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Adverse Events Associated with Testosterone Administration
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"In this study of older men with low testosterone levels and limitations in mobility, random assignment to daily application of a testosterone gel, as compared with a placebo gel, was associated with a greater frequency of adverse events, particularly cardiovascular, respiratory, and dermatologic events"
Shehzad Basaria, M.D., Andrea D. Coviello, M.D., Thomas G. Travison, Ph.D., Thomas W. Storer, Ph.D., Wildon R. Farwell, M.D., M.P.H., Alan M. Jette, Ph.D., Richard Eder, B.A., Sharon Tennstedt, Ph.D., Jagadish Ulloor, Ph.D., Anqi Zhang, Ph.D., Karen Choong, M.D., Kishore M. Lakshman, M.D., Norman A. Mazer, M.D., Ph.D., Renee Miciek, M.S., Joanne Krasnoff, Ph.D., Ayan Elmi, B.A., Philip E. Knapp, M.D., Brad Brooks, B.S., Erica Appleman, M.A., Sheetal Aggarwal, B.S., C.C.R.P., Geeta Bhasin, B.A., Leif Hede-Brierley, Ashmeet Bhatia, M.B., B.S., Lauren Collins, R.N.P., Nathan LeBrasseur, Ph.D., Louis D. Fiore, M.D., and Shalender Bhasin, M.D.
N Engl J Med 2010; 363:109-122July 8, 2010
ABSTRACT
Background
Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied.
Methods
Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group.
Results
A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load.
Conclusions
In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy.
Limited mobility is a common geriatric condition that is a predictor of disability, poor quality of life, and death.1-7 In men, an age-related decline in the serum testosterone concentration is associated with reduced muscle mass and lower-extremity strength, limitations in physical function, and poor mobility. 8-13 Testosterone supplementation increases muscle mass and strength and leg power, all of which are important determinants of mobility.14-21 Previous trials of testosterone supplementation have been conducted primarily among healthy older men. The safety and efficacy of testosterone treatment in improving muscle performance and physical function in older men with limitations in mobility have not been studied.
The Testosterone in Older Men with Mobility Limitations (TOM) trial was a placebo-controlled, randomized trial that was designed to determine the effects of testosterone administration on lower-extremity strength and physical function in older men with limitations in mobility and low serum levels of total or free testosterone.22 In December 2009, a data and safety monitoring board, established by the National Institute on Aging, determined that the incidence of adverse cardiovascular events in the TOM trial was significantly higher in the testosterone group than in the placebo group. The members of the data and safety monitoring board therefore recommended that enrollment and administration of the study medications be discontinued. We report here the adverse events associated with testosterone therapy in the TOM trial. The effects of testosterone therapy on efficacy outcomes are reported briefly.
Adverse Events
In the testosterone group, as compared with the placebo group, there were significantly more adverse events and significantly more subjects who reported one or more adverse events (Table 2 in the Supplementary Appendix). Twice as many men in the testosterone group as in the placebo group were referred for medical evaluation owing to an adverse event. Men who were assigned to testosterone also reported a greater number of serious adverse events and a greater number of adverse events that were considered to be life-threatening, although the differences between the groups were not significant (Table 3 in the Supplementary Appendix).
Significantly more men in the testosterone group than in the placebo group had adverse events in three MedDRA categories: cardiac disorders; respiratory, thoracic, and mediastinal disorders; and skin and subcutaneous tissue disorders (Table 2 in the Supplementary Appendix). Of particular concern to the data and safety monitoring board was the greater number of subjects with adverse cardiac events in the testosterone group than in the placebo group (10 vs. 1) (Table 3). In accordance with the recommendation of the data and safety monitoring board, two additional analyses of cardiovascular events were performed (Table 3Table 3Subjects with One or More Cardiovascular-Related Adverse Events.). A total of 23 men in the testosterone group and 5 in the placebo group had cardiovascular-related events; 7 men in the testosterone group and 1 in the placebo group had atherosclerosis-related events.
The risk of a cardiovascular-related adverse event remained significantly greater among men in the testosterone group than among men in the placebo group after adjustment for age group, body-mass index, smoking status, high-density lipoprotein cholesterol level, and presence or absence of diabetes, hyperlipidemia, and hypertension (Table 4Risk of Adverse Events with Testosterone Therapy, According to Category.). In time-to-event analyses, the relative risk of a cardiovascular-related event remained constant throughout the 24-week intervention period (Figure 1Time-to-Event Analysis of Adverse Events, According to Body System.). There were few adverse events during the 3-month observation phase after the end of the intervention period.
There was no evidence of a significant relationship between potential risk factors and cardiovascular-related events in time-to-event analyses (Figure 2 in the Supplementary Appendix). Men with testosterone levels in the highest quartile during the intervention period, as compared with all other subjects, were at elevated risk for cardiovascular-related events (hazard ratio, 2.4; P=0.05). Among subjects who were randomly assigned to the testosterone group, testosterone levels during the intervention period were available for 81 subjects. Cardiovascular-related events were reported in 4 of 14 subjects with testosterone levels higher than 1000 ng per deciliter during the treatment period, by 5 of 21 with levels of 500 to 1000 ng per deciliter, and by 7 of 46 subjects with levels of less than 500 ng per deciliter.
