Testosterone Not Just for Fun Anymore: 3 Questions About Risk

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The era of testosterone replacement got off on the wrong foot. In a 2013 VA study composed of 8709 men with low testosterone values, 19.9% of those not treated with replacement died after 3 years of follow-up versus 25.7% in the testosterone-replaced cohort.¹ But, the cohort chosen was made up of men after they underwent coronary angiography. This was a “selective” group-already at higher risk for heart disease.

So, here are some key questions about the risks of testosterone therapy:

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1. Is testosterone replacement safe in hypogonadal men?

Some new research may have shifted the paradigm. Another VA cohort (n=83,010), men aged 50 years and older with low testosterone values, was followed from 1999 to 2014.² The subjects were divided into 3 groups: low testosterone levels treated to normal, low testosterone treated but without levels returning to normal, and an untreated control group.

Testosterone treated to normal men were 56% less likely to die than no treatment men (24% less likely to have an MI and 36% less likely to have a stroke). The disparity between treated to normal and treated men still below normal testosterone levels was less but still significant.

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2. But isn’t there an increased risk of more aggressive prostate cancer?

The conclusion of a study of 149,354 men demonstrated this: “Testosterone use was not associated with aggressive prostate cancer and did not affect overall or disease specific mortality…our findings support growing evidence that testosterone replacement is safe with respect to prostate cancer.”³

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3. What about diabetics and testosterone? They have more cardiovascular disease. What should they do?

In 1 study, 33% of diabetic men had low testosterone values.⁴ Another study demonstrated that diabetic hypogonadal men have more advanced atherosclerotic disease markers.⁵ A study of 581 men with type 2 diabetes identified a 2-fold increased risk of mortality in the hypogonadal group.⁶ In 3 groups of men with diabetes (total n=857)-normal testosterone, low untreated, and low treated with full dose testosterone replacement-mortality was 11.2%, 16.8%, and 3.4%, respectively, over 5.8 years!⁶

It seems testosterone replacement has gone from bad to not only good but possibly very good, even in high-risk vascular groups like diabetics. Old teaching was that estrogen was beneficial for the endothelium but the converse for testosterone. I remember (at my age, that alone is pretty good) a paper I published with coworkers that showed nongenomic “good effects” on endothelium from testosterone in animals.⁷ The entire testosterone question-and-answer session is being rewritten as we speak.

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Take-aways:

• In a study of hypogonadal men, testosterone treated to normal men were 56% less likely to die than no treatment men.

• Study findings “support growing evidence that testosterone replacement is safe with respect to prostate cancer.”

• Testosterone replacement may have gone from bad to good or very good, even in high-risk vascular groups like diabetics.

References:

1. 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;310:1829-1836.

2. Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36:2706-2715.

3. Kaplan AL, Hu JC. Use of testosterone replacement therapy in the United States and its effect on subsequent prostate cancer outcomes. Urology. 2013;82:321-326.

4. Dhindsa S, Prabhakar S, Sethi M, et al. Frequent occurrence of hypogonadotrophic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. 2004;89:5462-5468.

5. Farias JM, Tinetti M, Khoury M, Umpierrez GE. Low testosterone concentration and atherosclerotic disease markers in male patients with type 2 diabetes. J Clin Endocrinol Metab. 2014;99:4698-4703.

6. Busko M, Vega CP. Erectile dysfunction drugs improve survival in diabetic men. July 29, 2015. Medscape Internal Medicine.

7. Costarella CE, Stallone JN, Rutecki GW, Whittier FC. Testosterone causes direct relaxation of rat thoracic aorta. J Pharmacol Exp Ther. 1999;277:34-39.