TOPLINE:

Men with Klinefelter syndrome (KS) showed an increased risk for metabolic conditions such as type 2 diabetes (T2D) and obesity-related disorders, regardless of diagnosis and treatment status. Undiagnosed men exhibited the most adverse metabolic phenotype, with a higher tendency for severe obesity and more late-stage T2D complications.

METHODOLOGY:

• Researchers in Denmark analysed national registry data from 1994 to 2022 to compare the incidence of metabolic disorders among men with KS who were undiagnosed, diagnosed and untreated, or diagnosed and treated with testosterone replacement therapy.
• They created matched cohorts of 508 testosterone-treated men, 2146 undiagnosed men, 2522 diagnosed and untreated men, and 46,241 control men from the background population.
• Outcomes included metabolic conditions such as incident T2D, hypertension, hypercholesterolaemia, and obesity.
• A separate T2D cohort, comprising 25 undiagnosed men, 106 diagnosed but untreated men, 86 testosterone-treated men, and 10,678 control men with T2D from the background population, was checked for diabetes-related complications.
• The study also evaluated whether parenteral vs transdermal testosterone affected the incidence of metabolic disorders in testosterone‑treated men.

TAKEAWAY:

• Testosterone‑treated men had a more than twofold higher risk for most metabolic conditions, including T2D, obesity, hypertension, and hypercholesterolaemia, than control men; this higher risk persisted irrespective of testosterone formulation.
• Compared with testosterone-treated men, undiagnosed men showed the most severe metabolic phenotype, with a tendency towards severe obesity (BMI > 40), a significantly higher risk for bariatric surgery (hazard ratio [HR], 10.60), and more late-stage T2D complications (HR, 2.83).
• Moreover, undiagnosed men had substantially lower health surveillance than testosterone-treated men, with a more than 90% reduction in blood testing (HR, 0.06).
• In the T2D cohort, all‑cause mortality after a T2D diagnosis was higher in diagnosed but untreated men than in control men (HR, 1.77); however, it did not differ significantly between testosterone‑treated and control men.

IN PRACTICE:

"T-KS [diagnosed and testosterone-treated KS] with T2DM [T2D] had reduced mortality compared with D-KS [diagnosed and untreated KS] with T2DM, which underlines the continued importance of ensuring optimal treatment of hypogonadism in KS, which again can only be achieved by ensuring early diagnosis," the authors wrote.

SOURCE:

This study was led by Simon Chang, PhD, Aarhus University Hospital, Aarhus, Denmark. It was published online on November 15, 2025, in The Journal of Clinical Endocrinology and Metabolism.

LIMITATIONS:

Potential bias from unmeasured confounders and differences in surveillance between patient groups may have affected the results. Unknown factors affecting testosterone replacement therapy could also have independently influenced the outcomes. Causal conclusions cannot be drawn on the basis of this study alone.

DISCLOSURES:

This study was supported by unrestricted research grants from multiple sources, including The A.P. Moller Foundation, Fonden af 17-12-1981, the Danish Diabetes and Endocrine Academy, and the Novo Nordisk Foundation. Few authors reported receiving unrestricted grants or honoraria for lectures from the Novo Nordisk Foundation, Aarhus University Hospital, and other sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.