Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men

November 2015

Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial.
Basaria S, Harman SM, Travison TG, et al. JAMA. 2015;314(6):570-581.

Currently there are only a few high quality studies investigating the effects of testosterone therapy for a duration of 3 years^1-4, and medical societies have long been urging for more long-term studies evaluating the safety and efficacy of testosterone therapy.^5-7

On August 11th 2015 a notable 3-year long RCT was published in JAMA (Journal of the American Medical Association), which attracted a lot of attention.⁸ While interpreted by many as showing that testosterone therapy does not confer any benefits on atherosclerosis, sexual function and quality of life, a closer look at the data actually does show two important findings.

KEY POINTS

The results of the 3-year long JAMA study were reported in the abstract as mainly neutral, concluding that testosterone therapy did not affect markers of atherosclerosis (intima-media thickness and coronary artery calcium score), nor improve overall sexual function or health-related quality of life.
As expected, hematocrit and PSA levels increased more in the testosterone group, but values stayed largely within the normal range. This within-normal-range increase is a physiological response to testosterone therapy.
Two important positive outcomes, which were not mentioned in the study abstract, were:
- The number of subjects reporting adverse events or serious adverse events did not differ between testosterone and placebo groups. This confirms that testosterone therapy is safe, even in men over 60 years of age.
- In men not taking statins, one marker of atherosclerosis (coronary artery calcium) was significantly lower in the testosterone group than in the placebo group.
An important problem of the study, also not mentioned in the abstract, was that testosterone levels declined over time, despite dose-adjustments aiming to achieve testosterone levels between 500 and 900 ng/dL. This suggests low adherence and sub-optimal testosterone therapy.

What is known

Evidence for and against testosterone therapy is conflicting. Previous studies have shown an increase (in men with pre-existing morbidities)⁹ or no increase in adverse events¹⁰, and either increased^11,12 or reduced^13-15 risk of stroke and heart attacks. Three other studies even show increased longevity (reduced mortality risk) with testosterone therapy.^14,16,17

Heart disease is caused by atherosclerosis.¹⁸ Two common techniques for measuring subclinical atherosclerosis – which reflects lifetime risk factor exposure¹⁹ – is carotid intima-media thickness (CIMT) and coronary artery calcium (CAC).

CIMT has been validated as a measure of the atherosclerotic burden²⁰ and of the risk for cardiovascular events.²¹ CAC reflects atherosclerotic plaque burden, because calcium deposits are related to the lipid and apoptotic remnants of the plaque.²²

Many studies show that low testosterone levels are associated with increased atherosclerotic burden (measured by CIMT)^23-33, and clinical trials of testosterone therapy have shown significant reductions in CIMT.^34,35

What this study adds

The new study in JAMA aimed to determine the effect of testosterone administration on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels.⁸

156 participants were randomized to receive 7.5 g of 1% testosterone gel and 152 were randomized to receive placebo gel daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL (see commentary below).

Results showed that testosterone therapy did not affect markers of atherosclerosis (intima-media thickness and coronary artery calcium score), nor improve overall sexual function or health-related quality of life.

Testosterone therapy elevated hematocrit and PSA levels increased more in the testosterone group, but values stayed largely within the normal range. The number of participants reporting adverse events or serious adverse events did not differ between groups.

Two important positive outcomes, which were not mentioned in the study abstract, were:

The number of subjects reporting adverse events or serious adverse events did not differ between testosterone and placebo groups. This confirms that safety is not a major issue in testosterone therapy.
In men not taking statins, one marker of atherosclerosis (coronary artery calcium) was significantly lower in the testosterone group than in the placebo group.

Commentary

The finding that hematocrit and PSA elevations largely stayed within normal range, and that the number of participants reporting adverse events or serious adverse events did not differ between groups, is positive news, especially considering that this is one of the few long-term studies in men of advanced age (mean age 67 years).

There are several issues with this study. An important methodological problem - also not mentioned in the abstract - was that testosterone levels declined over time despite dose-adjustments aiming to achieve testosterone levels between 500 and 900 ng/dL. This suggests low adherence and sub-optimal testosterone therapy. This was not reported in the study abstract or in media press releases.

Thus, the conclusion that testosterone therapy (that maintains effective therapeutic testosterone levels throughout the treatment duration) does not reduce atherosclerosis progression, is be premature.

Another important issue is that two thirds of the subjects in the testosterone group were taking statins. It is well-documented that statins^36-38 - which are widely prescribed to treat elevated cholesterol – significantly reduce testosterone levels in men. Hence, it is possible that statins could partly counteract benefits of testosterone therapy, which in this case would be the rate of progression (or regression) of subclinical atherosclerosis.

Regarding safety, it should be pointed out that the hematocrit and PSA elevations in the testosterone group stayed within the normal range, and are to be expected with testosterone therapy. More importantly, the number of subjects reporting adverse events or serious adverse events did not differ between testosterone and placebo groups. These are solid data supporting the concept that testosterone therapy does not increase atherosclerosis / cardiovascular risk – and may actually reduce it in men who are not taking statins - and confirms that long-term testosterone therapy is probably safe.

Regarding sexual function, most of the testosterone treated men already had good sexual function at baseline, and thus it is unrealistic to expect sexual function to improve, especially considering that the treatment failed to maintain effective therapeutic testosterone levels thoughts the 3 year treatment.

Finally, it is critical to remember that each androgen dependent effect has its own testosterone threshold.³⁹ Lack of improvement in sexual function and quality of life – two outcomes that require only relatively low testosterone levels⁴⁰ – does not mean that other effects (such as subclinical atherosclerosis, body fat loss and muscle gain) would not improve from testosterone therapy that achieves a higher and sustained therapeutic elevation in testosterone levels. In fact, previous studies that did achieve effective therapeutic testosterone levels for a sufficient duration have shown reductions in subclinical atherosclerosis^34,35, and previous 3-year long testosterone therapy studies did report significant body fat loss and increases in lean body mass (muscle) gain.^2,41

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References

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