Editorial: Gender affirming hormone therapy and its immunological implications

Transgender (trans) individuals identify with a gender that does not align with their biological sex. 13 For some, this leads to experiences of gender dysphoria and poor mental health. To address this, 14 some trans individuals, in consultation with health care providers, initiate gender affirming hormone 15 treatment (GAHT) to align their physical appearance with their experienced gender. Commonly, 16 assigned female at birth (AFAB, trans males) are treated with testosterone as monotherapy and 17 assigned male at birth (AMAB, trans females) are treated with a combination of anti-testosterone and 18 estradiol. GAHT can be lifesaving for individuals suffering from gender dysphoria and side effects 19 are in general mild (1). Due to stigma and political convictions, medical research into the effects of 20 GAHT has historically been limited. However, this is changing with more than 1300 publications 21 involving GAHT in PubMed since 2020. Several of these studies suggest that the effects of GAHT 22 extends beyond their impact on physical attributes to also impact aspects of immune with the level of testosterone. In contrast, the proportion of CD11c + B cells was lower in AFAB trans 41 males and decreased with increasing testosterone levels. This observation is as it aligns 42 with previous reports that these cells are increased in cis females and may also contribute to the 43 increased prevalence of autoimmune diseases in cis females (8). Several differences were also 44 observed in AMAB trans females, including lower levels of monocyte and dendritic cell subsets, 45 however as the AMAB trans female group was relatively small, these findings should be interpreted 46 with some caution. 47The second study by Cihan et al evaluated the impact of testosterone in AFAB trans males on clinical 48 blood cell counts as well as toll like receptor (TLR) expression in circulating immune cells. The team 49 observed increases in lymphocyte and monocyte abundances, as well as increased hemoglobin levels 50 after 6 months of testosterone-based GAHT compared to baseline values. Regarding expression of 51 TLR transcripts, an increase was observed for TLR8 and TLR10 transcripts and particularly the 52 increase in TLR8 further associated with increases in monocyte abundance and a decline in estrogen 53 levels. 54The expanding literature on the impacts of GAHT continues to improve our understanding of the 55 effects of sex hormones and the intricate balance and counter-regulation between estrogen and 56 testosterone. This counter regulation is essential to consider when observations in trans individuals 57 are extrapolated to describe cell-specific effect of a given hormone. Importantly, as the scientific 58 literature expands in the field, this will continue to improve confidence by clinical care providers and 59 if potential risks associated with treatment are identified, monitoring or management of potential side 60 effects can be addressed efficiently. This is essential as treatment itself in many cases is lifesaving 61 from a mental health perspective. 62Lastly, it should be noted that the immunological impact of sex hormones is not only relevant for 63 trans individuals but extends across several aspects of human biology and pathologies, including 64 hormone replacement therapy in older individuals, hormone restriction therapy in cancer patients, as 65 well as hormone-associated impacts in infectious or autoimmune disease. Targeting or mimicking 66 these effects may in the future be an important strategy to reduce the burden of several classes of 67 disease with benefits for both trans and cis populations. 68 1The authors declare that the research was conducted in the absence of any commercial or financial 70 relationships that could be construed as a potential conflict of interest. 71