Immune system adaptation during gender-affirming testosterone treatment
(2024) In Nature 633(8028). p.155-164- Abstract
Infectious, inflammatory and autoimmune conditions present differently 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 infections2. Females respond more strongly to vaccines, and adverse reactions are more frequent3, like most autoimmune diseases4. Immunological sex differences stem from genetic, hormonal and behavioural factors5 but their relative importance is only partially understood6–8. In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change... (More)
Infectious, inflammatory and autoimmune conditions present differently 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 infections2. Females respond more strongly to vaccines, and adverse reactions are more frequent3, like most autoimmune diseases4. Immunological sex differences stem from genetic, hormonal and behavioural factors5 but their relative importance is only partially understood6–8. 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 findings 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.
(Less)
- author
- organization
- publishing date
- 2024-09
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature
- volume
- 633
- issue
- 8028
- pages
- 10 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:39232147
- scopus:85203192791
- ISSN
- 0028-0836
- DOI
- 10.1038/s41586-024-07789-z
- language
- English
- LU publication?
- yes
- id
- 0c7ac354-a8aa-4c94-aae2-80ac858fbe37
- date added to LUP
- 2024-11-19 11:46:05
- date last changed
- 2025-07-02 19:47:44
@article{0c7ac354-a8aa-4c94-aae2-80ac858fbe37,
abstract = {{<p>Infectious, inflammatory and autoimmune conditions present differently 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 COVID<sup>1</sup>, similar to observations in other infections<sup>2</sup>. Females respond more strongly to vaccines, and adverse reactions are more frequent<sup>3</sup>, like most autoimmune diseases<sup>4</sup>. Immunological sex differences stem from genetic, hormonal and behavioural factors<sup>5</sup> but their relative importance is only partially understood<sup>6–8</sup>. 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 findings 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.</p>}},
author = {{Lakshmikanth, Tadepally and Consiglio, Camila and Sardh, Fabian and Forlin, Rikard and Wang, Jun and Tan, Ziyang and Barcenilla, Hugo and Rodriguez, Lucie and Sugrue, Jamie and Noori, Peri and Ivanchenko, Margarita and Piñero Páez, Laura and Gonzalez, Laura and Habimana Mugabo, Constantin and Johnsson, Anette and Ryberg, Henrik and Hallgren, Åsa and Pou, Christian and Chen, Yang and Mikeš, Jaromír and James, Anna and Dahlqvist, Per and Wahlberg, Jeanette and Hagelin, Anders and Holmberg, Mats and Degerblad, Marie and Isaksson, Magnus and Duffy, Darragh and Kämpe, Olle and Landegren, Nils and Brodin, Petter}},
issn = {{0028-0836}},
language = {{eng}},
number = {{8028}},
pages = {{155--164}},
publisher = {{Nature Publishing Group}},
series = {{Nature}},
title = {{Immune system adaptation during gender-affirming testosterone treatment}},
url = {{http://dx.doi.org/10.1038/s41586-024-07789-z}},
doi = {{10.1038/s41586-024-07789-z}},
volume = {{633}},
year = {{2024}},
}