Author + information
- James A. de Lemos, MD∗ ( and )
- Rebecca Vigen, MD, MSCS
- Division of Cardiology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- ↵∗Reprint requests and correspondence:
Dr. James A. de Lemos, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8830.
- biological markers
- coronary artery disease
- epidemiological studies
- growth hormone
- heart failure
- human growth hormone
- risk assessment
Anabolic hormone use is increasingly common and includes replacement in patients with hormone deficiencies, questionable uses in those with borderline-low levels, and clear abuses among athletes aiming to gain a competitive advantage. Recently, direct-to-consumer marketing touting the benefits of “low T” treatment has led to increased testosterone use among middle-aged and older men, despite inadequate cardiovascular safety data. Although the Testosterone in Older Men Trial showed improvements in strength among treated patients, it was prematurely halted due to increased cardiovascular events in the treatment arm (1). Additionally, observational studies have demonstrated an association between testosterone prescription and increased myocardial infarction rates (2), as well as associations between testosterone therapy and adverse cardiovascular outcomes including all-cause mortality, myocardial infarction, and ischemic stroke (3). Recently, the U.S. Food and Drug Administration (FDA) announced an investigation of the safety of testosterone use, emphasizing that testosterone is only approved for use in men with low levels who have an associated medical condition (4).
The other anabolic hormone with clear treatment indications, as well as a potential for “indication creep” and abuse, is growth hormone (GH). GH is only approved for adults with proven deficiency, acquired immune deficiency syndrome wasting syndrome, or short bowel syndrome, and the Federal Food, Drug, and Cosmetic Act prohibits GH use for off-label indications. Among adults with GH deficiency, replacement improves body composition (5), exercise performance (6), and bone density (7). Additionally, GH replacement was shown to improve surrogate cardiovascular disease markers, including lipids (5) and inflammatory markers (8). Whether GH replacement improves cardiovascular morbidity or mortality in this population remains unknown.
Beyond these indications, athletes have used high-dose GH for performance enhancement. Additionally, low-dose GH in combination with other hormones, including testosterone, has been marketed by antiaging clinics. Following the 1990 publication of a small study that demonstrated improvements in body composition among older men following GH supplementation, the use of GH as an antiaging therapy expanded rapidly and continues to increase (9,10). Despite no projected change in the prevalence of GH deficiency, the global market for GH is expected to increase from $3.5 billion in 2011 to $4.7 billion by 2018 (11). This is not unexpected, as previous data demonstrated that up to 30% of GH prescriptions in the United States were prescribed for off-label indications (10).
Despite high rates of unapproved GH use for performance enhancement and anti-aging, there are limited efficacy data to support improvements in physical status. Although GH administration increased lean body mass in a study of healthy, young individuals, it had no effect on strength or exercise capacity (12). A meta-analysis evaluating GH treatment in elderly individuals found improvements in body composition, but no changes in cholesterol, maximal rate of oxygen consumption, bone density, or blood glucose (13). Additionally, high rates of adverse events were noted in treatment groups, most commonly soft tissue edema, carpal tunnel syndrome, arthralgia, and gynecomastia (13). There are no clinical trials evaluating the long-term cardiovascular safety and efficacy of GH therapy in healthy individuals.
In this issue of the Journal, Hallengren et al. (14) report an interesting epidemiological study that may provide additional insights into the cardiovascular effects of GH. They measured GH with a novel high-sensitivity (hs) assay in 4,323 healthy participants in the Malmö Diet and Cancer study and evaluated the associations between GH concentrations and cardiovascular risk factors, as well as incidence of coronary artery disease, stroke, congestive heart failure, and all-cause and cardiovascular mortality (14). Although no direct comparisons with a standard GH assay were performed, the hs-GH assay used by Hallengren et al. (14) likely captures a full range of values below the detection limits of standard assays, allowing the investigators to explore cardiac associations with physiological and not pathological levels of the hormone. Although individuals with higher GH levels had more favorable body composition and lipid profiles, similar to observations from studies of GH replacement (5), they also had higher rates of coronary artery disease, stroke, congestive heart failure, and all-cause and cardiovascular mortality (14). These findings have potential implications for the use of hs-GH as a biomarker in the general population, as well as implications for the appropriate use of GH in those with a diagnosed deficiency and for those using GH inappropriately.
Although hs-GH levels were statistically associated with adverse cardiovascular endpoints in the Malmö study, the magnitude of the association was modest and led to only a very small improvement in the C-statistic (14). For biomarkers to be useful for risk assessment in the general population, the magnitude of association will need to be larger and associated with improvements in discrimination and/or clinical metrics of risk classification, such as net reclassification improvement (15,16). Moreover, GH is probably too difficult to measure to be useful as a routine biomarker. As highlighted by the authors (14), GH secretion is pulsatile and may differ based on sleep patterns, time of day, and food intake (17). For these reasons, we do not believe it is likely that hs-GH will emerge as an important biomarker for cardiovascular risk assessment. However, well-performed biomarker studies, such as the present one, may have therapeutic implications and contribute to our understanding of disease processes, even if the magnitude of association of the biomarker with outcomes is modest. In this case, the findings raise preliminary concerns about the potential for adverse cardiovascular safety with GH treatment or illicit use.
Several caveats need to be mentioned. First, the application of the results of this analysis to the treatment of adults and children with diagnosed GH deficiency is unclear, because there may be important differences between endogenous GH levels and GH replacement. Indeed, the associations reported here appear to counter those seen in studies of GH replacement. The same difficulty in applying these results to GH-deficient patients exists when we consider their application to individuals who use exogenous GH for antiaging or performance-enhancing purposes.
This interesting study by Hallengren et al. (14) should be considered hypothesis-generating and should prompt additional study of the effects of GH on the cardiovascular system. Thus far, the data are conflicting, with some studies showing protective effects and others (including the present study) suggesting potential hazards. It is imperative that the cardiovascular safety of GH in adults at risk for or with cardiovascular disease be determined before the “genie gets out of the bottle” and GH use expands even further. The current situation with testosterone, where cardiovascular safety concerns are now emerging after the “genie” was released, should serve as a cautionary tale. Additionally, patients who are using GH for indications beyond those that are U.S. Food and Drug Administration–approved should be informed of the uncertainty regarding benefits and the potential for harm.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. de Lemos has received grant support and consulting income from Roche Diagnostics and Abbott Diagnostics; and has received consulting income from Diadexus, Amgen, Janssen Pharmaceuticals, and Abbott Diagnostics. Dr. Vigen has reported that she has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- ↵U.S. Food and Drug Administration. Testosterone products: drug safety communication—FDA investigating risk of cardiovascular events. 2014. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm384225.htm?utm_source=rss&utm_medium=rss&utm_campaign=testosterone-products-drug-safety-communication-fda-investigating-risk-of-cardiovascular-events. Accessed July 22, 2014.
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