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

Jessica A Kerr, Boris Novakovic, Jeffrey D Zajac, Toby Mansell, Katherine Lange, David Burgner, Richard Saffery, Rebecca Shepherd, Lachlan M Angus, Bridget Arman, Bo Won Kim, Ken Pang, Ada Cheung

Journal: The Journal of clinical endocrinology and metabolism 2024;109(11):2857-2871

PMID: 38609170

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Abstract

CONTEXT

The plasma metabolome is a functional readout of metabolic activity and is associated with phenotypes exhibiting sexual dimorphism, such as cardiovascular disease. Sex hormones are thought to play a key role in driving sexual dimorphism.

OBJECTIVE

Gender-affirming hormone therapy (GAHT) is a cornerstone of transgender care, but longitudinal changes in the plasma metabolome with feminizing GAHT have not been described.

METHODS

Blood samples were collected at baseline and after 3 and 6 months of GAHT from transgender women (n = 53). Participants were randomized to different anti-androgens, cyproterone acetate or spironolactone. Nuclear magnetic resonance-based metabolomics was used to measure 249 metabolic biomarkers in plasma. Additionally, we used metabolic biomarker data from an unrelated cohort of children and their parents (n = 3748) to identify sex- and age-related metabolite patterns.

RESULTS

We identified 43 metabolic biomarkers altered after 6 months in both anti-androgen groups, most belonging to the very low- or low-density lipoprotein subclasses, with all but 1 showing a decrease. We observed a cyproterone acetate-specific decrease in glutamine, glycine, and alanine levels. Notably, of the metabolic biomarkers exhibiting the most abundant "sex- and age-related" pattern (higher in assigned female children and lower in assigned female adults, relative to assigned males), 80% were significantly lowered after GAHT, reflecting a shift toward the adult female profile.

CONCLUSION

Our results suggest an anti-atherogenic signature in the plasma metabolome after the first 6 months of feminizing GAHT, with cyproterone acetate also reducing specific plasma amino acids. This study provides novel insight into the metabolic changes occurring across feminizing GAHT.

Address: Molecular Immunity, Infection and Immunity Theme, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.; Department of Medicine (Austin Health), The University of Melbourne, Parkville, VIC 3052, Australia.; Department of Endocrinology, Austin Health, Heidelberg, VIC 3084, Australia.; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.; Inflammatory Origins, Infection and Immunity Theme, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.; Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia.; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia.; Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia.; Molecular Immunity, Infection and Immunity Theme, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.; The Centre for Community Child Health, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.; Department of Psychological Medicine, University of Otago, Christchurch 8011, New Zealand.; Murdoch Children's Research Institute, Centre for Adolescent Health, Population Health Theme, Parkville, VIC 3052, Australia.; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.; Brain and Mind Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.; Department of Adolescent Medicine, Royal Children's Hospital, Parkville, VIC 3052, Australia.

DOI: 10.1210/clinem/dgae226

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MeSH Terms: Humans, Female, Androgen Antagonists, Metabolome, Male, Cyproterone Acetate, Adult, Transgender Persons, Biomarkers, Young Adult, Gender-Affirming Procedures, Spironolactone, Child, Metabolomics, Adolescent, Transsexualism, Hormone Replacement Therapy, Middle Aged