Plasma proteome adaptations during feminizing gender-affirming hormone therapy

Area of Science:

• Endocrinology
• Proteomics
• Transgender Health

Background:

• Sex differences influence various traits and disease risks.
• Gender-affirming hormone therapy (GAHT) induces physical changes, but its effects on underlying physiological processes are not well understood.

Purpose of the Study:

• To examine plasma proteome changes in transgender individuals undergoing feminizing GAHT over six months.
• To compare the effects of two antiandrogens, cyproterone acetate and spironolactone, when used with estradiol.

Main Methods:

• Analysis of plasma proteome changes in 40 transgender individuals receiving feminizing GAHT.
• Measurement of 5,279 total proteins over a 6-month period.
• Comparison of proteomic profiles between groups receiving cyproterone acetate and spironolactone.

Main Results:

• Feminizing GAHT altered 245 proteins (cyproterone group) and 91 proteins (spironolactone group), with most decreasing (>95%).
• Proteins linked to male spermatogenesis decreased, particularly with cyproterone acetate, due to testosterone loss.
• GAHT remodeled the proteome toward a cis-female profile, affecting sex-associated proteins and showing overlap with menopausal hormone therapy effects.
• GAHT shifted protein profiles toward asthma and autoimmunity associations; cyproterone acetate specifically reduced atherosclerosis-associated profiles.

Conclusions:

• Feminizing GAHT reshapes the plasma proteome in a hormone-dependent manner.
• These proteomic changes have implications for reproductive capacity, immune regulation, and long-term health.
• The study highlights significant physiological shifts induced by GAHT, underscoring the need for further research into its long-term health implications.