed to antigens and represent the “reserve” of the adaptive immune system. Their increased abundance in trans males correlated with plasma testosterone levels.
2. T Cell Subset Changes
The study also identified alterations in T cell subsets:
Decrease in CD161+ T effector memory cells in trans males: This subset is involved in rapid immune responses and tissue surveillance. The decrease was associated with lower testosterone levels, suggesting a direct hormonal influence.
Other T cell subset differences in both trans males and trans females: While several differences were noted, only those in trans males showed a clear correlation with testosterone concentration.
3. Estrogen and Immune Cells in Transgender Females
While estrogen treatment in trans females was associated with some differences in immune cell populations compared to control males, these changes were generally not correlated with plasma estrogen levels. This suggests that, at least in young people, estrogen’s immunomodulatory effects may be less pronounced or more complex than those of testosterone in this context[1].
4. Broader Immune System Adaptations
The findings align with other recent research showing that testosterone therapy in trans men suppresses certain immune functions (such as type I interferon responses) while increasing inflammation markers like TNF-α[3][2]. These changes mirror the immune profiles typically seen in cisgender males and may have implications for susceptibility to infections and autoimmune diseases.
Mechanistic Insights: How Do Sex Hormones Modulate Immunity?
Sex hormones influence immune cells through:
Direct receptor-mediated effects: Immune cells express androgen and estrogen receptors, allowing them to respond directly to circulating hormones.
Epigenetic remodeling: Hormone receptors can alter chromatin structure and gene expression, leading to long-term changes in immune cell function and phenotype[4].
Cytokine regulation: Hormones modulate the production of cytokines—key signaling molecules in immune responses—shifting the balance between pro-inflammatory and anti-inflammatory states.
For example, testosterone has been shown to attenuate type I interferon responses in dendritic cells and monocytes while potentiating TNF-α and other inflammatory cytokines in monocytes and natural killer cells[3]. These effects are mediated through complex signaling pathways, including the activation of nuclear factor kappa B (NF-κB) and modulation of chromatin accessibility at immune-related genes[4][3].
Clinical Implications
1. Autoimmunity and Infection Risk
The observed shift toward a more “male-typical” immune profile in trans males on testosterone may have protective effects against autoimmune diseases, which are more prevalent in females. However, it could also increase susceptibility to certain infections or alter vaccine responses, reflecting patterns seen in cisgender males[2].
2. Monitoring and Personalized Care
Given these immunological changes, transgender individuals on GAH may benefit from tailored monitoring of immune function, particularly if they have pre-existing autoimmune conditions or are at risk for infections. Further research is needed to determine whether these cellular changes translate into clinically significant differences in disease risk or outcomes.
3. Implications for Transgender Health Research
This study underscores the importance of including transgender populations in immunological research. GAH provides a unique model to disentangle the effects of sex hormones from genetic sex, offering insights that may benefit not only transgender individuals but also broader efforts to understand sex differences in immunity[4].
Limitations and Future Directions
1. Cross-Sectional Design
The study’s cross-sectional nature limits the ability to infer causality or track changes over time. Longitudinal studies are needed to confirm these findings and assess the long-term impact of GAH on immune function.
2. Functional Outcomes
While the study documents changes in immune cell abundance, it does not directly assess functional immune responses (e.g., to infection or vaccination). Future research should include functional assays to determine the clinical significance of these cellular changes.
3. Age and Developmental Considerations
The study focuses on young people, whose immune systems are still maturing. The effects of GAH may differ in older individuals or those with underlying health conditions.
4. Diversity of Participants
Greater diversity in terms of race, ethnicity, and comorbidities would enhance the generalizability of the findings.
Broader Context: What Do Other Studies Show?
Other recent studies corroborate and extend these findings:
Longitudinal analyses in trans men reveal that testosterone therapy modulates a cross-regulated axis between type-I interferon and TNF, attenuating interferon responses and enhancing inflammatory cytokine production[3].
Epigenetic studies indicate that GAH can remodel the chromatin landscape of immune cells, potentially leading to lasting changes in immune function[4].
Comparative studies in cisgender and transgender populations highlight that the unique interplay between sex hormones and chromosomes shapes immune cell proportions and responses, with GAH providing a model to dissect these effects[4][2].
Conclusion
This study provides important new evidence that testosterone therapy in transgender young people is associated with significant changes in immune cell populations, particularly B and T cell subsets, and that these changes are correlated with plasma testosterone levels[1]. While estrogen therapy in trans females also affects immune cells, the associations with plasma hormone levels are less clear.
These findings have implications for understanding sex differences in immunity, the health of transgender individuals on GAH, and the broader field of immunology. Further research, especially longitudinal and functional studies, is needed to clarify the clinical significance of these changes and to inform personalized care for transgender individuals undergoing hormone therapy.
Key Takeaways
Testosterone treatment in trans males is linked to lower CD11c+ B cells, higher Tregs, and increased naïve B cells, with these changes correlating with plasma testosterone levels[1].
Estrogen treatment in trans females leads to some immune cell changes, but these are not consistently correlated with estrogen levels[1].
The immunomodulatory effects of GAH mirror known sex differences in immunity and may influence disease risk and treatment responses in transgender individuals[3][2].
Further research is essential to determine the functional and clinical implications of these immune changes and to optimize care for transgender populations.
By advancing our understanding of how sex hormones shape the immune system, studies like this not only improve transgender health care but also shed light on fundamental principles of human immunology.
References:
- Frontiers | Plasma testosterone concentration is correlated with circulating immune cell abundance in transgender young people on genderaffirming hormone treatment
- Immune dynamics throughout life in relation to sex hormones and perspectives gained from gender-affirming hormone therapy - PMC
- Immune system adaptation during gender-affirming testosterone treatment - PMC
- Frontiers | Epigenetic remodeling by sex hormone receptors and implications for gender affirming hormone therapy
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