Immune system adaptation during gender-affirming testosterone treatment

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Tadepally L, Consiglio C, Sardh F, Forlin R, Wang J, Tan Z, Barcenilla H, Rodriguez L, Sugrue J, Noori P, Ivanchenko M, Piñero Páez L, Gonzalez L, Habimana Mugabo C, Johnsson A, Ryberg H, Hallgren Å, Pou C, Chen Y, Mikeš J, James A, Dahlqvist P, Wahlberg J, Hagelin A, Holmberg M, Degerblad M, Isaksson M, Duffy D, Kämpe O, Landegren N, Brodin P

Nature 633 (-) 155-164 [2024-09-04]

Infectious, infammatory and autoimmune conditions present diferently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID1, similar to observations in other infections. Females respond more strongly to vaccines, and adverse reactions are more frequent, like most autoimmune diseases. Immunological sex diferences stem from genetic, hormonal and behavioural factors but their relative importance is only partially understood. In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change markedly but the immunological consequences are poorly understood. Here we performed longitudinal systems-level analyses in 23 trans men and found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-γ responses, primarily in natural killer cells. These fndings in trans men are corroborated by sex-divergent responses in public datasets and illustrate the dynamic regulation of human immunity by sex hormones, with implications for the health of individuals undergoing hormone therapy and our understanding of sex-divergent immune responses in cisgender individuals.

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PubMed 39232147

DOI DOI: 10.1038/s41586-024-07789-z

Crossref DOI: 10.1038/s41586-024-07789-z