Impact of Distinct Antiandrogen Exposures on the Plasma Metabolome in Feminizing Gender-affirming Hormone Therapy.

Forty-three metabolic biomarkers were altered after 6 months of feminizing GAHT in both anti-androgen groups.

• Blood samples were collected at baseline and after 3 and 6 months of GAHT from transgender women (n = 53).
• Participants were randomized to either cyproterone acetate or spironolactone as anti-androgens.
• Most of the 43 altered biomarkers belonged to the very low- or low-density lipoprotein (VLDL/LDL) subclasses.
• All but 1 of the 43 shared biomarkers showed a decrease, suggesting an anti-atherogenic signature.
• Nuclear magnetic resonance-based metabolomics was used to measure 249 metabolic biomarkers in plasma.

Cyproterone acetate specifically decreased plasma glutamine, glycine, and alanine levels, an effect not observed with spironolactone.

• The decrease in these amino acids was specific to the cyproterone acetate group and not shared with the spironolactone group.
• Glutamine, glycine, and alanine are the three amino acids identified as showing a cyproterone acetate-specific effect.
• This finding suggests differential metabolic effects between the two anti-androgen treatments beyond their shared hormonal effects.

Eighty percent of metabolic biomarkers exhibiting the most abundant sex- and age-related pattern were significantly lowered after GAHT.

• Sex- and age-related metabolite patterns were identified using data from an unrelated cohort of children and their parents (n = 3748).
• The relevant pattern was characterized as metabolites higher in assigned female children and lower in assigned female adults, relative to assigned males.
• The lowering of 80% of these biomarkers after GAHT reflects a shift toward the adult female metabolic profile.
• This pattern analysis used an independent reference cohort to contextualize the direction of GAHT-induced metabolic changes.

The plasma metabolome is associated with phenotypes exhibiting sexual dimorphism, including cardiovascular disease, and sex hormones are thought to drive this dimorphism.

• Sexual dimorphism in the plasma metabolome is established in the background literature cited by the authors.
• Cardiovascular disease is highlighted as a key phenotype with sex-related metabolic associations.
• The study framed GAHT as a model for examining how sex hormone changes affect metabolic profiles longitudinally.

Longitudinal changes in the plasma metabolome with feminizing GAHT had not been previously described prior to this study.

• The authors state that 'longitudinal changes in the plasma metabolome with feminizing GAHT have not been described.'
• The study design included three time points: baseline, 3 months, and 6 months of GAHT.
• The study represents a novel contribution to understanding metabolic changes in transgender women undergoing feminizing hormone therapy.

The study design was a randomized trial comparing two anti-androgen regimens in transgender women undergoing feminizing GAHT.

• Total sample size was n = 53 transgender women.
• Participants were randomized to cyproterone acetate or spironolactone as the anti-androgen component of GAHT.
• Blood samples were collected at three time points: baseline, 3 months, and 6 months.
• An additional reference cohort of n = 3748 individuals (children and parents) was used for sex- and age-related metabolite pattern analysis.
• 249 metabolic biomarkers were measured using nuclear magnetic resonance (NMR)-based metabolomics.