One man in the testosterone group had a hematocrit that was higher than 54%, and one reported having received a diagnosis of prostate cancer. One man in the placebo group underwent transurethral resection of the prostate.
Discussion
In this study of older men with low testosterone levels and limitations in mobility, random assignment to daily application of a testosterone gel, as compared with a placebo gel, was associated with a greater frequency of adverse events, particularly cardiovascular, respiratory, and dermatologic events. The divergence between the groups in the incidence of cardiovascular adverse events was maintained over the 6-month intervention period and did not diminish during the 3-month observation phase that followed the intervention period. The increased cardiovascular risk in the testosterone group was seen with all three definitions of cardiovascular events, and the increase persisted after adjustment for baseline risk factors. The increased risk was also evident in sensitivity analyses adjusted for baseline mobility status and Short Physical Performance Battery score and in sensitivity analyses performed after the exclusion of subjects whose eligibility deviated from the planned criteria. The pattern of adverse cardiovascular events associated with testosterone therapy was considered by the data and safety monitoring board to be of sufficient concern to warrant termination of the trial.
The generalizability of our data about the safety of testosterone therapy is limited by several factors. First, cardiovascular events were not a planned primary or secondary outcome, and therefore, a structured evaluation of cardiovascular events was not performed, a factor that may have influenced the ascertainment of events. Most of the cardiovascular-related events were verified from medical records or by direct examination. Second, the sample, although larger than those in most previous trials, was small, and the number of adverse events was small. The results of individual small trials may not be confirmed in large trials,28 and trials that have been stopped early tend to overestimate treatment differences. Third, the clinical characteristics of our study population differ from those of most other populations in which testosterone therapy has been administered in a clinical setting or as part of a clinical trial. Men who were younger than 65 years of age and men with severe hypogonadism were excluded from the trial. Participants had substantial limitations in mobility and a high prevalence of chronic conditions, including preexisting heart disease, obesity, diabetes, and hypertension. Frail elderly men with limitations in mobility are more likely to have clinical and subclinical cardiovascular disease than are those who do not have limitations in mobility.29,30
Previous studies provide very limited data to either reinforce or contradict the findings in this study with respect to the effects of testosterone therapy in older men with limited mobility. Meta-analyses of previous trials of testosterone therapy have not shown significant increases in cardiovascular risk with testosterone therapy, although nonsignificant increases have been noted among participants of all ages,31-33 as well as among older men.31,33 The trials in these meta-analyses were limited by inadequate methods of ascertaining adverse events or the poor quality of data on adverse events, by the small numbers of events or the small numbers of older participants, or by intervention periods that were shorter than the 6-month intervention in this trial. Some epidemiologic studies have shown that low testosterone levels are an independent risk factor for death from cardiovascular causes and from all causes.34-37 However, differences between the effects of endogenous hormones and those of pharmacologic hormonal therapy, as well as differences in the duration of exposure to testosterone, could contribute to the apparent discrepancies between these epidemiologic data and the results of our trial.
It is not likely that the adverse cardiovascular events seen in the TOM trial are a consequence of an unusual protocol for testosterone administration (Table 4 in the Supplementary Appendix). The upper limit of the testosterone threshold used for inclusion in the trial is not dissimilar to that used in most other trials.16-19,38-47 The testosterone doses in this trial may have been higher than those that are typically used in clinical practice48 and were higher than the doses used in some previous trials17,18,39-42 but were similar to those in other trials.16,21,43-46 The average testosterone concentrations during the intervention period among men in our testosterone group were in the middle of the normal range for young men; these levels were higher than those in some testosterone trials17,18,39-42 but did not differ from levels reported in other trials.16,19,21,43-46
The cardiovascular adverse events reported in the TOM trial were diverse and may have variable clinical importance. The lack of a consistent pattern in these events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone. The results of several separate analyses were consistent with the initial observation of a significant difference, but these analyses were not entirely independent of one another. In interpreting these findings, it is essential to recognize the role that chance may have played in the outcomes we observed.
The diversity of cardiac adverse events also renders the events less susceptible to a single mechanistic explanation. Testosterone causes salt and water retention,49-51 particularly in older men,14 and this could contribute to edema, hypertension, and congestive heart failure, although there are some trials in which testosterone has been administered in men with congestive heart failure.39,40 Testosterone and associated increases in estradiol may promote inflammation, coagulation, and platelet aggregation.52 The use of anabolic steroids has been associated with left ventricular hypertrophy and systolic and diastolic dysfunction.53,54 Changes in plasma lipid levels would not account for the rapid divergence in rates of cardiovascular adverse events.
Testosterone therapy was associated with significant improvements in leg-press and chest-press strength and in stair-climbing power with a load. Inferences regarding efficacy are limited because of the attenuation of statistical power owing to the early termination of the trial.
In conclusion, we evaluated the effect of testosterone supplementation in men 65 years of age or older who had limitations in mobility and low serum levels of total or free testosterone. The trial was stopped before enrollment had been completed because of an incidence of adverse cardiovascular events that was higher in the testosterone group than in the placebo group. However, caution is warranted in interpreting this finding, because of the small numbers of events and because of limitations with respect to the ascertainment of adverse events. Caution is also warranted in extrapolating these findings to other doses and formulations of testosterone or to other populations, particularly young men who have hypogonadism without cardiovascular disease or limitations in mobility.
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