Testosterone Use Linked to Increased Risk of Heart Attacks

Two recently published studies, appearing in the Journal of the American Medical Association (JAMA)[1] and the online scientific journal PLOS One[2], significantly add to a growing body of evidence suggesting that testosterone treatment exposes men to an increased risk of adverse cardiovascular events, such as heart attack and stroke, as well as death. These new results are particularly troubling given that many men today are using testosterone without having a clear medical need for such treatment, in many cases not even having had tests to measure their testosterone levels.[3] As this article went to press, the Food and Drug Administration (FDA) had failed to require companies selling products with testosterone to provide any warning about the increased risks of heart attacks or other cardiovascular risks.

Over the last decade, the use of testosterone treatment by men has expanded, driven in large part by effective pharmaceutical industry ad campaigns. Featuring prominent ads during broadcasts of sporting events and nightly news shows, these campaigns aggressively promote “low T” as a disease allegedly plaguing large numbers of men middle-aged or older.

However, many men using testosterone products either have normal testosterone levels or have symptoms that may be unrelated to their low testosterone levels. Many symptoms attributed to testosterone deficiency may be part of normal aging or caused by other unrelated disorders. In light of the accumulating evidence of cardiovascular risk, men should use testosterone drugs only when it has been documented that their testosterone levels are lower than the normally diminishing levels occurring with aging, when there is a clearly established medical indication for these drugs, and only after understanding the potentially serious risks of these products, including the increased risk of heart attacks.

Overview of testosterone

Testosterone is the primary androgen hormone produced in the body. The majority of testosterone is made by the testes, with a small amount produced by the adrenal glands.[4] During puberty, testosterone stimulates the development of male sexual characteristics and sexual behavior.[5] In adult males, testosterone plays a role in maintaining sexual drive and potency (the ability to have an erection), sperm production, muscle mass, bone mass and red blood cell production.[6]

Levels of testosterone typically reach normal male adult levels by age 17 and remain there until men are in their 30s and 40s.[7] Testosterone levels subsequently gradually decrease as part of normal aging.[8]

The inadequate production of testosterone by the testes is called hypogonadism. Some males are born with this condition (congenital hypogonadism), and others develop it late in life (acquired hypogonadism). Primary hypogonadism is caused by disorders that directly damage or destroy the cells in the testes that produce testosterone. Secondary hypogonadism is caused by disorders that suppress pituitary hormones that normally stimulate the testes to make testosterone. Hypogonadism does not include normal, age-related decreases in testosterone.

The most common symptoms of male hypogonadism are reduced sexual desire and sexual activity, erectile dysfunction and hot flashes.[9] Other symptoms and signs include small testes, male-factor infertility (i.e., inadequate sperm production), decreased body hair, gynecomastia (enlarged breasts), decreased muscle mass, osteoporosis with fractures that occur after only slight trauma, sleep disturbances and diminished cognitive function.[10]

Use is increasing

Many different formulations of testosterone drugs have been approved by the FDA for treatment of men with primary or secondary hypogonadism (see table below). These include topical, injectable, implanted and oral formulations. Topical gels are among the newest and most commonly prescribed.

A recent study in JAMA Internal Medicine demonstrated substantial increases in testosterone prescribing in the U.S. from 2001 to 2011.[11] Examining commercial health insurance records for 10.7 million men 40 years or older,[12] the researchers found that from 2001 to 2011, testosterone use among men age 40 or older increased more than three-fold (from 0.8 percent to 2.9 percent).[13] Of all formulations available, topical gels had the highest rate of overall use and the highest increase over the study time period — a more than five-fold increase.[14] The researchers also found that among all new testosterone users during the study period, one-fourth had not had a testosterone level measured in the preceding 12 months. Without such testing, hypogonadism in men cannot be reliably diagnosed.[15]

These trends in testosterone use suggest that many men are being prescribed testosterone therapy for normal, age-related declines in testosterone levels or for signs and symptoms of aging unrelated to low testosterone levels and not for hypogonadism, the only condition for which testosterone therapy is approved.

