The Reproductive Endocrine Scientific Committee of American Association of Clinical Endocrinologists' (AACE) issued a position statement in response to recent studies suggesting an association between testosterone replacement therapy (TRT) use and an increased risk of cardiovascular events and all-cause mortality. The Committee cited lack of compelling evidence that TRT increases or decreases the risk for cardiovascular events and stated that TRT may be a marker of cardiovascular disease rather than a causal factor.
The Basis for the Position Statement
In March 2015, the U.S. Food and Drug Administration issued the following statement in response to recent studies suggesting that TRT increases CVD risk:1
"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."
Flaws in Retrospective Studies of Testosterone Replacement Therapy
The AACE committee noted that randomized controlled trials on this topic 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, according to the committee.2-4
Additionally, the AACE position statement highlights the benefits of TRT in men with cardiovascular risk factors, including a decrease in fat mass, an increase in muscle mass, decreased insulin resistance, and a reversal of metabolic syndrome in some patients.
The Committee recommended that TRT therapy should be considered for men who are symptomatic and have unequivocally low total and/or free testosterone levels assayed on ≥2 samples drawn before 10 am. Extra caution should be used before initiating TRT in symptomatic elderly men until more outcome data are available, according to the position statement.
The AACE committee concluded that large-scale prospective randomized studies are needed to determine the impact of TRT on cardiovascular disease risk. In the interim, AACE recommends that clinical decisions on TRT use should be guided by individual patients' signs and symptoms as well as testosterone concentrations rather than the underlying cause of low testosterone such as aging.
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. U.S. Food and Drug Administration. 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. March 15, 2015. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm436280.htm.
2. 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.
3. 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.
4. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93(1):68-75.
Commentary by Tamara L Wexler MD, PhD
Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in neuroendocrinology and reproductive endocrinology. She is the Director of the NYU Langone Medical Center Pituitary Center in New York, NY, as well as an Attending in Medicine at Massachusetts General Hospital, Boston, MA.
This position statement by the Reproductive Endocrine Scientific Committee of American Association of Clinical Endocrinologists (AACE) was spurred by recent reports of cardiovascular risk with testosterone therapy, and by a March, 2015, US FDA statement suggesting limiting testosterone treatment to particular conditions of hypogonadism, and raising the issue of potential cardiovascular risk. AACE's statement reviews existing evidence, concluding that there is insufficient data to establish risk. The reviewed publications include several we profiled in our March of 2014 EndoScan, including those by Vigen and colleagues,1 and more specifically by Finkle and colleagues.2
The decision to start testosterone therapy is tailored to each patient. Broadly speaking, the use of testosterone treatment in adult men (that is, beyond puberty) can be separated into two categories: 1) use in adults with testosterone deficiency such as caused by disturbances in the hypothalamic-pituitary-testicular axis, and 2) use in adults with symptomatic hypogonadism of unknown cause. [Other uses may include induction of delayed puberty, use in transgendered individuals, and use in certain chronic disease states.] When the testosterone deficiency is due to known disease, the situation is more clear-cut for most physicians. It is less clear in older men with levels that begin to fall, as the normal range has not been established for all ages; identification of symptoms and signs (such as using bone densitometry) is important.
The Endocrine Society 2010 clinical practice guideline on testosterone therapy in men with androgen deficiency (also profiled in our March 2014 EndoScan, as the most current guideline on testosterone use at the time) recommends against general use of testosterone therapy in older men with low testosterone levels.3 In cases in which clinically significant symptoms accompany repeat low testosterone levels, opinions of the Endocrine Society committee varied as to the testosterone level below which testosterone treatment is warranted (<200 ng/dL or <300 ng/dL). The US Food and Drug Administration (FDA) approves testosterone use only as replacement in men with "low testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause a condition called hypogonadism." The FDA statement continues to note that "FDA has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging. The benefits and safety of this use have not been established."4 The FDA conclusion as to possible increased CV risk was based on available evidence at that time from published studies—including in older men—and expert input; the 2010 Endocrine Society guidelines are not listed as one of their references.4
The basic recommendations of the Endocrine Society, FDA, and AACE exist along a spectrum. They all agree that testosterone replacement should be reserved for situations in which testosterone is low when appropriately measured, and in which clinical symptoms are present. Differences between groups are most notable regarding allowed etiologies. The FDA approves use of testosterone in the setting of hypothalamic-pituitary-testicular axis disease. The Endocrine Society includes a broader range of diseases in its recommendation for screening of hypogonadism (eg, end-stage renal disease). AACE suggests that etiology not be one of the considerations in the decision to treat, though it advises caution in older men.
Regarding cardiovascular risk, the level of credence given to concerning published results may vary slightly, but all three groups agree that longer and larger studies are needed to establish the cardiovascular safety of testosterone use in different settings. Studies to date investigating cardiovascular risks or benefits of testosterone therapy have had limitations, including that none are randomized trials designed to measure cardiovascular endpoints.
Additional studies—such as the results of the cardiovascular T trial—will help characterize the cardiovascular effects of testosterone replacement, including in older men. At present, a description of what is known regarding benefits and risks should be shared with all patients in whom testosterone replacement is deemed appropriate. In sum, in each situation, it is important to weigh a patient's symptoms against potential risks before initiating treatment, and to monitor testosterone levels and clinical signs and symptoms.
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. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536–2559.
4. U.S. 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. February 3, 2015. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm