Abstract
BACKGROUND: Sex differences in immune responses are partly attributed to sex hormones, with testosterone generally associated with dampened immune responses. However, the specific impact of testosterone on the innate immune system in humans remains unclear. We examined changes in toll-like receptor (TLR) transcript levels and peripheral blood leukocyte parameters during masculinizing hormone therapy in transmasculine individuals. METHODS: We conducted a 6-month prospective observational study in 20 transmasculine individuals initiating testosterone-based gender-affirming hormone therapy. Peripheral blood mononuclear cells were collected at baseline and after 6 months of therapy. Gene transcript levels of TLR1-8, TLR10, MD2, and CD14 were quantified by RT-qPCR. Serum hormones and hematologic parameters were measured by standard assays. RESULTS: After 6 months of testosterone therapy, serum testosterone levels rose to values comparable to the range in cisgender men. Lymphocyte and monocyte counts increased (p = 0.02 and p = 0.006, respectively). TLR8 and TLR10 mRNA levels were increased relative to baseline (p = 0.003 and p = 0.001, respectively). TLR2 and MD2 transcript levels showed nominal declines (unadjusted p < 0.05) but did not remain significant after correction. No other TLRs showed significant changes. Exploratory correlation analyses show that the magnitude of estradiol decline and monocyte expansion was associated with changes in TLR1, TLR2, and TLR8 transcript levels. CONCLUSIONS: In this cohort, testosterone-based gender-affirming hormone therapy is associated with the upregulation of TLR8 and TLR10 transcripts, suggesting that sex hormone shifts (increased testosterone and decreased estradiol) may modulate certain innate immune receptors at the transcript level. These findings provide insights into how gender-affirming hormone therapy can influence the innate immune system in transmasculine individuals.