Testosterone Supplementation Does Not Alter Atherosclerosis Progression in Men With Low or Low-Normal Testosterone Levels
Introduction: The benefits and risks of long-term use of testosterone supplementation in older men with age-related low testosterone levels are poorly understood. While some studies have reported an association between low testosterone levels and increased risk of diabetes, metabolic syndrome, cardiovascular disease (CVD), and mortality, other studies have not shown a consistent association between testosterone levels and CVD events. The study authors cited a lack of research on the long-term consequences of testosterone supplementation on atherosclerosis in older men.
Methods: Researchers randomized 308 men (age ≥60 years) with low or low-normal testosterone levels to 7.5 g of 1% testosterone gel (n=156) or placebo gel (n=152) daily for 3 years. The testosterone dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL. The two groups had similar characteristics at baseline: average age, 68 years; 42% had hypertension; 15% had diabetes; 15% had CVD; and 27% were obese. The primary outcome measure was atherosclerosis progression as measured by changes in common carotid artery intima-media thickness or coronary artery calcium.
Results: Rates of subclinical atherosclerosis progression did not differ significantly between the testosterone and placebo groups (0.012 mm/year and 0.010 mm/year, respectively; mean difference adjusted for age and trial site, 0.0002 mm/year; 95%CI, −0.003 to 0.003, P=0.89). In addition, changes in intima-media thickness or calcium scores were not associated with the change in testosterone levels in the testosterone group.
Furthermore, the two groups did not differ in terms of the following secondary outcomes: sexual desire, erectile function, overall sexual function scores, partner intimacy, health-related quality of life and physical functioning, and serum lipid and blood glucose levels. In contrast, the testosterone group did show significantly greater increases in hemoglobin (model-estimated mean difference, 0.53 g/dL; P<0.001) and prostate-specific antigen levels (model-estimated mean difference, 0.28 ng/mL; P<0.01) compared with the placebo group.
Conclusion: Testosterone administration for 3 years did not affect the rate of atherosclerosis progression compared with placebo among older men with low testosterone levels. The authors noted that because the trial was only powered to evaluate atherosclerosis progression and not cardiovascular events, these findings should not be extrapolated to imply that testosterone is safe with respect to cardiovascular events. In addition, the cohort was not limited to men with hypogonadism men as established by the Endocrine Society Guidelines.
Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in neuroendocrinology and reproductive endocrinology. She is the Director of the NYU Langone Medical Center Pituitary Center in New York, NY, as well as an Attending in Medicine at Massachusetts General Hospital, Boston, MA.
Given the increasing use of testosterone in men, and the early termination of the TOM (Testosterone in Older Men with Mobility Limitations) trial due to cardiovascular events, Basaria and colleagues set out to investigate the effect of raising low or low-normal testosterone in older men to mid-normal levels (using reference range established in younger men) on of subclinical atherosclerotic progression.
This TEAAM (Testosterone's Effects on Atherosclerosis Progression in Aging Men) study was a placebo-controlled, double-blind randomized clinical trial looking at the use of testosterone (T) vs placebo over a 3-year period. The study included men with baseline T levels 100-400 ng/dL, stratified by age (60-70 years and >75 years; mean age was 67.6 years). Men had BMI ≤35 kg/m2. Subgroup analyses included men with obesity, diabetes, coronary artery disease (CAD), and no coronary calcium.
Testosterone gel formulation was used. Goal testosterone on treatment was 500-900 ng/dL (mid-normal range as established in younger men). Using EPAT (Estrogen in the Prevention of Atherosclerosis Trial) as a guide for estimating sample size, the authors began with a cohort of 250; the sample size was increased to 300 given a 30% dropout rate. Compliance was gauged by the number of used vs unused gel packs, and was found to be 95% in each arm. (Each study arm received 3 gel packs for daily application; the testosterone arm's treatment included 1 placebo pack.)
