Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

TRT and CV Outcomes in Men with Androgen Deficiency

JAMA Intern Med; ePub 2017 Feb 21; Cheetham, et al

Among men with androgen deficiency, prescribed testosterone replacement therapy (TRT) was associated with a lower risk of cardiovascular (CV) outcomes over long-term follow-up, a recent study found. This retrospective cohort study included men aged ≥40 years with evidence of androgen deficiency from January 1, 1999, to December 31, 2010; follow-up was through December 31, 2012. Researchers found:

  • 8,808 men were ever dispensed testosterone (median follow-up 4.2 years) and 35,527 men never dispensed testosterone (median follow-up 3.2 years).
  • Composite CV end point rates were 23.9 vs 16.9 per 1,000 person-years in the never-TRT and ever-TRT groups, respectively.
  • Adjusted HR for the composite CV end point in the ever-TRT group was 0.67.
  • Similar results were seen when the outcome was restricted to combined stroke events and combined cardiac events.


Cheetham TC, An J, Jacobsen SJ, et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. [Published online ahead of print February 21, 2017]. JAMA Intern Med. doi:10.1001/jamainternmed.2016.9546.


Beginning around age 30, testosterone levels begin to decline. 19% of men in their 60’s, 28% in their 70’s, and 49% in their 80’s have low testosterone levels. Most men with low testosterone levels are not symptomatic, but some have symptoms that include loss of sexual desire, erectile dysfunction, breast enlargement or tenderness, hot flashes, fatigue, irritability, and depression. Testosterone deficiency is defined as consistently low serum testosterone levels with 1 or more androgen deficiency symptoms.1 Testosterone needs to be drawn as a first morning specimen, as samples taken later in the day can be up to 50% lower than first morning samples and lead to false positive interpretations. Another article in this issue of JAMA Internal Medicine shows that testosterone replacement in testosterone deficient men who have osteoporosis improves bone mass.2 In addition, in testosterone deficient men who have unexplained anemia, testosterone raises the level of hemoglobin.3

On the issue of long-term cardiovascular safety, the jury is still out. Some studies show increased cardiovascular risk, though methodological questions have been raised about some of those studies.4 Furthermore, a study in this past week’s JAMA showed increase in coronary artery noncalcified plaque volume in hypogonadal men treated with testosterone. The article reviewed above from JAMA Internal Medicine lends support to the hypothesis that testosterone may be beneficial in older men with testosterone deficiency and may even improve cardiovascular outcomes, but further research is needed before this can be considered a firm conclusion. —Neil Skolnik, MD

  1. Bhasin S, Cunningham GR, Hayes FJ, et al; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
  2. Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: A controlled clinical trial. [Published online ahead of print February 21, 2017]. JAMA Intern Med. doi:10.1001/jamainternmed.2016.9539.
  3. Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of testosterone levels with anemia in older men: a controlled clinical trial. [Published online ahead of print February 21, 2017]. JAMA Intern Med. doi:10.1001/jamainternmed.2016.9540.
  4. Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.