Introduction

Gender is an independent risk factor for cardiovascular disease (CVD) in men. This led in the past to the assumption that testosterone might be a factor in the development of CVD - postmenopausal women still have a lower incidence of CVD than men of similar age. Further examination suggests, however, that testosterone may have a beneficial influence on other cardiovascular risk factors; for instance, low testosterone correlates with hyperinsulinemia, a known factor for CVD. Men with low testosterone levels have a higher BMI, waist-to-hip ratio, systolic blood pressure, fasting and postprandial blood glucose, fasting insulin level, and total cholesterol, compared with men with normal testosterone levels. And there's some evidence that low testosterone is associated with an increased risk of CVD and acute ischemic stroke.^{1 , 2}

Scientists in Japan have now reported on the relationship between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes. This is a summary of their findings.

Method

The investigators measured serum free and total testosterone (F-tes and T-tes, respectively) in 253 men with type 2 diabetes. In 154 of them, carotid artery ultrasonography was done; this yielded a measure of the intima-media thickness (IMT) and plaque score (PS). All the subjects had a battery of tests that assessed the severity of their diabetes and cardiovascular risk factors.

Correlations were sought between serum F-tes and IMT, PS, and cardiovascular risk factors, including glycemic control, age, BMI, blood pressure, and serum lipids.

Results

Low serum testosterone levels were found to be associated with evidence of carotid atherosclerosis; there were significant inverse correlations between F-tes concentration and IMT and PS in the 154 subjects examined.

In addition, significant inverse correlations were found between F-tes or T-tes levels and age, age at onset and duration of diabetes, BMI, and triglyceride levels. There was a positive correlation between F-tes and total cholesterol.

Multiple regression analyses showed that F-tes and systolic blood pressure were independent determinants of mean IMT and PS. Treatment with insulin was found to be associated with markedly lower serum F-tes levels.

Comment

Just how low were the testosterone levels in these men? The means were 10.8 ± 4.2 pg/mL and 4.4 ± 1.6 ng/mL for F-tes and T-tes, respectively. Normal ranges are 14.0 - 40.0 pg/mL and 2.7 - 10.7 ng/mL, respectively. Diabetics clearly have lowered circulating testosterone levels. And the actual levels recorded correlated with increased evidence of atherosclerosis, using generally accepted measures. Interestingly, there was no correlation between F-tes and the severity of diabetic microangiopathy (retinopathy and nephropathy).

Levels of F-tes below 10 pg/mL in men with hypogonadism are generally considered an indication for testosterone replacement therapy. Roughly half the men in this study had levels below this threshold point. Should they receive testosterone replacement? This is something that will continue to be debated in the coming months and years. While the relationship between low testosterone levels and atherosclerosis seems clear, from this study, demonstration of increased risk of CVD is less well founded. Indeed, in the present study, serum testosterone levels were roughly the same in patients with and without CVD.

An accompanying editorial has tried to assess the role of testosterone in atherogenesis.³ The authors come to following conclusion: "The available data suggest that serum testosterone levels in the range that is mid-normal for healthy young men are consistent with an optimal cardiovascular risk profile at any age, and that testosterone concentrations either above or below the physiological male range may increase the risk of atherosclerotic heart disease". They go on to say that well-controlled long-term clinical trials of the effects of testosterone replacement on atherosclerosis progression and cardiovascular event rates "are long overdue".