We recently reported that hypogonadism does not affect respiratory muscle performance and exercise capacity in men with chronic obstructive pulmonary disease (COPD). In COPD, however, the relationship between exercise capacity and quality of life is controversial, making it unreliable to extrapolate about quality of life from exercise data. Accordingly, we determined prevalence and impact of hypogonadism on health-related quality of life in men with COPD. We enrolled 101 stable outpatient men (FEV1 1.34 ± 0.04 L) older than 54 years; 38 patients were hypogonadal—a prevalence similar to that reported in the general population. The degree of airflow limitation did not predict levels of free testosterone. Quality of life, as quantified by a disease-specific instrument (St. George's Respiratory Questionnaire) and a general-health instrument (Veterans Short Form-36) were equivalent in the hypogonadal and eugonadal groups. Both groups demonstrated large decrements in perceived physical health and smaller decrements in perceived emotional and mental health. No relationship was found between free testosterone level and physical activity, respiratory symptoms, or quality of life. In conclusion, hypogonadism, although common among men older than 54 years with COPD, does not worsen the severity of respiratory symptoms or quality of life.
Most patients with chronic obstructive pulmonary disease (COPD) are middle-aged or older (1), and, by definition, all have a chronic illness. Aging and chronic illness have been associated with a decline in serum testosterone (2–5)—so-called androgen deficiency (6). Patients are defined as being hypogonadal when they have androgen deficiency combined with otherwise unexplained fatigue or diminished energy, a diminished sense of vitality, or a diminished sense of well-being (all commonly experienced by patients with COPD) (7–9).
On the basis of the chronicity of COPD and the usual age of the patients, some authors have suggested that men with COPD may be particularly vulnerable to developing hypogonadism (10–13). The issue is of more than theoretic interest because hypogonadism could contribute to poor quality of life in men with COPD.
Despite the potential detrimental effects of hypogonadism on health status (6, 14), we recently reported that hypogonadism did not decrease respiratory or limb muscle performance and exercise capacity in a group of 39 men with COPD, 19 of whom were hypogonadal (15). That skeletal muscle performance is not decreased in hypogonadal patients with COPD does not mean that quality of life might not be decreased in these patients. Indeed, the association between exercise capacity and quality of life in patients with COPD is controversial, with some investigators reporting a weak association between the two (16), while others reported no association (17). If hypogonadism was found to worsen the quality of life in patients with COPD, replacement therapy might then be justified.
The aim of this study was therefore to determine the prevalence and impact of hypogonadism on health-related quality of life in a sample of older men with COPD. The study used hormone levels, a respiratory-specific questionnaire, and a general-health questionnaire to assess the prevalence of hypogonadism and its impact on health-related quality of life in men with COPD. The study is the first systematic assessment of the effect of hypogonadism on health-related quality of life in men with COPD. Some of the results of these studies have been previously reported in abstract form (18, 19).
Further details on methods are available in the online supplement.
A total of 101 men with COPD were studied (Table 1)
|Age, yr||70 ± 1||69 ± 1||0.19|
|Free testosterone, pg/ml||27.8 ± 2.2||73.6 ± 2.7||< 0.0001|
|Total testosterone, ng/dl||206.3 ± 16.9||444.3 ± 21.6||< 0.0001|
|Luteinizing hormone, mIU/ml||7.6 ± 1.3||5.9 ± 0.6||0.18|
|Follicle-stimulating hormone, mIU/ml||10.9 ± 1.9||8.2 ± 0.7||0.12|
|Body mass index, kg/m2||29 ± 1||26 ± 1||0.002|
|FEV1, L||1.42 ± 0.07||1.29 ± 0.06||0.18|
|FEV1, %predicted||46.2 ± 2.0||42.0 ± 1.7||0.13|
|Residual volume, L||4.2 ± 0.3||4.4 ± 0.2||0.47|
|Residual volume, %predicted||175.5 ± 9.9||186.8 ± 9||0.42|
|TLC, L||7.1 ± 0.3||7.3 ± 0.2||0.57|
|TLC, %predicted||113.5 ± 3.8||118.6 ± 3.2||0.32|
|PaCO2, mm Hg||42.3 ± 1.2||40.6 ± 0.7||0.18|
|PaO2, mm Hg||70.3 ± 2.0||69.9 ± 1.3||0.87|
|Inhaled corticosteroids, number of patients, %||29 (76%)||46 (74%)||0.95|
|Oral prednisone, number of patients, %||11 (29%)||19 (31%)||0.96|
Morning blood samples were collected for measurement of free testosterone (equilibrium dialysis), total testosterone (competitive immunoassay), and serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone by two-site immunoassay. Intra- and interassay coefficients of variation were as follows: free testosterone, 5.4 and 6.2%; total testosterone, 4.7 and 4.7%; LH, 2.9 and 2.4%; and follicle-stimulating hormone, 2.9 and 2.7%.
