Testosterone therapy without documented evidence of deficiency associated with higher long-term cardiovascular risk: Findings from a global real-world study of over 350,000 men

One in three men had no documented evidence of deficiency

Testosterone therapy has become one of the most frequently prescribed hormone treatments in men worldwide. Current medical guidelines restrict its use to men with confirmed testosterone deficiency. Nevertheless, approximately one in three men initiating testosterone therapy in this study - around 127,000 of 358,957 men - had no recorded diagnosis, no documented low testosterone measurement, and no related symptoms before treatment began.

After statistically matching both groups on relevant clinical characteristics, men without documented evidence of deficiency showed a ten-year risk of major adverse cardiovascular events of 16.5%, compared with 11.8% in men treated in the setting of documented hypogonadism. All-cause mortality was 10.7% versus 6.0% over ten years. Elevated risks were also observed for ischaemic stroke, cardiac arrest, and heart failure. A negative control outcome - acute appendicitis, a disese with no plausible biological link to testosterone - showed no association, supporting the specificity of the cardiovascular findings.

A study that could not ethically be conducted as a clinical trial

The research team emphasises that these findings are observational and that the observed associations do not establish causation. Residual confounding, including missing documentation and false coding, unmeasured lifestyle factors, treatment adherence, dose, and prescribing setting, cannot be excluded. Importantly, over 90% of men in the "without evidence" group had no documented testosterone measurement before treatment, meaning this group is best understood as a proxy for potentially non–guideline-concordant prescribing rather than as confirmed biochemical eugonadism.

"This question cannot be answered by a randomised clinical trial," said Professor Ralf Ludwig, senior and corresponding author and Director at the Lübecker Institut für Experimentelle Dermatologie (LIED), University of Luebeck and UKSH. "Intentionally randomising men without confirmed deficiency to long-term testosterone exposure would be ethically unjustifiable. Retrospective analysis of large-scale real-world data is therefore the only realistic approach to study this at the scale and follow-up duration needed."

 From thesis defence to global dataset

The project has an unusual origin. It grew out of the doctoral thesis defence of Dr. Hatim Kerniss, cardiologist at the University Heart Centre Frankfurt and first author of the study, where Professor Ludwig served as head of the thesis commission. A scientific discussion about gaps in cardiovascular epidemiology (the topic of the thesis) during and after the defence led directly to a collaborative session on the TriNetX real-world data platform, and ultimately to several joint studies, including this.

 An interdisciplinary team across four countries

The study unites clinicians and researchers from cardiology, endocrinology, epidemiology, and dermatology (the latter contributing expertise in large-scale real-world evidence methodology). The team spans Germany (University Heart Centre Frankfurt, UKSH/University of Luebeck, German Centre for Cardiovascular Research DZHK), Sweden (Karolinska University Hospital and Karolinska Institutet), the United Kingdom (University of Liverpool, Liverpool University NHS Foundation Trust, Essex Cardiothoracic Centre), and Israel (Bar-Ilan University).

 Funding

The study was supported by the Deutsche Forschungsgemeinschaft (DFG) through the Cluster of Excellence Precision Medicine in Chronic Inflammation (PMI, EXC 2167), the Collaborative Research Centre PANTAU (SFB 1526), and an Individual Research Grant to Professor Ludwig (LU 877/25-1), as well as the Schleswig-Holstein Excellence-Chair Program. Co-author Dr Philip Curman was supported by Region Stockholm.

The authors call for guideline-concordant diagnostic evaluation before testosterone therapy initiation, close cardiovascular monitoring during treatment, and further mechanistic research to understand the biological basis of the observed patterns.