Differences in cardiorespiratory fitness by gonadotropin-releasing hormone agonist treatment before and after testosterone in transgender adolescents

There are known sex differences in cardiorespiratory fitness (CRF). Little is known about the impact of pubertal blockade with a gonadotropin-releasing hormone agonist (GnRHa) followed by hormone therapy on CRF for transgender adolescents. We aimed to <i>1</i>) determine the effect of GnRHa monotherapy on CRF and mitochondrial function and associations with metabolomic profiles and <i>2</i>) evaluate changes after 1 and 12 mo of testosterone therapy among transgender adolescents. Participants assigned female at birth (<i>n</i> = 19, baseline age of 15.0 ± 1.0 yr) from two groups: GnRHa⁺ (<i>n</i> = 8) and GnRHa^- (<i>n</i> = 11) were examined at baseline and 1- and 12-mo post-testosterone therapy in a longitudinal observational study to assess cardiorespiratory fitness, mitochondrial respiration, and metabolic profile. Fasted morning labs included assessment of metabolomics and peripheral blood mononuclear cell mitochondrial respiration and degree of mitochondrial coupling (respiratory control ratio, RCR). A graded cycle ergometer test was performed. Baseline differences were evaluated between groups. Changes were compared with mixed linear regression models evaluating time (baseline, 1 mo, and 12 mo), group (GnRHa treatment yes/no), and their interaction. At baseline GnRHa⁺ individuals had higher relative V̇o_2peak (30.1 ± 4.83 vs. 25.24 ± 4.47 mL/kg/min, <i>P</i> = 0.042) than GnRHa^- individuals. In regression models, GnRHa⁺ individuals had a significant increase in peak watts (<i>P</i> = 0.011) and total exercise time (<i>P</i> = 0.005) after 12 mo of testosterone (<i>P</i> = 0.012) but not GnRHa^- individuals. GnRHa⁺ individuals have significantly higher RCR under carbohydrate (<i>P</i> = 0.0007) and lipid (<i>P</i> = 0.0002) conditions than GnRHa⁺ individuals. Pretreatment with GnRHa positively influences peak CRF and mitochondrial respiration in adolescent transgender males undergoing testosterone therapy.<b>NEW & NOTEWORTHY</b> This study demonstrates differences in exercise capacity and mitochondrial respiration at baseline based on whether or not individuals had feminizing puberty blocked. Individuals who had puberty blocked had greater improvements in cardiopulmonary exercise testing parameters after 12 mo of testosterone than those who went through feminizing puberty.