Testosterone Products Available in the U.S.

Initial evidence of cardiovascular risk

The first study raising substantial concern about the safety of testosterone was a randomized clinical trial published in the New England Journal of Medicine (NEJM) on July 8, 2010.[16] The purpose of the study was to evaluate the safety and effectiveness of testosterone treatment in men 65 years of age or older with limited mobility and low blood testosterone levels.[17] The subjects were randomly assigned to receive testosterone gel or a placebo gel (a gel that looked like testosterone gel but contained no active drug) daily for six months.[18] The primary outcome of the trial was muscle strength as measured by a leg-press exercise test.[19]

The researchers had originally planned to enroll 252 subjects in the randomized trial, but the study was stopped early after only 209 men (106 in the testosterone group and 103 in the placebo group) had been enrolled because there was a significantly higher rate of adverse cardiovascular events in the group receiving testosterone.[20] The average age of the 209 subjects was 74.[21]

Twenty-three subjects (22 percent) in the testosterone group and five subjects (5 percent) in the placebo group experienced an adverse cardiovascular event.[22] Among the testosterone group subjects experiencing adverse cardiovascular events, two had confirmed heart attacks, one died from a suspected heart attack, one suffered a stroke, one had an exacerbation of congestive heart failure and two developed atrial fibrillation.[23] No such events occurred in the control group. The higher relative risk of adverse cardiovascular events was seen throughout the six-month treatment period. The risk of adverse cardiovascular events remained significantly greater in the testosterone group subjects after accounting for differences in cardiac risk factors, such as smoking, hypertension, cholesterol levels and diabetes, between the two groups.[24]

Systematic review

The next important evidence linking testosterone use to adverse cardiovascular events comes from a study in the journal BMC Medicine published online on April 18, 2013.[25] For this study, known as a systematic review and meta-analysis, researchers pooled adverse event data from all randomized, placebo-controlled trials of testosterone that had been published in English-language medical journals and that reported adverse cardiovascular events.

In general, individual clinical trials of testosterone have not been designed to detect statistically significant differences in important adverse events because they enrolled small numbers of subjects and were of relatively short duration. By pooling data across a large number of trials, a meta-analysis provides a useful tool for detecting risks of important adverse events associated with a particular treatment.

The researchers for the BMC Medicine study identified 27 randomized, placebo-controlled clinical trials published over a 25-year period (ending on Dec. 31, 2012) that reported adverse cardiovascular events for both testosterone-treated and placebo-treated subjects. (One of the trials was the NEJM study discussed earlier). The total number of subjects across all trials was 2,994 (1,733 in testosterone groups, 1,261 in placebo groups), most of whom were middle-aged or older.[26]

In the 27 trials, 180 subjects experienced an adverse cardiovascular event. Subjects receiving testosterone had a 54 percent greater risk of such events than placebo-group subjects. In addition, 30 subjects died from a cardiovascular-related event in these trials (22 testosterone-group subjects and 11 placebo-group subjects).[27] Overall, testosterone-group subjects had a 42 percent greater risk of experiencing cardiovascular-related death than placebo-group subjects.[28] Both findings were statistically significant.

Latest epidemiology research

The newest evidence linking testosterone use to an increased cardiovascular risk comes from two recent well-designed epidemiology studies that analyzed the occurrence of adverse cardiovascular events in much larger groups of men prescribed testosterone.

The first of these studies was published in JAMA on Nov. 6, 2013.[29] Researchers affiliated with the Department of Veterans Affairs (VA) analyzed medical records of all male veterans who underwent a cardiac catheterization (a medical procedure for identifying narrowed or blocked coronary arteries) at any of 76 VA medical centers nationwide between 2005 and 2011 and who had a total serum testosterone level below the lower limit of normal (300 nanograms/deciliter).[30] Men who had taken testosterone prior to the cardiac catheterization or prior to having their testosterone level checked were excluded from the study.[31] The final study included 8,709 men.[32]

