Background: Sex hormones orchestrate extensive transcriptional, proteomic, and metabolic programs in skeletal muscle. Gender-affirming hormone therapy (GAHT) provides a rare human model to interrogate androgen- and estrogen-driven molecular plasticity in vivo.
Methods: Transgender men (TM) and women (TF) initiating GAHT were profiled longitudinally. Physiological assessments included circulating hormones, DXA-derived body composition, aerobic capacity, and strength. By conference time, integrated blood and muscle RNA-seq, muscle proteomics, and paired blood and muscle metabolomics datasets will be available, enabling multi-omic network reconstruction of hormone-responsive pathways. Reference transcriptomes from cisgender male and female muscle were also generated for comparative inference.
Results: After 12 months of GAHT, TM showed testosterone elevation (~3→21 nmol/L) with lean-mass gain (+3 %), fat-mass loss (–4 %), and strength increase, whereas TF showed testosterone suppression (~16→0.4 nmol/L) and estradiol rise (~64→223 pmol/L), producing opposite compositional and performance trends. TF biopsies indicated a shift toward oxidative (type I) fibre predominance. Preliminary transcriptomic integration reveals differential regulation of myogenic, mitochondrial, and inflammatory modules aligning with hormone milieu.
Conclusions: GAHT induces coordinated physiological and molecular re-programming of skeletal muscle. The forthcoming multi-omic integration will define sex-hormone–responsive gene, protein, and metabolite networks in human tissue, providing mechanistic insight into endocrine regulation of muscle function and informing precision exercise and health strategies across diverse populations.