William J. Bremner, M.D., Ph.D.

From the Department of Medicine, University of Washington, Seattle.

Introduction

It is now clear that men have gradual declines in substantial in many men, they are quite varia- average serum testosterone levels as they age. ble. Some men, even in old age, maintain serum These decreases begin by middle age and con- testosterone levels similar to those of healthy tinue into old age.^1,2 Although the decreases are young men.

Many of the physical and behavioral changes that occur in men as they age are similar to those that occur in younger men with hypogonadism. These changes include decreases in muscle mass, strength, bone mass, and sexual function and in-creases in body fat, fatigue, and depressed mood. It is therefore reasonable to ask whether testosterone deficiency could be causing some of the adverse physical and behavioral changes of aging and whether these could be improved with the administration of testosterone.

The diagnosis of testosterone deficiency in older men is complicated by the fact that many older men (more than 20% in some studies) have tes-tosterone levels that are lower than the normal range in younger men. In addition, the clinical presentation of male hypogonadism is nonspecific and overlaps with that of other illnesses and with the aging process itself. Therefore, it is frequently unclear in caring for individual older patients whether the diagnosis of hypogonadism is appropriate and whether testosterone admin-istration might be helpful or might instead cause adverse effects.

Two articles in this issue of the Journal address these important issues.^3,4 Wu et al.³ report on a population survey of 3369 men, 40 to 79 years of age, in eight European centers. Results of the sur-vey with respect to subjects’ general, sexual, physical, and psychological health were compared with morning measurements of total and free testosterone levels in the subjects’ serum. Among many symptoms surveyed, three sexual symptoms (poor morning erection, low sexual desire, and erectile dysfunction) and three general symptoms (inability to perform vigorous activity, depression, and fatigue) were associated with low testosterone levels. Further analysis showed that the presence of at least three sexual symptoms in a man with a total testosterone level of less than 11 nmol per liter (3.2 ng per milliliter) could be used to define late-onset hypogonadism. This conclusion was validated in a second data set in the same study. These conclusions are a valuable addition to earlier research, as well as to society guidelines,^5,6 which have also proposed the combination of symptoms and low testosterone levels to establish the diagnosis of late-onset hypogonadism. The difficulty with using symptoms alone to define late-onset hypogonadism was highlighted by the finding that more than 25% of men with normal testosterone levels had similar sexual symptoms.

Among older men with testosterone deficiency, can we replace testosterone in an effective and safe manner? Many studies involving limited numbers of men have shown that the administration of testosterone results in improved muscle mass and strength, increased bone mass, and other positive effects.⁷ None of the studies have been of sufficient size or duration to adequately address potential risks, such as the risk of prostate disease. The study by Basaria et al.⁴ was designed to assess whether leg-muscle strength in older men with severe limitations in mobility was increased as a result of testosterone administration. Community-dwelling men 65 years of age or older with a testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) were randomly assigned to receive a transdermal gel containing testosterone (to achieve testosterone levels of 500 to 1000 ng per deciliter [17.4 to 34.7 nmol per liter]) or placebo. The 209 participants had a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity. During the experimental phase, the testosterone group showed greater leg and arm strength than did the placebo group but also had higher rates of cardiovascular adverse effects. The excess of cardiovascular events in the testosterone group led the data and safety monitoring board to recommend early termination of the study. Of initial concern was the fact that 10 of the 106 men receiving testosterone had adverse cardiac events, as compared with 1 of the 103 men receiving placebo. Further investigation at the request of the data and safety monitoring board showed excesses of “cardiovascular-related” events in the testosterone group. These results are surprising, since many studies with cumulative numbers of subjects greater than those reported here have not detected substantial increases in cardiovascular risk during testosterone administration (including many studies in which subjects achieved the same or higher serum testosterone levels, some for longer periods of time).⁸ As the authors state, there is a clear possibility that their results are due to chance.

Many readers may disagree with the decision of the data and safety monitoring board to terminate the study early. Results of studies terminated early may differ from those of larger, longer-term studies. Also, readers will speculate that the higher rates of adverse events in the testosterone group may have been due to the fact that the two groups of men had different baseline characteristics, with a higher rate of hyperlipidemia and statin use and of hypertension in the testos-terone group before the experimental interven-tions. To me, the decision of the data and safety monitoring board seems reasonable. For whatever reason, there were higher rates of cardiovascular disease in the group of men who were receiving testosterone in this study than in their counterparts who were receiving placebo.

Although this result sounds a note of caution in general concerning testosterone administration in older men, it certainly should not deter inves-tigators from proceeding with additional, larger studies of testosterone administration in well- characterized groups of older men to more clearly outline benefits and risks. Similarly, it should not prevent clinicians from prescribing testosterone replacement for well-established late-onset hypo-gonadism, although it should provide some new caution about the administration of testosterone in older men who have an extensive history of cardiovascular disease and immobility.

Ultimately, we will need large, carefully de-signed trials of testosterone administration, per-haps along the lines of the Women’s Health Ini-tiative. Such trials should include a sufficient number of subjects to allow the assessment of key clinical outcomes, such as bone-fracture rates, muscle strength, and avoidance of falls, and an assessment of the role of testosterone replacement in the prevention of psychiatric disease, as well as the risks for prostate, cardiovascular, and other adverse outcomes. The numbers of older men receiving testosterone are large and increasing. We owe it to our patients and their families as well as to our physician colleagues to have much better data and guidelines for the administration of this critical hormone.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

References

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Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2002;87:589-98. 

Wu FCW, Tajar A, Beynon JM, et al. Identification of late- onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363:123-35. 

Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363:109-22. 

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Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl 2009;30:1-9. 

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