Low Testosterone in Klinefelter Syndrome Identified by Waist Circumference

A simple tape measure is proving more effective than complex mathematical formulas at flagging low testosterone in untreated men with Klinefelter syndrome.

Published online in The Journal of Clinical Endocrinology & Metabolism, the study evaluated 328 men with genetically confirmed Klinefelter syndrome. Led by Andrea Graziani of the Department of Medicine at the University of Padua in Italy, researchers sought a way for clinicians to spot biochemical hypogonadism without relying on intricate metabolic scores.

A Closer Look at the Cohort

Klinefelter syndrome is the most common sex chromosome condition in men and a leading genetic cause of male infertility. Affected individuals face elevated rates of type 2 diabetes and metabolic syndrome.

To determine how standard markers apply to this population, investigators reviewed hospital records from January 2005 through December 2024 at a university hospital in Italy. The retrospective analysis focused on men with a median age of 31 and a median body mass index of 24.8. None had received testosterone replacement therapy before their initial clinic visit.

Diverging Baselines and Waist Sizes

Low calculated free testosterone was defined as a concentration below 0.220 nmol/L. Out of the total cohort, 213 participants—or 64.9%—met this threshold.

Patients with low testosterone tended to be older, with a median age of 33.9 compared to 26.4 years for men with normal levels. They also carried a larger waist size, registering a median waist circumference of 101 centimeters versus 87 centimeters, alongside higher rates of dyslipidemia and impaired fasting glucose or diabetes.

The prevalence of low testosterone climbed steadily alongside waist measurements. It rose from 36.6% in the lowest quartile to 89.4% in the highest quartile.

Outperforming Complex Diagnostic Tools

When researchers evaluated various diagnostic tools, waist circumference achieved the highest area under the curve at 0.747. That performance outpaced the lipid accumulation product at 0.704 and the triglyceride-glucose index at 0.612.

While the homeostatic model assessment of insulin resistance reached an area under the curve of 0.681, it did not demonstrate a statistically significant difference when compared directly to waist circumference.

Adjusting for age revealed that each additional centimeter of waist size correlated with a 5% increase in the odds of low testosterone. Furthermore, incorporating waist circumference into age models boosted the area under the curve from 0.744 to 0.796, whereas adding the lipid accumulation product yielded only a small, nonsignificant gain.

These findings support the use of parsimonious and easily applicable approaches for endocrine-metabolic stratification in KS. WC is inexpensive, universally available, rapidly obtainable and easily interpretable in routine clinical practice. Simple anthropometric assessment may support endocrine-metabolic stratification in patients with KS,

Andrea Graziani et al., The Journal of Clinical Endocrinology & Metabolism

Methodological Limitations

Study authors acknowledged several limitations tied to their design. The retrospective and cross-sectional nature of the research prevents any definitive establishment of a causal relationship between metabolic changes and testosterone status.

Because the project took place at a single university hospital center in Italy, the outcomes may not apply to other settings. Additionally, while the dataset represents a substantial cohort for a rare genetic condition, some data were missing, and the main analyses included only men with complete records.