Major Flaws in Testosterone Study

A recent study titled “Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men” was seriously flawed leading to erroneous conclusions. It was was published on January 29th in the journal PLoS ONE and funded by the National Institutes of Health.

It tracked about 56,000 older and middle-aged men who were prescribed testosterone between 2008 and 2010. The study looked specifically at their rate of heart attacks in the year before receiving their new prescriptions, and in the three months after.

Perhaps you saw the previous commentary from Cenegenics addressing this topic. This study and another one several months ago (similarly flawed) have led to a great deal of fear regarding testosterone therapy on the part of patients, as well as doctors who are not familiar with the details of the studies. Most doctors, like patients, have only heard the headlines.

On March 5th, 2014, a letter to the editor appeared in the Journal of the American Medical Association (JAMA), from Dr. Abraham Morgantaler, Harvard urologist and pioneer in the field. The editorial detailed numerous problems with the most recent study and can be viewed at Major Flaws in Testosterone Study. The editorial is a bit technical but brings attention to the fact that the study conclusions appear to be a gross distortion of the actual data. The authors of the editorial state: “These results contradict the literature spanning more than 20 years. Should testosterone therapy be considered unsafe based on this study? We do not believe so.”

The new study compared men receiving a prescription for testosterone to a separate group of 170,000 older and middle-aged men who filled prescriptions for Viagra and Cialis, who did not experience more heart attacks.

Men ages 65 and up had double the rate of heart attacks in the months after starting testosterone, as did those younger than 65 with a previous diagnosis of heart disease. One might expect that those older than 65 might have an increased likelihood of unsuspected heart disease simply based on advanced age.

Problems with the study:

  • This was an observational study, not placebo controlled. Such studies can raise cause for concern but cannot be considered proof of cause and effect.
  • The study only compared men given testosterone prescriptions to men given prescriptions for Viagra and Cialis.
  • Medications such as Cialis and Viagra increase nitric oxide and are actually cardio-protective. This could have resulted in a reduced incidence of heart attacks in the Viagra/Cialis group rather than an increase in risk in the testosterone group (for those over 65, and younger men with known heart disease).
  • There was no mention of pre or post treatment testosterone levels or estrogen levels (high levels are associated with increased cardiovascular risk).
  • Appropriateness of the prescription was not assessed.
  • Monitoring for blood pressure, cholesterol and polycythemia (increased red blood count) was not mentioned.

An increased risk of heart attack and death in patients with cardiac disease taking testosterone could be attributed to:

  • Poor monitoring of testosterone and estrogen levels.
  • Polycythemia (elevated red blood count) that can occur with testosterone treatment and increase the risk of clotting. Polycythemia should be treated by reducing the red blood count (by reducing testosterone dose, giving blood or even therapeutic phlebotomy). Again, poor monitoring.
  • Inappropriate strenuous physical activity resulting from an improved sense of well being.

In response to this study, Dr. Peter J. Snyder of the University of Pennsylvania School of Medicine, who is leading a $50 million series of trials looking at testosterone treatment in men ages 65 up with documented low levels, was quoted in the NY Times saying that he cautioned against drawing conclusions based on the new study. “We don’t know if these findings apply to men who have low testosterone and meet the criteria for a prescription, or if it applies only to men who have normal levels and then take testosterone in addition,” he said. Dr. Snyder said he and his colleagues found it plausible that testosterone might actually protect against heart disease, in part by reducing body fat and improving blood sugar metabolism.”

There may indeed be an increased risk of cardiovascular events in older patients with cardiac disease when treated with testosterone. However, these risks would likely be greatly diminished and possibly eliminated, if patients had close monitoring of levels, were given aspirin therapy (there was no mention of this in the study) and treated for polycythemia if it occurred.

These results, if proven to be correct, underline the importance of proper monitoring of testosterone therapy especially in patients with known or suspected heart disease. Testosterone therapy should not be prescribed indiscriminately or by physicians not experienced in its use. Cenegenics physicians have a great deal of experience in managing hormone therapy. Properly used, testosterone has a highly favorable risk-benefit ratio, and its safety and efficacy is markedly enhanced when combined with positive lifestyle interventions. While it is possible there are individuals who carry an increased risk for vascular events when placed on testosterone, this is likely a very small fraction of patients and a small increase in risk. In addition, this risk, if present, would likely be mitigated by the use of low dose aspirin and nitric oxide supplementation.

Over the last 16 years, we have treated over 30,000 patients with hormone therapy. Our patients have experienced extraordinarily low rates of heart attacks, stroke, cancer, diabetes and osteoporosis among others. We carefully monitor for blood levels and polycythemia so that our patients achieve maximum benefit at minimal risk.. We recommend people at risk for, or with established vascular disease to be treated with low dose aspirin as well as supplements to improve vascular function, such as nitric oxide supplements.

At Cenegenics, we are continuing to research new and better ways to care for our patients, and keep them at the lowest possible risk for a variety of conditions associated with the aging process. These advancements are leading to new programs and therapies designed to keep our patients as healthy and vital as possible.

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