Gender-affirming hormone therapy visibly changes the body of transgender women, but what happens inside, at the molecular level, had remained largely a mystery. An international team has this time looked at the proteome — the full set of proteins circulating in the blood — and has found that it is deeply and measurably reorganised after only six months of treatment.
The work, published in Nature Medicine, followed 40 transgender women who started gender-affirming hormone therapy with estradiol combined with one of two antiandrogens: cyproterone acetate or spironolactone. Before and after six months of treatment, the levels of 5,279 proteins were measured in their plasma, one of the most complete maps yet produced of the biochemical effect of these hormones.
The results show abundant changes, but above all in one direction: most of the altered proteins decreased. There were 245 in the cyproterone group and 91 in the spironolactone group. Proteins associated with spermatogenesis — sperm production — fell markedly in the first group, in parallel with the drop in testosterone, which was far more intense with cyproterone than with spironolactone.
The change is not limited to the reproductive system. As body fat increased, so did leptin, the hormone that regulates appetite and energy balance, and proteins related to breast volume appeared in the blood. The protein profile as a whole shifted towards a pattern more typical of cisgender women: it reordered 36 of the 100 proteins most associated with sex in the UK Biobank in the cyproterone group and 22 in the spironolactone group.
There is also a finding with clinical implications. 43% of the proteins affected by cyproterone acetate matched those that change in menopausal hormone therapy in cisgender women, and in the same direction. The protein profile leaned towards traits linked to asthma and autoimmunity, but treatment with cyproterone moved it away from a profile associated with atherosclerosis, which could point to a cardiovascular protective effect worth studying in depth.
The study is descriptive and does not yet allow us to state what concrete long-term health consequences these changes will have. But it shows something important: gender-affirming hormone therapy does not act only on what is visible; it coordinately remodels the physiology and the biochemistry of the blood, a key step towards understanding and better caring for the long-term health of transgender women.
Source: Plasma proteome adaptations during feminizing gender-affirming hormone therapy. Nguyen NNL, Celestra D, Angus LM, et al. Nature Medicine 2026;32:139-150. DOI: 10.1038/s41591-025-04023-9.
Read the publication: Nature Medicine.
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