The VA researchers divided the study patients into those who were prescribed testosterone gels, patches or injections following their cardiac catheterization (1,223 men) and those who were not (7,486 men).[33] They then measured the amount of time it took for the men from each of the groups to die from any cause or to be hospitalized for heart attack or ischemic stroke.[34] Of note, the testosterone-treated patients tended to be younger and healthier (for example, lower incidence of congestive heart failure and renal disease at the start of the trial).[35]

At three years of follow-up after undergoing cardiac catheterization, patients who were prescribed testosterone were more likely to die or be hospitalized for a heart attack or ischemic stroke during the follow-up period than patients not prescribed testosterone (26 percent versus 20 percent, respectively).[36] After adjusting for the presence of coronary artery disease at the time of cardiac catheterization and other differences between the groups, the VA researchers found a 29 percent higher relative risk of one of the adverse outcomes in testosterone-treated patients compared with those not treated with testosterone.[37]

The second recent epidemiology study linking testosterone use to adverse cardiovascular outcomes was published online in PLOS One on Jan. 29, 2014.[38] For this study, the researchers analyzed data from a very large health care database that included information on employees, dependents and retirees across the U.S. enrolled in commercial or Medicare health insurance plans.[39] The database included data on diagnoses, procedures and prescriptions for all enrolled patients. From the database, the researchers identified 55,593 men who had received an initial prescription for testosterone therapy between Jan. 1, 2008, and Sept. 30, 2010.[40] The number of men exposed to testosterone for this study was more than 40 times greater than in the prior largest previous study, the VA study.

They also identified a control group of 167,279 patients who received an initial prescription for a phosphodiesterase type 5 inhibitor (PDE5I, which are erectile dysfunction drugs that have not been found to be associated with adverse cardiovascular events) during the same time period.[41] The primary result being studied was the diagnosis of an acute nonfatal heart attack.[42] The researchers compared the incidence rates of nonfatal heart attacks in each group of men before and after prescription of each of the specified study drugs.[43]

For all patients in the testosterone-treated group, the incidence rate of a nonfatal heart attack was 36 percent higher during the 90 days following prescription of testosterone compared with the time period before starting testosterone.[44] The study found that men ages 65 and older, whether or not they had previous heart disease, were significantly at increased risk of heart attacks, with the relative incidence rate being 2.2-fold higher following testosterone prescription compared to the time period before starting testosterone.[45] For men younger than age 65, increased risk with testosterone treatment was limited to those patients with a prior history of heart disease (2.9-fold increase in nonfatal heart attack incidence in 90 days following prescription of testosterone).[46] This finding of increased heart attacks following testosterone use in younger men with a history of heart disease was documented for the first time in this study, since earlier studies had not examined very large numbers of younger men. Statistically significant increases in heart attack risks were not seen in any of the groups of patients prescribed the PDE5I drugs.[47]

Conclusions

Taken together, the evidence from the studies summarized here strongly supports an association between testosterone therapy and serious adverse cardiovascular events, including heart attacks and death.

The exact mechanism by which testosterone drugs increase cardiovascular risk is unknown. However, testosterone treatment has been shown to increase red blood cell counts,[48],[49] blood viscosity[50] and the tendency of platelets to stick together,[51] all of which could predispose a patient to blood clots forming in the blood vessels. Testosterone treatment also is associated with increased blood pressure[52] and reduction in “good” (HDL) cholesterol.[53] All of these effects could plausibly increase the risk of adverse cardiovascular events such as heart attacks and strokes.

In an editorial discussing the JAMA epidemiology study, Dr. Anne Cappola at the Perelman School of Medicine at the University of Pennsylvania concluded the following:[54]

In light of the high volume of prescriptions and aggressive marketing by testosterone manufacturers, prescribers and patients should be wary. There is mounting evidence of a signal of cardiovascular risk, to which the study by Vigen et al contributes. This signal warrants both cautious testosterone prescribing and additional investigation.

We agree. We will be pressuring the FDA to add strong warnings to testosterone products about the risks of cardiovascular disease, especially heart attacks, none of which is present in the current FDA-approved labels, patient information or in company advertisements.

