Cytokine dynamics following initiation of gender-affirming hormone therapy in transgender subjects

Sex is an important determinant for various immune system-related pathologies and sex steroids might possess immunomodulatory properties.

To study the effects of sex steroid exposure on the serum levels of immune-related biomarkers (irBMS), using a model of transgender individuals receiving gender-affirming hormone therapy (GAHT).

Serum samples were collected from hormone-naïve trans women (TW) (n = 30) and trans men (TM) (n = 30) who initiated GAHT at baseline and after ±6 months of treatment. Cisgender men (n = 10) and cisgender women (n = 10) were included as controls. High-sensitivity C-reactive protein (hs-CRP) was measured using an immunoassay. Serum levels of several irBMs, including cytokines and chemokines were determined using a commercial multiplex assay (Olink®). Serum estradiol and testosterone were determined using liquid-chromatography tandem-mass spectrometry (LC-MS/MS).

After ±6 months of GAHT in TW, serum levels of 10 cytokines (CCL2, CCL7, CCL11, CCL13, CCL19, CXCL9, CXCL10, CXCL11, IL15, and TNFSF10) significantly decreased, whereas IL7 increased. In TM, 8 factors significantly increased (CCL2, CCL7, CCL11, CCL13, CCL19, IL17C, MMP1, and TNFSF10). Other immune-related biomarkers were not significantly affected, and levels of hs-CRP did not show a clinically relevant change over time.

Six months of estrogen with antiandrogen treatment resulted in decreased serum levels of several cytokines and chemokines in TW, whereas cytokine and chemokine levels often increased in TM upon treatment with testosterone. These distinct and generally opposite changes suggest a sex steroid-dependent impact, which could contribute to sex-related disparities in (auto)inflammatory diseases. However, additional research should explore potential clinical consequences, as well as the mechanisms involved.