Impaired Cardiorespiratory Fitness in Adolescents and Young Adults With 47,XXY/Klinefelter Syndrome

ABSTRACT Background 47,XXY/Klinefelter syndrome is associated with high rates of obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Objective This study compared cardiorespiratory fitness (CRF) in adolescents and young adults (AYA) with and without XXY and investigated the relationship between CRF and other biomarkers of cardiometabolic health. We hypothesized that CRF would be lower in XXY compared to healthy male controls. Materials and Methods This cross‐sectional analysis included AYA with non‐mosaic 47,XXY ( n = 56) and 46, XY male controls ( n = 37) without hypertension, diabetes, or exercise restrictions. Participants completed graded exercise testing with oxygen consumption (VO 2 ) measured continuously. The primary outcome was VO 2 peak, with secondary outcomes including other CRF test parameters at maximal exertion and at the anaerobic threshold; as well as the prevalence of chronotropic incompetence defined as failure to achieve ≥85% of age‐predicted maximal heart rate during maximal exercise. Body composition completed via dual‐energy X‐ray absorptiometry (DXA), habitual physical activity, and serum biomarkers including lipids, hemoglobin A1c, hematocrit, and total testosterone were explored as covariates. Results Compared with controls, CRF was markedly reduced in XXY despite similar effort, with 24% lower peak VO 2 (31.2 ± 8.3 vs. 41.2 ± 7.9 mL/kg/min, p < 0.001). Chronotropic incompetence was more common in XXY (30.4% vs. 8.1%, p = 0.018) and associated with lower VO 2 peak. Anaerobic threshold occurred earlier and at lower oxygen consumption in XXY. Individuals with XXY had higher adiposity with 7.0 ± 1.3% greater body fat for a given BMI, and in multivariable models, percent fat mass was the only independent predictor of VO 2 peak ( p < 0.001). CRF was not associated with testosterone treatment status nor testosterone concentrations. Discussion AYA with XXY demonstrated reduced CRF and earlier anaerobic threshold compared with controls, indicating diminished physiologic reserve. Higher adiposity and presence of chronotropic incompetence were associated with lower fitness, suggesting multifactorial mechanisms. These results support the need for prospective studies and targeted exercise‐based interventions to improve cardiometabolic health in this population. Conclusions AYA with XXY have markedly reduced CRF driven primarily by excess adiposity, identifying an underrecognized target for early intervention to reduce cardiometabolic risk.