Testosterone in the News: Another Reason to Read Articles, Not Just Headlines

M. PreFontaine, R.Ph. FAAFM

The importance of reading the details of research articles, particularly when the title or conclusion is contrary to previously published articles and research, is critical to the practice of medicine. A timely example: the recently published JAMA article on testosterone-replacement therapy in older men entitled “Association of Testosterone Therapy with Mortality, Myocardial Infarction, and Stroke in Men with Low Testosterone Levels“1. Simply reading the article’s abstract would lead one to the conclusion that testosterone replacement therapy increases a male’s risk of adverse cardiovascular events. There are several significant shortcomings in the study’s design and methodology, and the results appear to conflict with an existing body of research showing that low testosterone increases a man’s risk of heart problems.

Randomized, placebo-controlled studies (RCT) are currently considered the gold standard methodology for clinical trials. It is of importance to note that, rather than being an RCT, the referenced study is observational and retrospective in nature. Thus, instead of following randomized groups of subjects who differ only by treatment(s) versus control, these findings were based off of retrospective observances with treatment and variables outside of the control of the investigator. Reading the article in its entirety brings to light several concerns that cause one to question the findings. First, the article states the scientists only verified the testosterone treatment was initiated when the patient filled a prescription and then “a patient was assumed to have continued treatment”. This means a critical aspect of this study and therefore conclusions was assumed. In fact 17.6% of subjects filled their prescription only once but were included as having testosterone therapy. Those patients who actually refilled their prescription only averaged use for 376 days so they basically discontinued therapy after 1 year. This concern is further strengthened by the knowledge that only 60% of study subjects had a follow-up blood test to assess their testosterone levels. Among those actually tested, the average total testosterone levels only increased to 332.2ng/dL – which is just slightly above the initial cut-off for study inclusion and their definition of hypogonadism for the study. I would have personally concluded this study revealed low compliance and sub-therapeutic treatment with testosterone replacement may lead to increased heart risks in patients who already have an increased risk due to low natural testosterone levels.

Just as important as actual compliance with therapy, estradiol and hematocrit levels were not evaluated or taken into account during testosterone treatment in this study. Elevated estradiol, possible with testosterone replacement therapy as a result of aromatization, increases hypercoagulability and is a known risk factor for MI and stroke, the major death categories in the study. Men being treated with testosterone replacement therapy should have their estradiol serum level checked to ensure the testosterone is not excessively converting to estradiol. Hematocrit levels were also not monitored during therapy. Erythrocytosis is associated with an increased risk in the development of heart disease and thrombosis. Elevated hematocrit can be associated with testosterone replacement therapy.

Since we have previous research that clearly indicates naturally low testosterone levels in men increase cardiac risks, we wish to know if replacement will prove beneficial for cardiac outcomes. What can be confidently concluded from this study is that further research (using gold standard methodology of randomized, placebo controlled studies where subjects are actually required to use the medication and are monitored appropriately) is necessary to clarify whether testosterone replacement improves cardiac outcomes or increase risks.

Resources
  1.  Vigen, R, O’Donnell C, Baron A, Grunwalk G, et al. Association of Testosterone Therapy with Mortality, Myocardial Infarction , and Stroke in Men with Low Testosterone Levels. JAMA. 2013; 310(17)1829-1836.
  2.  Ohlsson C, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. J Am Coll Cardiol. 2011 Oct 11;58(16):1674-81.
  3.  Jones RD, Nettleship JE, Kapoor D, Jones HT, Channer KS. Testosterone and Atherosclerosis in Aging Men. Am J Cardiovasc Drugs. 2005; 5(3): 141-154.
  4.  Khaw K, Dowsett M, Folkerd E, et al. Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men. Circulation. 2007; 2694-2701.
  5. Hyde A, Norman P, Flicker L, et al. Low Free Testosterone Predicts Mortality from Cardiovascular Disease But Not other Causes: The Health in Men Study. 2012 97(1) 179-189.
  6. Abbott, RD et al. Serum estradiol and risk of stroke in elderly men. Neurology. Feb 20 2007;68(8):563-8.
  7. Jankowska EA et al. Circulating estradiol and mortality in men with systolic chronic heart failure. JAMA. 2009;May 13 301(18):1892-1901.
  8. Merchant, S et al. Erythrocytosis. In Hematopathology. 2nd Ed. His, E., (Ed.) Philadelphia; Elsevier/Saunders, 2012.
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2 Responses to Testosterone in the News: Another Reason to Read Articles, Not Just Headlines

  1. Pretty great post. I simply stumbled upon your weblog and wished to mention that I have really loved
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    • Keystone says:

      Thank you! Our pharmacists and CNC write monthly on a variety of issues we see in our compounding pharmacy. I hope you continue to find value in their blogs!

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