New Evidence Refutes Testosterone Benefits for Age-Related Symptoms

Testosterone is the primary male sex hormone that is made mainly in the testicles. Men experience a gradual, normal decline in their blood testosterone levels as they age.

Misleading direct-to-consumer advertisements coupled with permissive regulation and poor physician compliance with professional guidelines have contributed to a surge in the use of testosterone products among men.[1] Many men have thereby been misled into thinking that testosterone treatment will cure the impaired memory, cardiovascular disease, sexual dysfunction, fatigue and decreased mobility that often accompany aging.

Overall, the use of testosterone products in the U.S. grew nearly 10-fold from 2000 to 2011, and by 2013, more than 5 million U.S. prescriptions for testosterone products were being filled annually.[2],[3] Yet strong evidence of testosterone’s benefits in older men with normal age-related declines in testosterone blood levels has been lacking.

In an attempt to stop the widespread misprescribing of testosterone, the Food and Drug Administration (FDA) required testosterone makers to implement labeling changes in 2015.[4] These changes clarify that the approved use of these products is limited to replacement therapy in men with “classic” hypogonadism, defined as inadequate production of testosterone by the testicles due to certain disorders of the reproductive system: genetic diseases, testicular damage from chemotherapy or infection, and disorders of the pituitary gland or the hypothalamus.

In our April 2017 issue, we discussed a review of clinical trials from 1950 to 2016 that found no consistent benefit of testosterone therapy in men with low testosterone for a variety of uses that are not approved by the FDA, including sexual function, muscle strength, physical functioning, psychological well-being and treating cognitive impairment of Alzheimer’s disease.[5]

New data from randomized, controlled trials, called the Testosterone Trials (T-Trials) — which were jointly funded by the federal government and industry — show that testosterone treatment in older men with low testosterone blood levels does not improve memory or other cognitive functions and actually increases the buildup of cholesterol in coronary arteries. The studies were published in the February 21, 2017 issue of the Journal of the American Medical Association (JAMA).

The cognition study[6]

The cognition study involved 493 men out of nearly 800 who participated in the main T-Trials and also met the criteria for age-related memory impairment, a mild form of impairment that is much less severe than dementia. Impairment was determined by self-reported symptoms of memory decline and low performance on certain memory tests. To participate in the T-Trials, men had to be 65 or older; have low testosterone blood levels due to no known cause other than normal aging; and have reported sexual dysfunction, diminished vitality or reduced physical functioning.[7]

The mean age of the men in the cognition trial was 72 years. Half were randomly assigned to receive testosterone gel applied to the skin daily, and the other half were assigned to receive a placebo gel. The testosterone group had their doses adjusted throughout the study to keep the blood levels of testosterone within the normal range for young men aged 19 to 40 years. Subjects in both groups completed memory and cognitive function tests at baseline, 6 months and 12 months.

At the end of the 12-month period, there were no improvements in memory or other cognitive functions in the testosterone group men compared with those in the placebo group. A separate analysis conducted by the researchers on all men in the T-Trials — regardless of their initial memory status — also showed no significant differences between the groups.

These findings are consistent with those from a previous, smaller, 36-month trial that found that testosterone injections are not beneficial for improving cognitive function in older men.[8]

The cardiovascular study[9]

This study assessed the effect of testosterone treatment on the buildup of noncalcified plaque, a fibrous and fatty build-up within the walls of the coronary arteries. These plaques, which are often referred to as atherosclerosis, can block blood flow to the heart muscle. The study focused on a subsample of 138 subjects from the main T-Trials: 73 were assigned to the testosterone group and the remaining 65 were assigned to the placebo group.

The mean age for these subjects was 71 years. Most had severe coronary atherosclerosis and had risk factors for cardiovascular disease, including obesity, diabetes, high blood pressure and elevated cholesterol levels, at the beginning of the trial.

