Cambridge, UK - High endogenous levels of testosterone in men are associated with low mortality from all causes, cardiovascular causes, and cancer, a new study shows, and the authors suggest that low testosterone may be a predictive marker for those at high risk of cardiovascular disease [1].

The study, published online November 26, 2007 in Circulation, found an inverse relation between endogenous testosterone concentrations and mortality due to cardiovascular disease, cancer, and all causes.

Lead author Dr Kay-Tee Khaw (University of Cambridge School of Clinical Medicine, UK) commented to heartwire: "This is the largest study of testosterone levels ever conducted. We don't know whether the association shown between higher levels of testosterone and lower mortality is causal or just a marker of something else, but regardless of this, it appears that low testosterone levels do identify a group at increased risk of cardiovascular death who could benefit from more aggressive treatments in terms of cholesterol and blood-pressure lowering."

She added that it was far too soon to be recommending testosterone supplementation, but this study should ease the concerns that have prevented studies of such interventions from being conducted. She explained: "There has been a worry that testosterone supplementation may increase the risk of prostate cancer, but we did not see any more cases of prostate cancer in men with higher testosterone levels compared with those with lower levels. This is reassuring and should open the way for studies of testosterone supplementation in men with low levels to take place."

She said that research into raising testosterone levels in men has also been hampered somewhat by the negative results with estrogen replacement in women. "The observational studies of estrogen replacement in women were encouraging, but randomized controlled trials actually showed harm. That has put people off the idea of hormone therapy in men as well. But the observational studies in women were mainly with estrogen supplements and suffered from many biases, as women who took estrogen supplements were different in many other ways from women who didn't. In contrast, our study in men looked at endogenous testosterone levels, which should have fewer biases," Khaw said.

In the paper, Khaw and her colleagues note that the role of testosterone in men's health is controversial. High doses of exogenous testosterone or other anabolic steroids have been associated with adverse health effects, including sudden cardiac death and liver disease, but hypogonadism in men is also adversely associated with health, and the use of lower doses of exogenous testosterone is increasingly widespread because of the belief that supplementation has benefits for well-being. They add that high endogenous testosterone concentrations in men are associated with a more favorable cardiovascular disease risk-factor profile, including higher HDL levels and lower blood pressure, triglycerides, and glucose concentrations, but prospective studies to date have not found significant relationships between endogenous testosterone concentrations and cardiovascular disease events. In addition, high endogenous testosterone concentrations have been postulated to be a risk factor for prostate cancer, although again, prospective studies have found no consistent relationships.

Noting that most of these studies have had limited power for disease events, they analyzed data on testosterone levels from the large European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study conducted between 1993 and 2003. They examined the prospective relationship between endogenous testosterone concentrations and mortality due to all causes, cardiovascular disease, and cancer in a nested case-control analysis of the 11 606 men who participated in the study. Among those without cancer or cardiovascular disease at baseline, 825 men who subsequently died were compared with a control group of 1489 men still alive, matched for age and date of baseline visit. Of the 825 deaths in the study, 369 were attributed to cardiovascular disease and 304 to cancer.

Results showed that endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes, cardiovascular disease, and cancer.

Compared with men who had testosterone levels of 12.5 nmol/L or less, men with testosterone levels of at least 19.6 nmol/L had a 41% lower risk of dying in 10 years. For every 6-nmol/L increase in endogenous testosterone, the risk of death decreased 14%.
 
The authors say that although they cannot exclude residual confounding from other factors not measured here, "these findings are consistent with existing evidence from epidemiological and clinical studies indicating that endogenous testosterone concentrations may be an indicator of good health." The link between testosterone and mortality could provide insights and better understanding of disease mechanisms and hence the possibility of new therapeutic pathways, they comment.

But they caution that that these results require replication in other population studies, adding that the adverse results of HRT trials in women emphasize the necessity for end-point trials. They note that paradoxically, although many men are already using testosterone supplementation, concern about increased cancer risk has been one reason trials have not been conducted in this area. But now data from this study should encourage further research into the role of testosterone in health in men, they conclude.