What You Can Do

You should take testosterone drugs only if you have clear clinical evidence of primary or secondary hypogonadism. The diagnosis of hypogonadism requires a finding of abnormally low testosterone levels measured on blood samples collected in the morning on two occasions, plus signs or symptoms of testosterone deficiency. You should never start testosterone without undergoing such blood tests.

Furthermore, you should seek to undergo testing for testosterone deficiency only if you have specific signs or symptoms of hypogonadism, such as reduced sexual desire and sexual activity, erectile dysfunction, hot flashes, small testes, male-factor infertility, decreased body hair, or gynecomastia. You should not take testosterone simply because of concerns about fatigue, decreased energy level, depressed mood or difficulty sleeping. Such symptoms are usually caused by many other conditions.

If you are prescribed testosterone, you should be alert for warning signs of adverse cardiovascular events, such as chest pain or pressure; shortness of breath; a rapid or irregular heart rate; or transient neurologic symptoms such as weakness, numbness or tingling on one side of the body.

You should not discontinue the use of any medication without first consulting your prescribing doctor.

References

[1] Vigen R, O’Donnell CI, Baron AE, 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] Finkle, WD, Greenland S, Ridgeway GK, et al. Increased risks of non-fatal myocardial infarction following testosterone therapy prescription in men. PLOS One. 2014; 9(1):e85805.

[3] Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173:1465-6.

[4] Testosterone and Aging: Clinical Research Directions. Catharyn T. Liverman, Dan G. Blazer, Editors; Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy. The National Academies Press. 2004.

[5] Ibid.

[6] Ibid.

[7] Ibid.

[8] Ibid.

[9] Dohle GR, Arver S, Bettochi C, et al. Guidelines on male hypogonadism. European Association of Urology. 2013.

[10] Ibid.

[11] Baillargeon J, Urban RJ, Ottenbacher KJ, et al. Trends in androgen prescribing in the United States, 2001-2011. JAMA Intern Med. 2013;173(15):1465-1466.

[12] Ibid.

[13] Ibid.

[14] Ibid.

[15] Ibid.

[16] Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-22.

[17] Ibid.

[18] Ibid.

[19] Ibid.

[20] Ibid.

[21] Ibid.

[22] Ibid.

[23] Ibid.

[24] Ibid.

[25] Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled trials. BMC Medicine. 2013;11:108.

[26] Ibid.

[27] Ibid.

[28] Ibid.

[29] Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.

[30] Ibid.

[31] Ibid.

[32] Ibid.

[33] Ibid.

[34] Ibid.

[35] Ibid.

[36] Ibid.

[37] Ibid.

[38] Finkle WD, Greenland S, Ridgeway GK, et al. Increased risks of non-fatal myocardial infarction following testosterone therapy prescription in men. PLOS One. 2014; 9(1):e85805.

[39] Ibid.

[40] Ibid.

[41] Ibid.

[42] Ibid.

[43] Ibid.

[44] Ibid.

[45] Ibid.

[46] Ibid.

[47] Ibid.

[48] Fernandez-Balsells MM, Murad MH, Lane M, et al. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95(6):256-2575.

[49] Eli Lilly and Company. Drug label for Axiron – testosterone solution. Revised 6/2013. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6e9cbce2-6e73-400f-9333-421a42afa3ae. Accessed January 6, 2014.

[50] Panin LE, Mokrushnikov PV, Kunitsyn VG, Zaitsev BN. Interaction mechanism of anabolic steroid hormones with structural components of erythrocyte membranes. J Phys Chem B. 2011;115:14969-14975.

[51] Ajayi AA, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation. 1995;91(11):2742-2747.

[52] Spitzer M, Huang G, Basaria S, et al. Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol. 2013;9(7):414-424.

[53] Fernandez-Balsells MM, Murad MH, Lane M, et al. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95(6):256-2575.

[54] Cappola AR. Testosterone therapy and risk of cardiovascular disease in men. JAMA. 2013;310(17):1805-1806