© 2005 American Thoracic Society doi: 10.1164/rccm.2508008
Low Testosterone in Chronic Obstructive Pulmonary DiseaseDoes It Really Matter?Loyola University Medical Center, Hines VA Hospital, Maywood, Illinois Middle-aged and elderly men exhibit a decline in the concentration of serum testosterone (1). When excessive, this decline may contribute to diminished energy level, libido, bone density, and muscle mass (2). This constellation of signs and symptoms has been termed late-onset hypogonadism, symptomatic late-onset hypogonadism, androgen deficiency in the aging male, or andropause (3). The observation that many patients with COPD, most of whom are middle-aged or elderly, fit the profile of late-onset hypogonadism (4–6) has spurred a flurry of research on the incidence (6–8), functional impact (6, 8–10), and possible treatment (11) of this abnormality. In this issue of the Journal (pp. 1105–1111), Van Vliet and coworkers (8) extend our knowledge on late-onset hypogonadism in men with COPD. They compared, for the first time, patients with COPD and age-matched control subjects. Half of the 78 patients with COPD had low levels of free testosterone, whereas a quarter of the 21 control subjects were hypogonadal. Does this mean that late-onset hypogonadism has a high prevalence in patients with COPD? Probably not. First, the prevalence of hypogonadism in the small control group of Van Vliet and colleagues is much lower than the 34 to 40% prevalence of hypogonadism for subjects in their 60s (1, 12) and than the near 70% prevalence for subjects in their 70s (1) reported in population studies in North America (1) and Europe (12). Second, when the data of Van Vliet and colleagues are pooled with three other recent studies (6, 7, 10), the overall prevalence of hypogonadism in men with COPD is 43%. This is within the range reported in population studies of generally healthy men of the same ages (1, 12). Third, the conclusion that late-onset hypogonadism in men with COPD is not something unique to these patients—and probably not different from late-onset hypogonadism in the general population—is further supported by the lack of correlation between testosterone levels and severity of obstruction (6, 8) or with potential causes of hypogonadism specific to patients with COPD, such as hypoxemia or glucocorticoid therapy (6, 8, 10). The similar prevalence of comorbidities in the hypogonadal and eugonadal men with COPD, reported for the first time by Van Vliet and colleagues, further supports the possibility that hypogonadism in these patients is not a different entity from late-onset hypogonadism in the general population. In their investigation, Van Vliet and coworkers (8) noted a correlation between quadriceps strength and testosterone concentrations. This finding adds information to a complex and often contradictory body of literature (9–11, 13, 14). For instance, Debigare and associates (10) reported that the prevalence of hypogonadism among men with COPD is equivalent among patients with and without muscle wasting. Similarly, we (9) recorded no difference in quadriceps strength (and endurance) between hypogonadal and eugonadal men with COPD. In addition, when Bhasin and colleagues (13) administered a long-acting gonadotropin-releasing hormone agonist to induce hypogonadism in elderly men and then supplemented the men with subtherapeutic doses of testosterone enanthate, they found no difference in fat free mass or muscle strength. When the same investigators doubled the circulatory levels of total and free testosterone by administering higher doses of testosterone enanthate, the increases in fat free mass and strength were within the noise of the measurement. The same team of investigators, however, reported a 17% increase in quadriceps strength (and endurance) when administering 100 mg/week of testosterone enanthate for 10 weeks to men with COPD undergoing resistance training (11). It is not known why low testosterone should cause decreased strength in some series and not in others, nor whether the statistical differences in quadriceps strength—when present—are clinically important. Despite less quadriceps strength among their hypogonadal patients, Van Vliet and colleagues (8) reported equivalent exercise capacity (6-minute walk distance) in the two groups of patients. This result confirms previous observations of equivalent exercise capacity, quantified either as 6-minute walking distance (6) or maximal bicycle ergometry (9), in men with COPD with and without hypogonadism. The similar exercise performance in the two groups is also consistent with the observation that administration of anabolic steroids to unselected patients with COPD (15, 16) or testosterone enanthate to men with COPD and variable testosterone levels (11) produces no improvement in whole body exercise capacity. A crucial question is whether the results of Van Vliet and coworkers (8) support the use of testosterone supplementation in men with COPD who have low testosterone levels. The investigators express caution. Men who have COPD and low testosterone levels do not differ from their eugonadal counterparts in respiratory symptoms, quality of life, respiratory muscle strength and endurance, and exercise capacity (6, 8, 9). Therefore, it is difficult to justify that goals of replacement therapy are to improve these parameters. Replacement therapy does not increase exercise capacity or respiratory muscle strength in these patients (11). The use of testosterone replacement therapy to increase quadriceps strength in patients participating in rehabilitation programs is promising (11), but requires larger trials. The caution expressed by Van Vliet and colleagues (8) on whether (or not) to advocate testosterone replacement in men with COPD and low testosterone levels reflects the ongoing controversy regarding indications for testosterone replacement in older men in general (2, 3). Long-term testosterone supplementation can be associated with side effects, including increase in hematocrit, sleep apnea, and prostatic hypertrophy (2, 3). The effects of testosterone administration on the risk of atherosclerotic heart disease and prostate cancer remain unknown (2, 3) because all current studies are underpowered to answer these questions. For example, more than 6,000 elderly hypogonadal men randomly assigned to receive testosterone or placebo for 6 years would be necessary to determine whether testosterone treatment increases the risk of prostate cancer by 30% (2). In a recently published report from the Institute of Medicine, an expert committee concluded that unless more convincing studies are published, there is currently insufficient evidence to support testosterone therapy in older men (the case of most patients with COPD) (2). So, does it matter if a man with COPD has low testosterone levels? The question raises the issue of whether clinically important functional differences between hypogonadal and eugonadal patients do exist, which, in turn, could have important therapeutic implications. For some clinical aspects, the accumulating evidence suggests that men with COPD and late-onset hypogonadism are not different from their nonhypogonadal counterparts. Therefore, if testosterone is administered, it would be unclear what therapeutic effects should be monitored. Despite these considerations, several questions remain unanswered. For example, would men with COPD and low testosterone levels benefit from long-term testosterone therapy to treat osteoporosis? Does low testosterone level affect sexual function, intellectual capacity, or mood in men with COPD? Should testosterone be used during rehabilitation? FOOTNOTES Conflict of Interest Statement: F.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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