In the January 29, 2014 PLoS One article, “Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men,” the authors improperly draw causal inferences from retrospective, observational connections between testosterone therapy and non-fatal myocardial infarctions in unmatched cohorts [1]. Comparing cardiac risks in a group of men with low testosterone, a known major risk factor for heart disease, to men on Cialis® or Viagra® is incommensurate. This “cohort” study should be considered associative at best.

What is disturbing is all the sensationalism surrounding these findings by “medical staff writers” who have reported findings as though definitive. Their lack of medical knowledge and skills to interpret the data is obvious and leads to very subjective and biased reporting.

Clearly ignored in these recent “news” articles are the documented benefits of testosterone therapy including cardiac protection as well as a lack of cardiovascular events documented in two well-designed meta-analyses of prospective, controlled trials [2,3].

Furthermore, over 80% of published epidemiologic studies are later disproven or shown to be false [4]. The known physiologic effects of testosterone at the androgen receptor and the lack of biologic plausibility make this a likely outcome in this case. Most importantly, many higher quality studies and trials have supported the benefits and safety of testosterone therapy in both men and women.

Is there another way to explain the purported ‘finding’ in the unlikely case that is was valid?

Aromatization of testosterone to estradiol is rarely addressed in studies on testosterone and was not addressed in this study, even though patients with heart disease have many risk factors for increased aromatase activity: age, obesity, sedentary life style, insulin resistance and medications (statins, cardiac and anti-hypertensive medications) [5]. Side effects from increased local aromatization to estradiol (which is immeasurable in serum), including fluid retention, weight gain and edema, may potentially have adverse cardiovascular effects [6,7,8]. However, these are easily prevented with the use of low dose aromatase inhibitors [9,10]. Interestingly, some, albeit not all, studies in men have shown an increased risk of myocardial infarction with elevated estradiol or a high estradiol/testosterone ratio; this is not necessarily causal and should be approached with caution [11-18]. The confounders (e.g., age, obesity, sedentary life style, insulin resistance and medications), associated with low testosterone and increased aromatization to estradiol, are most likely causative.

As with many cohort studies there are severe methodical limitations including selection bias and lack of a suitable control group. As physicians and scientists, we should not ignore these results but rather keep them in perspective and, as suggested by the FDA, investigate them further with properly designed studies that also address signs and symptoms of aromatization as well as confounding variables.

References

1. Finkle WD, Greenland S, Ridgeway GK, Adams… JL. Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PLOS ONE. 2014
2. Calof OM, Singh AB, Lee ML et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005;60:1451-1457.
3. Fernández-Balsells MM, Murad MH, Lane M et al. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. Journal of Clinical Endocrinology & Metabolism. 2010;95:2560-2575.
4. Ioannidis JPA. Why most published research findings are false. PLoS medicine. 2005;2:e124.
5. Cohen PG. Obesity in men: the hypogonadal–estrogen receptor relationship and its effect on glucose homeostasis. Medical hypotheses. 2008;70:358-360.
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