Plasma proteome adaptations during feminizing gender-affirming hormone therapy.

Feminizing GAHT changed the levels of 245 proteins in the cyproterone group and 91 proteins in the spironolactone group out of 5,279 total proteins measured.

• 40 transgender individuals were treated with estradiol plus one of two antiandrogens: cyproterone acetate or spironolactone over 6 months.
• More than 95% of changed proteins showed a decrease in both treatment groups.
• Testosterone levels dropped markedly in the cyproterone group but less so in those receiving spironolactone.
• 5,279 total proteins were measured in plasma samples.

Proteins associated with male spermatogenesis showed a marked decrease in the cyproterone group, attributable specifically to loss of testosterone.

• This finding was specific to the cyproterone group, which experienced a greater reduction in testosterone levels.
• The spironolactone group showed less testosterone reduction and correspondingly fewer protein changes.
• The effect on spermatogenesis-associated proteins was attributed specifically to testosterone loss rather than estradiol addition.

Feminizing GAHT remodeled the plasma proteome toward a cis-female profile, altering 36 (cyproterone) and 22 (spironolactone) of the top 100 sex-associated proteins identified in UK Biobank adult data.

• The UK Biobank adult data was used as a reference dataset for sex-associated protein profiles.
• The cyproterone group showed greater feminization of the proteome, consistent with greater testosterone suppression.
• Both groups showed directional shifts toward a cis-female protein profile.

43% of cyproterone-affected proteins overlapped with those altered by menopausal hormone therapy in cis women, showing the same directional changes.

• Notable exceptions to the shared directional changes included CXCL13 and NOS3.
• This comparison was made between feminizing GAHT in transgender individuals and menopausal hormone therapy in cis women.
• The overlap suggests shared hormonal mechanisms between the two forms of hormone therapy.

Changes in body fat percentage and breast volume following GAHT were reflected in the plasma proteome, including an increase in leptin expression.

• Leptin, a hormone associated with adipose tissue, showed increased expression following feminizing GAHT.
• Physical changes including body fat percentage and breast volume were captured in proteomic data.
• These changes suggest the proteome reflects body composition remodeling induced by feminizing hormone therapy.

Feminizing GAHT skewed the protein profile toward one linked to asthma and autoimmunity.

• This shift was observed across both antiandrogen treatment groups.
• The shift toward an asthma- and autoimmunity-associated protein profile has implications for immune regulation.
• This finding is consistent with known sex differences in immune-mediated conditions, where cis females have higher rates of autoimmune diseases.

GAHT with cyproterone specifically skewed the protein profile away from an atherosclerosis-associated profile, suggesting a protective cardiovascular effect.

• This protective shift was specific to the cyproterone group and not observed in the spironolactone group.
• The authors suggest this represents a potential protective effect against atherosclerosis.
• The differential effect between treatment groups is attributed to the greater testosterone suppression achieved with cyproterone acetate.

Sex differences manifest in the risk of cardiovascular, metabolic and immunological conditions, motivating study of how GAHT affects underlying physiological and biochemical processes.

• Little was previously known about how GAHT affects underlying physiological and biochemical processes despite clear physical changes.
• The study examined plasma proteome changes over 6 months of feminizing GAHT.
• Two antiandrogen regimens were compared: cyproterone acetate and spironolactone, both combined with estradiol.