British researchers say men with severe angina who wore a testosterone patch were better able to tolerate chest pain and reported a better quality of life. (Source: New Line Cinema)

Worldwide, men are twice as likely to die from coronary heart disease (CHD) than women, who appear to be protected by endogenous or exogenous estrogens. Because abuse of anabolic steroids has been linked to sudden cardiac death, it had been thought that high levels of androgens in men might have a deleterious effect on the cardiovascular system. But now it seems that androgens not only appear to have an antiatherogenic effect in men, but testosterone may be an effective antianginal agent. "In this study, we have demonstrated that daily administration of small doses of supplemental testosterone to men with chronic stable angina prolongs the time to myocardial ischemia compared with the effect of placebo," the researchers say.

In recent studies, significant improvements in angina threshold have been demonstrated in patients given supplemental IM, oral, or IV testosterone, although the doses used in most of these trials were supraphysiological and there is concern about the potential carcinogenicity of high doses of testosterone on the prostate gland. One recent study, however, looked at intracoronary administration of physiological doses of testosterone and showed that it led to an increase in coronary blood flow in men with ischemic heart disease.

In this pilot study, 46 men - who had relatively low levels of testosterone to begin with - and chronic stable angina were randomized to low-dose 2.5 mg testosterone patches (provided by SmithKline Beecham) or placebo twice-daily after a 2-week "run-in" period when all participants were on a placebo. The men all had similar coronary risk factors and continued with their normal medications.

Skin irritation at the site of patch application was reported by 11 patients on active treatment and 6 on placebo. "We used patches because these deliver a physiological (low-dose) of testosterone which mimics the normal diurnal variation. We did find some problems with skin irritation but there are other patches coming along in development which will probably be better tolerated," Dr Kevin Channer (Royal Hallamshire Hospital, Sheffield, UK), one of the study authors, told heartwire

Many of the men in the study had low or borderline levels of testosterone. When it was restored to normal levels they felt better, had more strength and were in a better mood.

Participants were given treadmill testing and quality of life questionnaires - which assessed pain perception, whether physical or emotional problems limited daily activities, social interaction, and general health perception among other things - at the beginning of the study, and again at weeks 6 and 12. They also kept diaries of angina pain. A participant's performance on the treadmill test was measured by the amount of time he could walk on the treadmill before reaching one-millimeter ST-segment depression on an electrocardiogram (ECG). ST-segment depression on an ECG is an indicator of ischemia.

The time to 1-mm ST-segment depression was not much different between the two groups of men at the beginning of the study. However, 6 weeks into the trial, the men taking testosterone lasted 34 seconds longer on the treadmill before reaching 1-mm ST-segment depression, while those on placebo improved their treadmill time by 18 seconds. At the end of the study, the testosterone group had improved their treadmill time by 52 seconds, while the placebo group improved by 25 seconds (p=0.02). The increase in time to 1-mm ST-segment depression in the placebo group was similar to that seen in other studies.

The active treatment group showed improvements in all 8 domains of quality-of-life assessments at weeks 6 and 14 compared with baseline; these changes were statistically significant for limitations resulting from physical problems (p=0.02) and pain perception (p=0.03). Not only did low-dose testosterone therapy improve pain tolerance and the men's ability to perform daily tasks despite physical limitations but it also appears to produce objective evidence of improvements in ischemia, or coronary blood flow, as measured by treadmill testing, the researchers say.

"Patients with long term problems learn to cope with angina at a certain level. The men probably noticed an improvement and began to push themselves to do more daily activities, accepting a certain level of angina," according to lead author Dr Katherine English. "The treated group reported they were able to deal with pain better. This suggests that there may be significant numbers of men with coronary artery disease who may benefit from this treatment."

"Many of the men in the study had low or borderline levels of testosterone. When it was restored to normal levels they felt better, had more strength and were in a better mood," English says, adding that the incidence and consequences of absolute or relative male hypogonadism are "poorly defined and probably underestimated."

"Evidence already suggests that androgen replacement therapy may be beneficial in elderly men, but its use remains controversial. In this study we have demonstrated that replacement of androgens to physiological levels in men with coronary artery disease improves their myocardial ischemic threshold and feeling of well-being and does not adversely affect other biochemical parameters," English adds.

Channer says he knows of no large-scale studies planned at present, but that his research team feels this is "an important area."

The researchers say their study has not determined the mechanism behind the improvement in inducible myocardial ischemia seen with testosterone. Animal studies have shown that testosterone has a vasodilatory effect and that the coronary circulation is more sensitive to this effect than larger vessels, such as the aorta. But they saw no suggestion of significant peripheral vasodilatation and although low-dose testosterone may act selectively on the coronary circulation, this is "speculative and requires further clarification," they say.