Primary outcomes were measurements of atherosclerosis via B-mode intima-media thickness (IMT) of the distal right common carotid artery, or proximal coronary artery calcium by Multidetector CT. Secondary outcomes included effects on sexual function and quality of life (QOL). Sexual function was measured by the International Index of Erectile Function, and health-related QOL by the SF-36.
Over the time period studied, in men with baseline T levels 100-400 ng/dL, the increase of T levels to 500-900 ng/dL did not cause statistically significant changes in either IMT or coronary calcium score. This was true after adjusting for baseline obesity, CAD, and diabetes, as well as for age and study site. There was also no significant difference in the secondary outcomes of erectile function, ejaculatory function, libido, or health-related QOL.
What is the relevance of atherosclerotic progression as measured by IMT/coronary artery calcium to cardiovascular events? In a 2007 meta-analysis, Lorenz and colleagues1 found that common carotid IMT difference was associated with future cardiovascular events, with relative risk of myocardial infarction 1.15 and of stroke 1.18 with every 0.10 mm IMT difference. However, IMT and coronary calcium should be seen as associated biomarkers; this study was not designed to establish the risk of cardiovascular events themselves. The authors did note a small number of cardiovascular events that occurred in the testosterone group more than the placebo group, but the events were unadjudicated; numbers were small (eg, 3 in testosterone and 0 in placebo group had a stroke; 3 in T and 2 in placebo group had MI), with no statistically significant differences.
The observed increase in prostate-specific antigen and hematocrit with testosterone level is to be expected. More surprising is the absence of a difference in measures of sexual function and health-related QOL. The lack of change in ejaculatory function parallels the results reported by Paduch and colleagues. However, previous studies have established a difference in libido and erectile function with testosterone replacement (Bhasin 2010, Foresta et al 2004, Mikhail 2006).2-4 It may be that this is related to the number of participants (powered for the primary outcome.) As noted by Basaria and colleagues, it is also quite possible that any impact of T replacement on measures of sexual desire and function was diluted by the inclusion of men without low testosterone levels; the men studied by Foresta and colleagues, for example, all had testosterone levels <200 ng/dL.
As noted, the defined baseline testosterone range of the cohort includes men with both low testosterone and testosterone levels in the low-normal range were included (T 100-400 ng/dL). The lower level of normal is usually defined as somewhere between 270 and 300 ng/dL (depending on the laboratory), though reference ranges were established using younger men. The study also excluded men with pituitary/hypothalamic disease or testicular disease (ie, known reasons for hypogonadism). The results may reflect the inclusion of men who do not have testosterone below the normal range, and thus would not meet Endocrine Society guidelines for hypogonadism. Results of the cardiovascular substudy (n~140) of the TTrials are anticipated as adding to this literature, and will provide additional data as to the effects in men with low testosterone as defined by Endocrine Society guidelines. As noted in our review of baseline data from the TTrials, the TTrials cohort consisted of community-dwelling men ≥65 years old with two early-morning low T levels (<275 ng/dL and <300 ng/dL; none <100 ng/dL unless further testing was consistent with primary and not secondary hypogonadism).
Overall, this study provides the longest-term results of a randomized clinical trial of testosterone use in a large cohort of older men. It is double-blinded and placebo-controlled. The trial is well-designed, but did not look only at men with low testosterone (below the lower limit of normal). The inclusion of men with low and low-normal testosterone in the same analysis group limits interpretation and application of the results. It would be interesting to see a subanalysis of men with documented low testosterone, both in terms of primary and secondary outcomes, and in terms of the dropout rate observed.
1. Lorenz MW, Markus HS, Bots ML, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness. A systematic review and meta-analysis. Circulation. 2007;115:459-467.
2. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
3. Foresta C, Caretta N, Rossato M, et al. Role of androgens in erectile function. J Urol. 2004;171(6 Pt 1):2358-2362.
4. Mikhail N. Does testosterone have a role in erectile function? Am J Med. 2006;119(5):373-382.