Hormone affects heart patients' risk

A study has found that “men with higher testosterone levels are less likely to die of heart disease”, reports The Daily Telegraph .

This seven-year study of 930 men with heart disease found that those who had low testosterone had a greater risk of dying from any cause and of dying from a vascular cause. This appears to be a reliable association, and one that is clearly worthy of further investigation.

However, these results cannot be used to conclude that men with testosterone deficiency are more likely to have heart disease. This study did not have a comparison group of healthy men, and found no evidence that there is a higher prevalence of testosterone deficiency among men with coronary artery disease, or that lower testosterone directly plays a role in the development of heart disease.

The reasons why men with heart disease and testosterone deficiency may have higher mortality rates cannot be established from this research alone. It could be that testosterone is an independent risk factor for mortality, or that both low testosterone levels and higher mortality risk are linked to another disease process in the body. As such, it is also not possible to say whether hormone replacement therapy would be of benefit. This study raises important questions and further research is anticipated.

Where did the story come from?

The study was carried out by researchers from Royal Hallamshire Hospital, Sheffield, the University of Sheffield Medical School, and Barnsley Hospital. Funding was provided by the South Sheffield Charitable Trust. The study was published in the peer-reviewed medical journal Heart .

The Daily Mail and The Daily Telegraph have been overly optimistic about these findings. The Telegraph implies that a protective factor has already been found and that "more aggressive men" are less likely to die of heart disease. The Mail says that "many men at risk of heart disease would benefit from testosterone replacement therapy". Neither of these points are supported by the current research, which cannot establish whether testosterone is a causative factor in the development of heart disease or whether it directly influences mortality risk.

What kind of research was this?

This cohort study investigated how testosterone levels affect the survival of men with coronary heart disease. It is known that men have a higher risk of coronary heart disease and death from heart disease than women, but it is not known why.

The researchers say that it is a common assumption that testosterone is bad for the cardiovascular system and that it contributes to the risk of heart disease. There is little evidence that this is the case, however. Previous studies have shown that testosterone is actually beneficial for men with cardiac disease, and that testosterone therapy is associated with positive cardiovascular health factors and outcomes. Meanwhile, low testosterone levels have been linked with other cardiovascular risk factors, such as higher lipids, obesity and diabetic tendency. Ageing is also associated with a low testosterone level (affecting an estimated 30% of men over 60).

This study aimed to examine the theory that low testosterone is associated with adverse survival.

What did the research involve?

This study recruited 930 men (average age 60) from a specialist cardiac centre between June 2000 and June 2002. All the men were undergoing coronary angiography, a type of X-ray where dye is injected into the arteries to show up where and how severely the blood vessels have narrowed.

On the morning of their procedure, the men completed questionnaires on their medical history, and had several body measurements taken. Men were excluded if they had a heart attack within the past three months or they had other inflammatory or medical conditions that can affect testosterone levels.

The men’s testosterone levels were measured after the angiography. Men whose angiography revealed normal healthy coronary arteries were then excluded. As testosterone levels can be affected by stress, a further measurement was taken in a sample of the group two weeks later.

The men were tracked through the Office of National Statistics to notify the researchers when any of them died and the cause of death. The current analysis was performed an average 6.9 years later in 2008.

The researchers were interested in the relationship between testosterone levels and death from all causes and vascular deaths (attributed to atherosclerotic vascular disease, heart failure or heart attack). Hypogonadism (symptoms and biochemical evidence of testosterone deficiency) was defined as a total testosterone level of less than 8.1nmol/L, or a bio-available testosterone level of less than 2.6nmol/L. Total testosterone refers to the total amount of testosterone in the body, that which is freely circulating in the blood and that which is bound to proteins. Only the freely circulating unbound testosterone is active testosterone that is available for use. This is therefore termed bio-available testosterone.

The researchers adjusted their analyses between testosterone and mortality for any factors that were also found to be linked to higher mortality (in this case, poor left ventricular function, aspirin therapy and beta-blocker therapy).

What were the basic results?

The mean (average) total testosterone levels in the total sample were 12.2 to 12.4nmol/L. After 6.9 years of follow-up, 129 of the 930 men had died, with 73 deaths related to a vascular cause.

When the relationship between all medical factors and all-cause mortality was examined, poor function of the left ventricle was found to be associated with higher mortality risk. Use of beta blockers was also associated with lower mortality risk. Use of aspirin was associated with a borderline reduced risk.

Men who had testosterone deficiency as defined by a bio-available testosterone level of less than 2.6 nmol/L, had a greater risk of dying from any cause than men with a higher level, and of dying from a vascular cause (respectively - hazard ratio 2.2, 95% confidence interval [CI] 1.4 to 3.6) and HR 2.2, 95% CI 1.2 to 3.9).

The prevalence of hypogonadism (testosterone deficiency) was 20.9% of the sample using the cut-off of bio-available testosterone level of less than 2.6nmol/L; and 16.9% when using the cut-off of total testosterone of less than 8.1nmol/L. Using either of these definitions, there was a 24% prevalence of hypogonadism. Comparing these men to those without testosterone deficiency, there was significantly higher all-cause mortality during follow-up among men with hypogonadism (21%) than in men without testosterone deficiency (12%).

There was no difference in the prevalence of testosterone deficiency among the 930 men with coronary artery disease (24%) and the 148 who were excluded from the study because they had normal coronary arteries on the angiography (28%).

How did the researchers interpret the results?

The researchers conclude that testosterone deficiency is common among people with coronary artery disease, and it has a negative effect on survival. They recommend that prospective trials of testosterone replacement are needed to assess whether such treatment could influence survival.

Conclusion

This study demonstrated that there was a relatively high prevalence of testosterone deficiency among 60-year old men with established coronary artery disease. This deficiency was associated with a greater risk of dying over a seven-year follow-up period. However, there a few important points to bear in mind:

Of the 930 men with coronary artery disease (CAD) who were included in the study, 24% were defined as having testosterone deficiency. This is a similar proportion (28%) to that found in the 148 men who were excluded because their angiography did not indicate CAD. Therefore, it cannot be concluded that there is a higher prevalence of testosterone deficiency among men with CAD. To show this, the study would have needed to compare these men to a random sample of men from the general population. These results in fact indicate a high possibility that the prevalence of testosterone deficiency among 60-year-old men with CAD is no different from that in the general population.

Following on from this point, and the fact that testosterone samples were taken at the time when CAD had already been established, the study cannot provide any evidence that low testosterone levels may or may not have a causative role in the initial development of heart disease.

A comparison random sample of men from the general population without coronary artery disease would be beneficial, not only to indicate more reliably the true prevalence of testosterone deficiency among men of this age group, but also to see whether testosterone is associated with all-cause mortality during follow-up of healthy men without heart disease.

Within the sample of 930 men with confirmed CAD, having testosterone deficiency (a level below a cut-off threshold) was associated with a higher risk of death from any cause and of death from a vascular cause. This is clearly a finding worthy of further study. It is possible that once a man has developed CAD, testosterone may be an independent risk factor for cardiovascular mortality. However, it is also possible that lower testosterone levels indicate another underlying disease process that is increasing cardiovascular disease risk (this would confound the relationship between testosterone and mortality).

As the researchers acknowledge, it is not known what medical care or vascular events these men received after their initial angiography. This could have included medical treatment, revascularisation procedures or complications, which could have affected both hormone levels and mortality risk.

As such, taking all of these points into consideration, it is not possible to say at this stage whether some form of ‘hormone replacement therapy’ would be beneficial in men with coronary artery disease. This study raises important questions, and further randomised trials are anticipated.