They completed a special type of heart scan to measure the amount of coronary artery plaque at the beginning of the trial and 12 months later. The trial showed that the amount of noncalcified coronary artery plaque increased significantly more in the men who received testosterone compared with those who received a placebo. Additionally, testosterone treatment caused greater increases in the amount of total plaque — both calcified and non-calcified — in the coronary arteries. The researchers cautioned that their study was not large enough to draw conclusions about whether testosterone treatment affects the risk of major adverse cardiovascular events, such as strokes and heart attacks. However, they concluded that their findings are concerning because any narrowing of the coronary arteries can be detrimental.

Other findings

Two articles in the April 2017 issue of JAMA Internal Medicine regarding other T-Trial studies showed that testosterone treatment improved anemia[10] and increased both bone mineral density and estimated bone strength in older men.[11]

A 2016 article in the New England Journal of Medicine reported the results of the main T-Trials and showed that testosterone use does not improve walking distance or vitality, but did lead to low to moderate improvements in sexual desire.[12] However, testosterone’s effect on erectile dysfunction was less than that seen in studies of other medications, such as sildenafil (REVATIO, VIAGRA).

Conclusion

Despite the findings that testosterone products may help to correct anemia and increase bone density, the collective results of the T-Trials demonstrate that testosterone products should not be used in older men with low testosterone levels due to aging because the risks outweigh the benefits.

An accompanying editorial of the JAMA articles called for strengthening the warnings on adverse cardiovascular events associated with testosterone use based on the increased coronary artery plaque finding from the cardiovascular study.[13] In fact, Public Citizen’s Health Research Group petitioned the FDA in 2014 to require a black-box warning (the most serious warning required by the FDA) on the labels of all testosterone products to inform prescribers and consumers of the increased risk of heart attacks and strokes with the use of these products.[14] The agency denied our petition, but eventually required a non-black-box warning.[15]

What You Can Do

Unless you are a man with confirmed hypogonadism due to a problem with your testicles, pituitary gland or hypothalamus, you should not use testosterone products.

Testosterone products are not useful for treating symptoms associated with normal aging, and they also can increase your risk of cardiovascular and other serious adverse effects.

Exercising and maintaining a healthy weight may provide more benefits than testosterone products for improving cognitive status, cardiovascular health, one’s sense of well-being and overall functioning.

Women and children should not be exposed to testosterone products.

If you are prescribed testosterone for an FDA-approved use, you should be alert for warning signs of adverse cardiovascular effects, such as chest pain or pressure, shortness of breath, rapid or irregular heart rate, neurologic weakness, or numbness or tingling on one side of the body. If you experience any of these warning signs, seek medical help immediately.

References

[1] Handelsman DJ. Irrational exuberance in testosterone prescribing: When will the bubble burst? Med Care. 2015;53(9):743-745.

[2] Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med J Aust. 2013;199(8):548–551.

[3] QuintilesIMS data on U.S. testosterone prescriptions for gel, patch and oral dosage forms, 2013.

[4] Food and Drug Administration. FDA drug safety communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. March 3, 2015. https://www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Accessed July 7, 2017.

[5] Study rebuts health benefit claims for off-label testosterone. Worst Pills, Best Pills News. April, 2017. /newsletters/view/1094##ref_12. Accessed July 7, 2017.

[6] Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA. 2017;317(7):717-727.

[7] Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611-624.

[8] Vaughan C, Goldstein FC, Tenover JL. Exogenous testosterone alone or with finasteride does not improve measurements of cognition in healthy older men with low serum testosterone. J Androl. 2007;28(6):875-882.

[9] Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017;317(7):708-716.

[10] Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of testosterone levels with anemia in older men: A controlled clinical trial. JAMA Intern Med. 2017;177(4):480-490.

[11] 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. JAMA Intern Med. 2017;177(4):471-479.

[12] Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611-624.

[13] Handelsman DJ. Testosterone and male aging: Faltering hope for rejuvenation. JAMA. 2017;317(7):699-701.

[14] Public Citizen. Petition to the FDA for black box warnings on all testosterone products. February 25, 2014. https://www.citizen.org/sites/default/files/21841.pdf. Accessed July 7, 2017.

[15] Food and Drug Administration. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. March 3, 2015. https://www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Accessed July 7, 2017.