Comments by Neil F. Goodman, MD, FACE and Tim W. Irvin (a spokesperson for the FDA’s Center for Drug Evaluation and Research)
“It is incumbent on all physicians who provide TRT to men to clearly diagnose hypogonadism using the available guidelines,” said Neil F. Goodman, MD, FACE, Chairman, Reproductive Endocrine Scientific Committee, AACE and Clinical Professor of Medicine, Department of Endocrinology, University of Miami Miller School Of Medicine, Miami, Florida.
“The use of TRT in elderly men should be provided with caution, especially in the presence of clinical cardiovascular disease (CVD),” Dr. Goodman said. “All men receiving TRT should be carefully followed to evaluate efficacy and monitoring of CVD and other risk factors. Goals of therapy should be defined and continue TRT only if these goals are realized. If the physician is uncertain regarding the diagnosis of hypogonadism, a referral to an endocrinologist is recommended,” Dr. Goodman said.
The Basis for the Position Statement
“The Reproductive Endocrine Scientific Committee of AACE developed the position statement regarding the cardiovascular risks of testosterone therapy in response to two published papers that received extensive media attention but contained significant statistical inaccuracies regarding CVD risk and testosterone therapy,” Dr. Goodman said. “This was followed by the FDA statement presenting a warning regarding CVD risk and testosterone replacement therapy (TRT) in men but also recommended a narrowed view of which men with hypogonadism, documented by low testosterone, should be considered for TRT,” Dr. Goodman explained.
The following is an excerpt of the U.S. Food and Drug Administration’s statement:
“Health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests. Health care professionals should make patients aware of the possible increased cardiovascular risk when deciding whether to start or continue a patient on testosterone therapy. Patients using testosterone should seek medical attention immediately if symptoms of a heart attack or stroke are present, such as chest pain, shortness of breath or trouble breathing, weakness in one part or one side of the body, or slurred speech. Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.”
Flaws in Retrospective Studies of Testosterone Replacement Therapy
In the position statement, the AACE committee noted that randomized controlled trials have not been adequately powered to examine the effects of TRT on cardiovascular events or mortality. The two retrospective reports on this topic had major flaws, and a more recent retrospective cohort study showed no association between TRT and risk of myocardial infarctions, but this study also had limitations that precluded meaningful conclusions to be drawn.1-3
“Epidemiological studies strongly support the association of low testosterone concentrations and hypogonadism with cardiovascular events and all-cause mortality, especially in elderly men,” Dr. Goodman said. “TRT favorably changes many cardiovascular risk factors. It decreases fat mass, increases muscle mass, decreases insulin resistance and can reverse metabolic syndrome in some men. While TRT is widely believed to lower HDL concentrations, that effect appears limited to over replacement (ie, achieving supra-therapeutic concentrations of testosterone). Appropriate TRT therapy has minimal and clinically non-significant effect on lipid parameters. Testosterone therapy provides significant benefits for hypogonadal men,” he said.
“There is no compelling evidence that testosterone therapy increases or decreases cardiovascular risk,” Dr. Goodman said. “Large-scale prospective randomized controlled trials on testosterone therapy, focusing on cardiovascular benefits and risks, are clearly needed,” he added.
Furthermore, Dr. Goodman said, “AACE is concerned regarding the widespread prescribing of TRT, especially by ‘low T and anti-aging’ clinics, without properly diagnosing hypogonadism. Physicians should carefully adhere to published guidelines in making the diagnosis of hypogonadism and should focus on the cardiovascular risks of their patients. Monitoring of TRT regarding risks and benefits is essential.”
Statement From the FDA
“The FDA reviewed data informing the use, risks, and benefits of TRT in reaching its conclusions and recommendations,” according to Tim W. Irvin, a spokesperson for the FDA’s Center for Drug Evaluation and Research. “Based on the available evidence from observational studies and expert input from an advisory committee meeting, the FDA cannot definitively conclude that there is an increased risk of serious heart problems associated with TRT,” Mr. Irvin said.
“Some large studies, however, showed an increased risk of heart attack and stroke associated with prescription testosterone, while others did not,” Mr. Irvin said. “Testosterone is FDA-approved as replacement therapy only for men who have absent or low testosterone levels due to disorders of the testicles, pituitary gland, or brain. Health care professionals should consider whether the benefits of TRT are likely to exceed the risks of treatment for each patient,” Mr. Irvin concluded.
October 12, 2015
Goodman N, Guay A, Dandona P, Dhindsa S, Faiman C, Cunningham GR; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the association of testosterone and cardiovascular risk. Endocr Pract. 2015;21(9):1066-1073.
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(17):1829-1836.
2. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805.
3. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93(1):68-75.