Clinical Context

The cardiovascular (CV) effects of testosterone therapy among men have been controversial, with multiple studies reporting a mix of results. Corona and colleagues sought to provide clarity for this issue in a systematic review and meta-analysis, which was published in the June 2018 issue of Journal of Sexual Medicine.^[1]

Researchers assessed 93 randomized controlled trials as well as 15 pharmaco-epidemiologic studies. Combining the results of the latter, researchers found that testosterone therapy was associated with lower rates of overall mortality, myocardial infarction, and stroke; however, there was no overall effect on these outcomes when assessing data from randomized trials.

Several secondary analyses focused on particular populations of men. Testosterone therapy was associated with lower rates of CV events in clinical trials when the population was limited to men with obesity. In contrast, testosterone was associated with a higher risk for CV events when a higher then recommended dosage of testosterone was used, or in cases of frail older men.

Endothelial function is a key variable in cardiovascular disease (CVD). The current study by Chasland and colleagues compared exercise and testosterone therapy with a combination of both interventions and placebo in their effects on endothelial function.

Study Synopsis and Perspective

Exercise training -- but not testosterone therapy -- improved vascular health in aging men with widening midsections and low to normal testosterone, new research suggests.

"Previous studies have suggested that men with higher levels of testosterone, who were more physically active, might have better health outcomes," Bu Beng Yeap, MBBS, PhD, University of Western Australia, Perth, told theheart.org | Medscape Cardiology. "We formulated the hypothesis that the combination of testosterone treatment and exercise training would improve the health of arteries more than either alone."

To test this hypothesis, the investigators randomly assigned 80 men, aged 50 to 70 years, to 12 weeks of 5% testosterone cream 2 mL applied daily or placebo plus a supervised exercise program that included machine-based resistance and aerobic (cycling) exercises 2 to 3 times/wk or no additional exercise.

The men (mean age, 59 ±5 years) had low-normal testosterone (6-14 nmol/L), a waist circumference of ≥ 95 cm (37.4 inches), and no known CVD, type 1 diabetes, or other clinically significant illnesses. The study excluded current smokers and men on testosterone or medications that would alter testosterone levels.

The investigators used high-resolution ultrasound of the brachial artery to assess flow-mediated dilation (FMD) and sublingual glyceryl trinitrate (GTN) responses. Flow-mediated dilation has been shown to be predictive of CVD risk, with a 1% increase in FMD associated with a 9% to 13% decrease in future CVD events.

According to participants' daily dairies, testosterone adherence was 97.6%. Exercise adherence was 96.5% for twice-weekly attendance and 80% for thrice-weekly attendance, with no between-group differences.

As reported in the April issue of Hypertension,^[2] testosterone levels increased, on average, 3 nmol/L in both testosterone groups by week 12 (P = .003). In all, 62% of these men had levels of the hormone exceeding 14 nmol/L compared with 29% of those men receiving placebo.

Testosterone levels improved with exercise training plus placebo by 0.9 nmol/L but fell with no exercise and placebo by 0.9 nmol/L.

In terms of vascular function, exercise training increased FMD when expressed as both the δ change (mm; P = .004) and relative rise from baseline diameter (%; P = .033).

Ex = exercise; NoEx =no exercise; P = placebo; T= testosterone.

There was no effect of exercise on GTN%, which is generally in line with exercise literature indicating that shear-mediated adaptations in response to episodic exercise occur largely in endothelial cells, the authors noted.

Testosterone did not affect any measures of FMD nor was there an effect on GTN response, despite previous evidence that lower testosterone doses might enhance smooth muscle function.

"Our main finding was that testosterone -- at this dose over this duration of treatment -- did not have a beneficial effect on artery health, nor did it enhance the effect of exercise," said Yeap, who is also president of the Endocrine Society of Australia. "For middle-aged and older men wanting to improve the health of their arteries, exercise is better than testosterone!"

Shalender Bhasin, MB BS, director of research programs in men's health, aging, and metabolism, Brigham and Women's Hospital, and professor of medicine, Harvard Medical School, Boston, said the study is interesting from a mechanistic perspective and adds to the overall body of evidence on how testosterone affects performance but was narrowly focused.

"They looked at very specific markers and what they're showing is that this is not the mechanism by which testosterone improves performance," he said. "That may be so, but it doesn't negate the finding that testosterone improves endurance and has other vascular effects: it increases capillarity, increases blood flow to the tissues, and improves myocardial function."

Although well done, the study doesn't get at the larger question of whether testosterone increases CV risk, observed Bhasin. "None of the randomized studies have been large enough or long enough to determine the effect on [CV] events rates. There's a lot of argument on both sides but we need some data to address that."

The 6000-patient TRAVERSE trial^[3] is specifically looking at long-term major CV events with topical testosterone compared with placebo in hypogonadal men aged 45 to 80 years who have evidence of or are at increased risk for CVD. The study, which is set to be completed in June 2022, should also provide information on fracture risk in these men, said Bhasin, one of the trial's principal investigators and lead author of the Endocrine Society's 2018 clinical practice guideline on testosterone therapy for hypogonadism in men.^[4]

William Evans, MD, adjunct professor of human nutrition, University of California, Berkley, said in an interview that the positive effects of testosterone occur at much lower doses in men and women who are hypogonadal but, in this particular population, exercise is the key and the major recommendation.

"Testosterone has been overprescribed and overadvertised for essentially a lifetime of sedentary living, and it's advertised as a way to get all that back without having to work for it," he said. "Exercise has a profound and positive effect on control of blood pressure, function, and strength, and testosterone may only affect in people who are sick, people who have really low levels."

The study was funded by the Heart Foundation of Australia. Lawley Pharmaceuticals provided the study medication and placebo. Yeap has received speaker honoraria and conference support from Bayer Healthcare Pharmaceuticals; Lilly USA, LLC; and Besins Healthcare; research support from Bayer HealthCare Pharmaceuticals, Lilly USA, LLC; and Lawley; and served as an advisor for Lilly USA, LLC; Besins Healthcare; Ferring Pharmaceuticals;, and Lawley. Shalender reports consultation or advisement for GTx Inc.; Pfizer Inc. and TAP Pharmaceuticals; grant or other research support from Solvay Pharmaceuticals, Inc. and GlaxoSmithKline; and honoraria from Solvay Pharmaceuticals, Inc. and Auxilium Pharmaceuticals, Inc.. Evans reported having no relevant conflicts of interest.

Clinical Implications

• A previous meta-analysis by Corona and colleagues found that testosterone therapy was associated with lower rates of CV events and mortality in observational studies, but there was no significant effect of testosterone therapy on these outcomes in randomized trials. Men with obesity appeared to have a lower CV risk associated with testosterone therapy, but frailty and high dosages of testosterone were associated with elevated CV risk on testosterone treatment.
• The current study by Chasland and colleagues found that exercise but not testosterone therapy improved endothelial function among men with low-normal testosterone levels at baseline.
• Implications for the healthcare team: The healthcare team should encourage exercise among middle-aged and older men. Adding testosterone therapy may not improve endothelial function to the same degree as exercise.

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