Metabolism and type 2 diabetes across life stages in Klinefelter syndrome: a population-based cohort study

Background Klinefelter syndrome (KS) is underdiagnosed, undertreated, and associated with metabolic dysfunction. We compared incidences of metabolic disorders among men with KS, either undiagnosed (U-KS), diagnosed and untreated (D-KS), or treated with testosterone replacement therapy (T-KS). Methods This was a national Danish registry-based study from January 1994 to December 2022. We computed hazard ratios (HR) for incidence and severity of metabolic disorders between risk set matched strata of U-KS, D-KS, and T-KS and male controls. We evaluated the effect of parenteral versus transdermal testosterone supplementation on incidence of metabolic disorders in T-KS, applying inverse probability weighting. Results We included 508 age-matched strata of U-KS, D-KS, and T-KS, and included 46,241 male controls. Incidence of metabolic conditions was more than twofold increased in KS, including type 2 diabetes (HR 2.56 (1.85-3.44)). U-KS presented with the most severe metabolic phenotype, with more obesity and more late-stage diabetes complications compared with T-KS (HR 2.83 (1.33-6.02)). All-cause mortality following diagnosis of type 2 diabetes was increased in D-KS compared with controls (HR 1.77 (1.28-2.45)), but non-differential for T-KS and controls (HR 1.30 (0.68-2.48)). We saw a pattern of less obesity and type 2 diabetes, but more hypertension and hypercholesterolemia, with parenteral versus transdermal testosterone supplementation in T-KS. Conclusions The metabolic profile in men with KS is dependent on diagnosis and treatment status, with pronounced metabolic dysfunction in U-KS. Better diagnosis and treatment of KS are needed to alleviate metabolic dysfunction and improve survival in men with KS.