Plasma proteome adaptations during feminizing gender-affirming hormone therapy

Sex differences manifest in various traits, as well as in the risk of cardiovascular, metabolic and immunological conditions. Despite the clear physical changes induced by gender-affirming hormone therapy (GAHT), little is known about how it affects underlying physiological and biochemical processes. Here we examined plasma proteome changes over 6 months of feminizing GAHT in 40 transgender individuals treated with estradiol plus one of two antiandrogens: cyproterone acetate or spironolactone. Testosterone levels dropped markedly in the cyproterone group, but less so in those receiving spironolactone. Among 5,279 total proteins measured, feminizing GAHT changed the levels of 245 and 91, in the cyproterone and spironolactone groups, respectively, with most (>95%) showing a decrease. Proteins associated with male spermatogenesis showed a marked decrease in the cyproterone group, attributable specifically to loss of testosterone. Changes in body fat percentage and breast volume following GAHT were also reflected in the plasma proteome, including an increase in leptin expression. We show that feminizing GAHT remodels the proteome toward a cis-female profile, altering 36 (cyproterone) and 22 (spironolactone) of the top 100 sex-associated proteins in UK Biobank adult data. Moreover, 43% of cyproterone-affected proteins overlapped with those altered by menopausal hormone therapy in cis women, showing the same directional changes, with notable exceptions including CXCL13 and NOS3. Feminizing GAHT skewed the protein profile toward that linked to asthma and autoimmunity, while GAHT with cyproterone specifically skewed it away from an atherosclerosis-associated profile, suggesting a protective effect. These results reveal that feminizing GAHT reshapes the plasma proteome in a hormone-dependent manner, with implications for reproductive capacity, immune regulation and long-term health outcomes.

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Publication Details

Journal
Nature Medicine
Published
2025-10-20
DOI
https://doi.org/10.1038/s41591-025-04023-9
Citations
3
Primary Topic
Sex and Gender in Healthcare
Type
article
Field-Weighted Citation Impact
5.64

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article

Plasma proteome adaptations during feminizing gender-affirming hormone therapy

Bridget M Arman, Tania O. Crișan, Boris Novakovic, Ken C. Pang et al.
3 citations
Nature Medicine
Sex and Gender in Healthcare
5.64
article

Plasma proteome adaptations during feminizing gender-affirming hormone therapy

Bridget M Arman, Tania O. Crișan, Boris Novakovic, Ken C. Pang, Ada S. Cheung, Leo A. B. Joosten, Rebecca Shepherd, Toby Mansell, Musa M. Mhlanga, Georgiana Cabău, Camille Laberthonnìère, Lachlan M. Angus, David Burgner, Richard Saffery, Gilda Tachedjian, Rachel A. Davey, Ngan K. Nguyen, Bo Won Kim, Den Celestra
article en
3 citations

Abstract

Sex differences manifest in various traits, as well as in the risk of cardiovascular, metabolic and immunological conditions. Despite the clear physical changes induced by gender-affirming hormone therapy (GAHT), little is known about how it affects underlying physiological and biochemical processes. Here we examined plasma proteome changes over 6 months of feminizing GAHT in 40 transgender individuals treated with estradiol plus one of two antiandrogens: cyproterone acetate or spironolactone. Testosterone levels dropped markedly in the cyproterone group, but less so in those receiving spironolactone. Among 5,279 total proteins measured, feminizing GAHT changed the levels of 245 and 91, in the cyproterone and spironolactone groups, respectively, with most (>95%) showing a decrease. Proteins associated with male spermatogenesis showed a marked decrease in the cyproterone group, attributable specifically to loss of testosterone. Changes in body fat percentage and breast volume following GAHT were also reflected in the plasma proteome, including an increase in leptin expression. We show that feminizing GAHT remodels the proteome toward a cis-female profile, altering 36 (cyproterone) and 22 (spironolactone) of the top 100 sex-associated proteins in UK Biobank adult data. Moreover, 43% of cyproterone-affected proteins overlapped with those altered by menopausal hormone therapy in cis women, showing the same directional changes, with notable exceptions including CXCL13 and NOS3. Feminizing GAHT skewed the protein profile toward that linked to asthma and autoimmunity, while GAHT with cyproterone specifically skewed it away from an atherosclerosis-associated profile, suggesting a protective effect. These results reveal that feminizing GAHT reshapes the plasma proteome in a hormone-dependent manner, with implications for reproductive capacity, immune regulation and long-term health outcomes.

Nature MedicineVol. 32(1)
Royal Children's Hospital (AU), Radboud University Nijmegen (NL), Burnet Institute (AU), The University of Melbourne (AU), Iuliu Hațieganu University of Medicine and Pharmacy (RO), Mercy Hospital for Women (AU), Radboud University Medical Center (NL), Peter Doherty Institute (AU), Radboud Institute for Molecular Life Sciences (NL), Murdoch Children's Research Institute (AU), Austin Health (AU), Monash University (AU)
Burnet Institute, Children’s Hospital of Wisconsin Research Institute, Austin Medical Research Foundation, Murdoch Children's Research Institute, Australian Government, Endocrine Society of Australia, Monash University, Radboud Universiteit, State Government of Victoria, Radboud Universitair Medisch Centrum, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Institute of Allergy and Infectious Diseases, Institute of Infection and Immunity
Openalex Percentile: Top 4%
Sex and Gender in Healthcare
5.64
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