Metabolism and Type 2 Diabetes Across Life Stages in Klinefelter Syndrome: A Population-Based Cohort Study

CONTEXT: Klinefelter syndrome (KS) is underdiagnosed, undertreated, and associated with metabolic dysfunction. OBJECTIVE: 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 control individuals. We evaluated the effect of parenteral vs 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 2-fold 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 nondifferential 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 vs transdermal testosterone supplementation in T-KS. CONCLUSION: 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.