The St. George's Respiratory Questionnaire (SGRQ) is a self-administered questionnaire that is disease-specific for patients with chronic airflow limitation (16). The SGRQ has three components: Symptoms, Activity, and Impacts. The three components, scoring 0 (best health) to 100 (worst health), can be summarized into a total score that provides a global estimate of the patient's respiratory health (16).
The Veterans Short Form-36 (Veterans SF-36) is a general health questionnaire developed for veteran patients receiving ambulatory care (20). It was adapted from the Medical Outcomes Study SF-36 health survey, a registered trademark of the Medical Outcomes Trust, Boston, Massachusetts (21). The Veterans SF-36 questionnaire covers four dimensions that have a primary physical health component (Physical Functioning, Role Limitations, Pain, General Health) and four dimensions that have a primary mental health component (Vitality, Social Functioning, Role Emotional, Mental Health). The eight dimensions, scoring 0 (worst health) to 100 (best health), can be summarized into two component summary scores: Physical and Mental. Validated conversion algorithms (22) were used to allow for comparisons of Veterans SF-36 scores to studies that have used the Medical Outcomes Study SF-36.
A six-minute walking test was performed according to standard procedure (23) and was used as a measure of impairment and disability complementary to the disease-specific and general quality-of-life questionnaires (16).
Lung volumes were measured by plethysmography and timed spirometry. Arterial blood was sampled from the radial artery in 91 patients.
Patients who agreed to take part in the study underwent pulmonary function testing. Blood samples for hormone studies were collected. The use of inhaled corticosteroids and oral prednisone was recorded. Patients were also asked to complete the SGRQ and the Veterans SF-36 questionnaires. Thereafter, the six-minute walking distance was measured. Twenty-five of the 101 patients who participated in the current study also participated in our previous investigation on the impact of hypogonadism on respiratory muscle function and exercise capacity (15).
Comparisons between patients with hypogonadism and eugonadism were performed using an unpaired t test and χ2 tests where appropriate. Linear regression analysis was used to examine the relationship between free testosterone and test scores, lung function, and six-minute walking distance.
Of the 101 participants, 38 were hypogonadal (free testosterone < 50 pg/ml; Table 1) (15). Testosterone concentrations were lower and body mass index was higher in the hypogonadal group than in the eugonadal group. The two groups of patients had similar age and severity of COPD (Table 1).
Of 38 hypogonadal patients, 29 (76%) had a concentration of LH that was low or normal (LH ⩽ 9 mIU/ml), suggesting hypogonadotrophic hypogonadism. The remaining nine patients had appropriate elevations of LH (LH > 9 mIU/ml), suggesting testicular dysfunction.
When the two groups of patients were analyzed as a whole, there was no relationship between free testosterone level and degree of airflow limitation (FEV1), air trapping (residual volume), or hyperinflation (total lung capacity).
Results obtained with the SGRQ questionnaire are shown in Figure 1. The scores for all the components of the questionnaire were equivalent in the two patient groups, and within the range reported by other investigators (7, 24, 25). The scores were 28 to 51 points higher (worse) than scores reported in the general population for subjects 60 to 69 years old (26).
In both patient groups, restriction of activities of daily living—secondary to respiratory symptoms (Symptoms score) and to the effects of physical activities on dyspnea (Activity score)—caused relatively more distress than did the social and psychologic impact of COPD on variables such as social contact and being in control of health (Impacts score; Figure 1). Free testosterone was not associated with the perceived impact of chronic airflow limitation on health and well-being.
The results of the Veterans SF-36 questionnaire are shown in Figure 2. The scores for all components of Veterans SF-36 in the hypogonadal and eugonadal group were within the range reported for veteran patients with COPD (27) and nonveteran patients with COPD (8, 28, 29).
