Researchers studied testosterone therapy’s effect on men at risk for heart disease. They also warned the hormone should not be taken to restore youthful vigor.
Millions of aging men have been prescribed testosterone replacement therapy to boost their sex drive and overall vitality. Now, a much-anticipated study shows the controversial treatment doesn’t increase the risk of “major” cardiac events such as heart attacks or heart-related deaths, nor does it protect the heart against them.
The finding is likely to ease concerns that supplemental testosterone poses a potential cardiovascular threat, but the study’s scientists also warned that men should not misinterpret the results and take testosterone as a way to restore youthful vigor.
“Men should not use testosterone for anti-aging,” said the study’s senior author, Steven E. Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic. “I don’t want our study to be misused by physicians to prescribe it to men who simply want to feel younger.”
The research, known as the TRAVERSE study (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy ResponSE), was published in the New England Journal of Medicine and presented simultaneously at the annual meeting of the Endocrine Society on Friday.
It found that testosterone-replacement therapy did not produce a higher rate of “major adverse cardiac events” — including heart attacks and heart-related deaths — in middle-aged and older men with low testosterone (hypogonadism) who had preexisting heart disease or a high risk of developing it.
The authors stressed that men should take supplemental testosterone only when it is medically necessary — when a patient has a testosterone deficiency confirmed by a blood test and symptoms such as reduced body and facial hair, loss of muscle mass, low libido, hot flashes, poor concentration, irritability, depression, and thinning bones.
Testosterone, the major sex hormone in men, gradually declines with age, at about 1 to 2 percent every year.
Worries about heart effects
The study was conducted in response to concerns from the Food and Drug Administration over conflicting data regarding testosterone’s effects on the heart, including a small study that showed an increased incidence of heart-related problems among men taking it.
This prompted the FDA in 2015 to change the label on testosterone products, cautioning that the use of testosterone should be limited to treating hypogonadism, not signs of aging, and warning of the potential heart disease risk.
The agency ordered testosterone manufacturers to sponsor a clinical trial to determine if the products posed a cardiovascular or stroke danger to men taking them.
The study included 5,198 men ages 45 to 80 with low testosterone, all of whom had preexisting cardiovascular disease, or had cardiovascular disease risk factors such as hypertension, diabetes, smoking, and Stage 3 kidney disease.
Patients were randomly assigned to receive a daily testosterone gel or a placebo gel through the skin. Results showed that after an average 22 months of treatment, the drug did not cause more major heart problems than the placebo, the researchers said.
A higher risk of afib
Those who took testosterone, however, did experience a statistically significant higher incidence of atrial fibrillation — an irregular heartbeat that raises the risk of stroke — acute kidney injury, and issues arising from blood clots in the veins. (Current guidelines recommend that testosterone should be used with caution in men who have had previous blood clots, the researchers said.)
“This is a concern. I can’t give testosterone a completely clean bill of health,” Nissen said. “I can say it didn’t cause the most important adverse events” — meaning heart issues — although “it did cause increases in other events of less gravity.”
The results probably will be a relief to men anxious about the drug’s effects on the heart, said Robert Eckel, a professor of medicine emeritus at the University of Colorado School of Medicine, with a joint appointment in endocrinology and cardiology, who was not part of the study. “However, we still need to be cautious about prescribing it because of these unexpected risks,” said Eckel, a past president of the American Heart Association.
The study found no worrisome occurrences of prostate cancer cases in either group, said lead study author Michael Lincoff, vice chair for research in the Cleveland Clinic Department of Cardiovascular Medicine, although men with prostate cancer or elevated prostate-specific antigen (PSA) were not eligible for the trial. (Prostate cancer is related to male hormones and testosterone-blocking medications are prescribed for certain types of prostate cancer, according to the Prostate Cancer Foundation.)
In financial disclosures related to the study, both Nissen and Lincoff reported they had overseen clinical trials for several pharmaceutical companies, including one manufacturer that makes testosterone.
A consortium of testosterone manufacturers funded the study, including AbbVie, Acerus Pharmaceuticals, Endo Pharmaceuticals and Upsher-Smith Laboratories, and was conducted by the Cleveland Clinic Coordinating Center for Clinical Research with support from a contract research organization, Labcorp Drug Development.
The growing debate about supplemental testosterone
Treatment for low testosterone — or “low T” — has been the subject of growing debate in the United States. Supplemental testosterone is especially controversial because many men use it to feel youthful or to build strength and muscle mass. There has been a proliferation in recent years of what are known as “T Centers” — anti-aging clinics — where physicians dispense testosterone prescriptions, often without testing for a deficiency, the researchers said
A study published in JAMA Internal Medicine showed prescriptions for testosterone therapy tripled between 2001 and 2011 for men over age 40.
“Men want to feel like they felt at 18 to 25, with their sexual performance the way it was when they were youthful,” Nissen said. “Some men see it as a potential fountain of youth and — unfortunately sometimes it is marketed that way. Men want to feel like Arnold Schwarzenegger did when he was 25. And that is not a reason to be taking it.”
“Men want to turn back the clock,” said William Schaffner, a professor of preventive medicine at Vanderbilt University Medical Center, who was not part of the study. “But low testosterone is not a life-threatening condition. You don’t want to take any medication unless there is a reasonable chance you’re going to benefit from it.
Beth Abramson, a professor of cardiac prevention and women’s health at the University of Toronto, also sounded a cautionary note. “As cardiologists, we need to look at the benefits versus the risks, and this study will help us individualize therapy for our patients,” said Abramson, who was not involved in the study. “This doesn’t mean that men with normal testosterone should be taking more of it.”
The debate over testosterone supplementation resembles an earlier, decades-long one over the risks and benefits of hormone replacement therapy (HRT) for menopausal women.
For years physicians routinely prescribed HRT as a preventive therapy in hopes of protecting women from heart disease, based on observational studies that suggested a benefit. A major study called the Women’s Health Initiative instead found that in certain women, a combination of estrogen and progestin increased the risk of breast cancer, heart attacks and stroke. (The drugs are still recommended for the treatment of menopausal symptoms including hot flashes.)
“It’s almost the same kind of story, in that we have been trying to modify the normal physiology of aging with replacement hormones,” Lincoff said. “But we need to ensure there aren’t any adverse consequences in doing so.”
