[Open Access] Goodman N, Guay A, Dandona P, Dhindsa S, Faiman C, et al. 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):1066-73.
http://journals.aace.com/doi/full/10.4158/EP14434.PS
This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.
ABBREVIATIONS: CI = confidence interval FDA = Food and Drug Administration LH = luteinizing hormone MI = myocardial infarction TRT = testosterone replacement therapy.
EXECUTIVE SUMMARY
Several recent publications have raised concern that testosterone replacement therapy (TRT) in men increases cardiovascular risk (1,2). This resulted in the U.S. Food and Drug Administration (FDA) holding a hearing and issuing the following statement on March 3, 2015:
“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.”
It is the purpose of this document to state briefly the position of American Association of Clinical Endocrinologists on the association of TRT with cardiovascular risk. A detailed document presenting the scientific evidence for the association of low testosterone concentrations with and the effects of testosterone therapy upon cardiovascular risk follows this statement.
The key points described in the document are:
Epidemiologic studies strongly support the association of low testosterone concentrations and hypogonadism with cardiovascular events and all-cause mortality, especially in elderly men (3,4). However, low testosterone could be a marker of illness and not a causal factor.
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 (5).
Randomized controlled trials have not been powered to evaluate the effect of testosterone replacement in men on cardiovascular events or mortality. However, 2 retrospective reports have raised concern that testosterone therapy increases cardiovascular risk (1,2). As reviewed in the accompanying document and in the March 3, 2015 FDA report (available online at:
http://www.fda.gov/drugs/drugsafety/ucm436259.htm), these studies have major flaws precluding meaningful conclusions to be drawn. A more recent retrospective cohort study using enrollment and claims data for Medicare beneficiaries showed no effect of TRT on myocardial infarctions (6). However, this study suffered from the same limitations as those mentioned above.
Following a formal in-depth review, the FDA released a new warning and updated labeling on TRT to reflect the possible increased risk of heart attacks and strokes associated with testosterone use. The Committee concurs in the FDA conclusion that the signal for cardiovascular risk is weak and that we need definitive studies.
The FDA also recommended that: “Testosterone is an FDA-approved replacement therapy only for men with disorders of the testicles, pituitary gland or brain that cause hypogonadism” and that “it should not be used to relieve symptoms in men who have low testosterone for no reasons other than aging.”
This recommendation is not clear. It is our opinion that any patient being considered for TRT must undergo a thorough diagnostic work-up (7–9). The decision to replace testosterone should be guided by the signs/symptoms and testosterone concentrations rather than the underlying cause. These men should be told that we do not have definitive studies demonstrating efficacy or risk for treating men with these conditions. The committee agrees that the risk/benefit ratio of TRT is not well established in aging-associated hypogonadism. Our recommendations follow:
a) We recommend that symptomatic men who have unequivocally low total and/or free testosterone levels that are assayed on at least 2 samples drawn before 10 am should be considered for TRT.
b) We advise the practicing clinician to be extra cautious in the symptomatic elderly with demonstrably low testosterone levels prior to embarking on replacement therapy and to avoid treatment of the frail elderly until better outcome data are available.
Conclusion: Recent reports related testosterone treatment to increased cardiovascular events. However, there is no compelling evidence that testosterone therapy either increases or decreases cardiovascular risk. Large-scale prospective randomized controlled trials on testosterone therapy, focusing on cardiovascular benefits and risks, are clearly needed. As with therapeutics in general, common sense, experience, and an individualized approach are recommended.