In both groups, the scores for Physical Functioning, Role Limitations, General Health, three of the four domains pertaining to physical health, were approximately 26 to 56 points less (worse) than the scores reported for healthy subjects older than 65 years (30) and for members of the general population with a mean age of 60 years (31). The scores for these three domains were also 15 to 29 points less than the scores reported for veterans with no medical comorbidities and with a mean age of 72 years (32). The score for Pain was 14 to 15 points less (worse) than the scores reported for healthy subjects older than 65 years (30) and for members of the general population with a mean age of 60 years (31). The score for Pain was similar to that reported for veterans with no medical comorbidities and with a mean age of 72 years (32). The Physical Component Summary score was 31.3 ± 1.4 in the hypogonadal group and 32.9 ± 1.2 in the eugonadal group. These values are 2 SDs lower (worse) than scores in the general population (20), and nearly 1 SD lower than scores in elderly veterans with no medical comorbidities (32).
Scores for the four domains pertaining to mental health were approximately 7 to 36 points lower (worse) than scores recorded in the general population (30, 31) and approximately 4 to 16 points lower than scores in veterans with no medical comorbidities (32). The Mental Component Summary scores recorded in the hypogonadal (50.0 ± 1.7) and eugonadal (48.4 ± 1.3) group were not different from the corresponding scores in the general population (7) and among elderly veterans with no medical comorbidities (32).
Free testosterone was not associated with the Veterans SF-36 Physical Component Summary score. Likewise, free testosterone was not associated with the Veterans SF-36 Mental Health Component Summary score.
The six-minute walking distance, recorded in 75 patients (26 of whom were hypogonadal), was similar for hypogonadal (1,126 ± 57 ft) and eugonadal (1,089 ± 56 ft) patients (p = 0.68). Similar to the SGRQ scores and to the Veterans SF-36 Physical and Mental Health Component Summary scores, free testosterone was not associated with six-minute walking distance.
This is the first report that determines the prevalence of hypogonadism in older men with COPD and its impact on health-related quality of life. Our major finding is that hypogonadism does not worsen respiratory symptoms and quality of life. These results extend our recent finding that hypogonadism does not decrease respiratory or limb muscle performance and exercise capacity in men older than 55 years with COPD (15).
Using the determination of serum free testosterone concentration by dialysis—a technique considered the reference standard against which other assays are compared (33)—38% of our patients exhibited hypogonadism. This prevalence falls between prevalences reported in two recent studies of men with COPD (11, 34), in which the gonadal state was assessed using measurements of free testosterone by ultrafiltration (11) or measurements of bioavailable testosterone (34). Both techniques correlate well with determinations of free testosterone levels by dialysis (33). In the first study (11), 25 of 36 (69%) patients were hypogonadal. In the second study (34), 10 of 45 (22%) patients were hypogonadal.
The 47% difference in the prevalence of hypogonadism between the two previous studies (11, 34) cannot be ascribed to age or severity of disease, nor can it be ascribed to the test used for identifying gonadal status (33). The different prevalence could have resulted from patient selection: most (84%) patients in one study had concurrent chronic diseases (11), whereas patients with chronic diseases were excluded in the second study (34). A difference in comorbidities, however, only explains 15 of the 47% observed difference in testosterone concentrations between the two studies (35). Sample size is a more likely explanation. When data from the two investigations (11, 34) are combined, 35 of 84 patients (43%) exhibit hypogonadism, similar to the prevalence of 38% among our larger sample of 101 patients.
The lack of association between free testosterone and severity of COPD might suggest that hypogonadism is not more prevalent among men with COPD than among the general population. Indeed, a lack of association between severity of COPD and hypogonadism is supported by similar findings in the Baltimore Longitudinal Study of Aging (2). That study, however, was not primarily designed to assess whether COPD could increase the risk of hypogonadism (2) but rather to determine the prevalence of hypogonadism over time in a group of 890 generally healthy men. In the Baltimore study, prevalence of hypogonadism—using measurements of free testosterone index (total testosterone-to-sex hormone–binding globulin ratio)—was 34% for subjects in their 60s and 68% for subjects in their 70s (2).
