With increasing visibility of transgender populations, gender-affirming hormone therapy (GAHT) has become a pivotal component of healthcare for individuals aligning their physiology with their gender identity. GAHT involves administering testosterone for transgender men (TM) and estrogen for transgender women (TW), impacting not only skeletal muscle composition but also the molecular and genomic profiles within muscle tissue. This study explores GAHT’s influence on muscle transcriptomics, aiming to reveal genomic factors that underpin these physiological adaptations.
We conducted a longitudinal study, collecting blood samples, skeletal muscle biopsies, and fitness measurements, including VO₂max and strength tests, at baseline (prior to GAHT) and at 6 and 12 months post-GAHT commencement for TM, TW, and cisgender control groups. RNA was extracted from muscle biopsies at baseline and 12-month timepoints, and RNA-sequencing (RNA-seq) was performed to capture transcriptomic changes over time. Initial analyses of publicly available datasets (35 datasets, 1600 samples) have revealed a distinct transcriptomic signature in skeletal muscle for cisgender males and females, establishing a foundation for comparative analysis of GAHT-induced changes in transgender individuals. Through meta-analysis, we aim to identify the molecular changes occurring in response to GAHT and correlate these with physiological outcomes, such as VO₂max and/or strength.
Testosterone therapy in TM is hypothesised to promote anabolic pathways that contribute to increased muscle mass and altered muscle characteristics, whereas estrogen therapy in TW may lead to different genomic adaptations that affect muscle structure and metabolic function. By examining these hormone-driven molecular changes, this research aims to deepen understanding of GAHT’s impact on skeletal muscle health and inform clinical practices in transgender healthcare.