Simple treatment can save lives for men with a common chromosomal disorder

More than half of all men with Klinefelter syndrome (KS) are unaware that they have the condition. Among those who do receive a diagnosis, only about half get the treatment they need.

Now, a Danish study reveals that testosterone treatment not only improves quality of life—it can also save lives.

Klinefelter syndrome is the most common sex chromosome disorder in men, affecting approximately one in 600 male births.

The condition results from being born with an extra X chromosome, leading to low testosterone production, which in turn increases the risk of cardiovascular disease, type 2 diabetes, and overall higher mortality rates.

“Our previous studies have shown that men with KS have a significantly higher risk of developing a range of diseases. However, we did not know to what extent testosterone treatment could reduce this risk. Until now, no large studies have been able to document the actual clinical effects of treatment,” explains postdoc and MD Simon Chang from Aarhus University and Aarhus University Hospital, describing the motivation behind the study.

Mortality rates on par with the general population

This is the first study of its kind and shows that testosterone treatment nearly halves the mortality rate among men with KS.

Male participants who received treatment lived significantly longer than untreated men, with their mortality rate approaching that of the general population.

“This is an extremely important discovery because it means that we can save lives by providing the right treatment. Today, only half of diagnosed men with KS receive the necessary testosterone therapy,” says Simon Chang.

A powerful hormone

Researchers cannot yet fully explain why the treatment leads to such a significant reduction in mortality.

According to Simon Chang, the effect may be linked to improved metabolism, increased muscle mass, and reduced body fat as a result of testosterone therapy.

“Testosterone is a powerful hormone that affects nearly every function in the body. We also suspect that it may have positive effects on the immune system, bone health, and possibly even cognitive functions,” he explains.

The study, he adds, underscores the importance of identifying more men with KS who remain undiagnosed. More than half of those born with KS are never diagnosed, even though a simple screening test at birth could identify the syndrome through the routine blood sample taken from all newborns.

Testosterone is safe—but what about side effects?

The study confirms that testosterone therapy does not increase the risk of serious cardiovascular diseases, heart attacks, or strokes.

However, there is a slightly increased risk of heart failure among men receiving treatment.

“It is important to emphasize that the benefits far outweigh the potential drawbacks. The reduction in mortality is so significant that it outweighs concerns about a potential increased risk of heart failure,” says Simon Chang.

New guidelines on the way

International guidelines for the treatment of KS are currently in development and are expected to be presented in 2027.

Simon Chang anticipates that the study’s results will directly influence these guidelines, potentially improving, prolonging, and saving lives for many men with KS.

“We expect the new guidelines to recommend initiating testosterone treatment as soon as the diagnosis is made,” he concludes.

Behind the research findings

Study Type: Register-based cohort study

Collaborators: Aarhus University Hospital, Department of Clinical Epidemiology, Department of Clinical Genetics, and Department of Molecular Medicine

External Funding: A.P. Møller Foundation, Danish Diabetes and Endocrine Academy, Novo Nordisk Foundation, Independent Research Fund Denmark, Sygesikringen danmark

Potential Conflicts of Interest: None

Link to Scientific Article: Cardiovascular risk and mortality in men receiving testosterone replacement therapy for Klinefelter syndrome in Denmark: a retrospective cohort study - The Lancet Regional Health – Europe