That hypogonadism is not more prevalent among patients with COPD than among healthy men is further suggested by the results of a cross-sectional survey of 572 adult blood donors (5). The prevalence of hypogonadism, as determined by measurements of serum free testosterone, was approximately 40% for the cohort of 107 subjects in their 60s and 70s (5), similar to the prevalence of 39.5% in our patients of similar age.
Of our patients with hypogonadism, low gonadotrophin levels were found in 76% and the remainder had testicular dysfunction. Several mechanisms, including hypoxemia (36), obesity (37), glucocorticoid therapy (38), and (possibly) chronic disease (3, 4), can cause hypogonadotrophic hypogonadism. None of these possibilities, however, seemed to play an important role in our patients. First, we, like others (34), did not demonstrate an association between free testosterone concentrations and partial pressure of arterial oxygen. The lack of association is not surprising because serum testosterone levels tend not to fall to the hypogonadal range until the partial pressure of arterial oxygen drops below 55 mm Hg (36), a threshold crossed by only three of our patients while breathing room air (all three were receiving long-term oxygen therapy). Second, the same fraction of patients with hypogondism and eugonadism were prescribed glucocorticoids (Table 1), excluding a likely contribution from this factor. Third, severity of lung disease did not predict the hormonal abnormalities, making chronic disease an unlikely cause of hypogonadism. Fourth, the hypogonadal group had a greater body mass index than did the eugonadal group (Table 1). The difference in weight, however, could have explained only 3.6% of the decrease in free testosterone (37) and not the observed difference of 62.2%.
The finding that our patients with hypogonadism had a greater body mass index than did the patients with eugonadism could be explained through several mechanisms. First, in men, testosterone stimulates lipolysis, inducing an increase in free fatty acid release from the visceral fat depots (39). Second, low testosterone levels in men are usually associated with increased abdominal fat (40). Third, another mechanism that could contribute to increased body weight in patients with hypogonadism is a state of leptin resistance (41). Leptin is the peptide product of the ob gene, which is synthesized in white and brown adipose tissue (42). Acting on the hypothalamus, leptin might suppress food intake and stimulate energy expenditure (43).
Several mechanisms could have been responsible for the testicular dysfunction recorded in a quarter of our patients, including the following: atrophy of Leydig cells (12), increased cytokine concentrations (44, 45), and use of glucocorticoids (45, 46). We cannot accept or refute the first two possibilities because testicular biopsies were not performed and cytokine levels were not measured. As previously discussed, it seems unlikely that glucocorticoid therapy could have played any role in causing hypogonadism in our patients.
Three observations suggest that hypogonadism is not directly caused by COPD. First, free testosterone was not related to the severity of COPD. Second, free testosterone was not related to potential causes of hypogonadism specific to patients with COPD, such as hypoxemia or glucocorticoid therapy. Third, the prevalence of hypogonadism was equivalent in men with COPD to that in healthy subjects (5). More likely, normal aging per se is responsible for the hypogonadism. Purported mechanisms whereby old age causes hypogonadism include the following: decreased responsiveness of the testes to human chorionic gonadotrophin; increased testosterone feedback at the hypothalamic–pituitary level; decreased responsiveness of the pituitary to gonadotrophin-releasing hormone; and, perhaps most important, asynchronous (chaotic) release of gonadotrophin-releasing hormone from the hypothalamus (14).
As expected (8, 47, 48), our patients perceived serious impairment in health-related quality of life measured either with a disease-specific instrument (Figure 1) or a general-health instrument (Figure 2). Both patient groups exhibited scores in the domains of the SGRQ that were above (worse) the 90th to 95th percentile as compared with members of the general population of similar age (26).
Our most important finding is that SGRQ scores were equivalent in the hypogonadal and eugonadal groups (Figure 1). Scores were least favorable for Activity and less so for Impacts in the two patient groups (Figure 1). These results indicate that patients were somewhat better able to partially cope with the social limitations and the psychologic impact of the respiratory dysfunction (Impacts score) than to deal with the distress of respiratory symptoms caused by physical activities (Activity score). The equivalent Activity score was matched by the equivalent decrease in 6-minute walking distance in the two groups, and by the moderate correlation between six-minute walking distance and Activity score (r = −0.46, p < 0.0001). Patients with better results in the walking tests perceived less restriction when performing activities of daily living. The comparable limitation in physical activities because of respiratory symptoms and decrease in six-minute walking distance (49) in the two groups support, and expand, our previous observation that respiratory and limb muscle performance and exercise capacity are not affected by the gonadal state of men with COPD (15).
General health in the physical domains, assessed with the Veterans SF-36 questionnaire, was worse than that reported for the general population (7, 30). Hypogonadism, however, had no impact on the physical function component of the Veterans SF-36 questionnaire (Figure 2). Supporting our conclusion that hypogonadism has no effect on the magnitude of physical impairment and disability is the observation of Debigare and collaborators (34) that the prevalence of hypogonadism among men with COPD is equivalent among patients with and without muscle wasting.
In contrast to the scores pertaining to physical health, the Mental Component Summary score was similar to scores reported in elderly veterans without medical comorbidities (32) and in the general population (Figure 2) (7). Our observation that physical health was rated worse than mental health is in agreement with the observation that dyspnea (baseline dyspnea index of Mahler) is more closely related to most domains of physical health in SF-36 than to domains focusing on mental health in patients with COPD (28).
The greater impact of COPD on general physical health than on general mental health is further supported by two additional observations. First, in an outcome study of 321 men with COPD, worsening of 1 SD in the Physical Component Summary score was associated with a 30% increase in total mortality, whereas Mental Component Summary score was not associated with mortality (47). In the same investigation, the mean Mental Component Summary score in patients who survived and in patients who died was not different from the score reported in the general population (7). Second, as compared with patients with COPD receiving placebo, patients receiving 50 μg of salmeterol for 16 weeks experienced significant improvements in the Physical Functioning, Role Physical, and Vitality scores of the SF-36 questionnaire, but did not experience any improvement in Mental Health scores (8).
Hypogonadism has been associated with depressed mood (50). We did not use specific questionnaires, such as the Beck Depression Inventory (50), to detect depression in our patients. We cannot say that depressed mood was not more prevalent among the patients with hypogonadism, but two observations suggest it was not. First, the SGRQ Impact score, which has been reported to parallel depression scores obtained with the Hospital Depression Scale (16) were equivalent in the two patient groups. Second, the SF-36 Mental Health domain, which has been shown to be a powerful tool in uncovering psychiatric disorders (including major depression ), was equivalent in the two patient groups.
Sexual function and bone mineral density—both of which can be decreased by hypogonadism (6, 52)—were not assessed. The possibility that sexual function is impaired more often among hypogonadal than eugonadal men with COPD, however, is tempered by the equivalent prevalence of sexual difficulties among men with COPD independent of their free testosterone levels (11).
By study design, we assessed only men with COPD. Women with COPD have been shown to report worse health-related quality of life than men (53). Whether menopause and hormone supplementation in women with COPD could affect the health-related quality of life remains untested.
The value of testosterone treatment in older men with COPD remains to be demonstrated (14). The issue is more than a theoretic concern because long-term testosterone supplementation can be associated with side effects, including increase in hematocrit, sleep apnea, and prostatic hypertrophy (6, 54, 55). Long-term effects of testosterone administration on the risk of prostate cancer and atherosclerotic heart disease remain unknown (54, 56). 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) (57).
The results of our investigation do not support the administration of androgens to hypogonadal patients with COPD if the sole goal of therapy is to improve health-related quality of life. This finding complements the results our previous investigation (15), which could not support the administration of androgens to hypogonadal patients with COPD if the sole goal of therapy was to improve respiratory muscle function, limb muscle function, or exercise capacity.
In conclusion, hypogonadism, although common among men 55 years or older with COPD, does not worsen the severity of respiratory symptoms and quality of life.
|1.||National Heart, Lung, and Blood Institute. Data fact sheet. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, MD. Available from:(accessed October 26, 2004).|
|2.||Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724–731.|
|3.||Nierman DM, Mechanick JI. Hypotestosteronemia in chronically critically ill men. Crit Care Med 1999;27:2418–2421.|
|4.||Gray A, Berlin JA, McKinlay JB, Longcope C. An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis. J Clin Epidemiol 1991;44:671–684.|
|5.||Leifke E, Gorenoi V, Wichers C, Von Zur MA, Von Buren E, Brabant G. Age-related changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone binding globulin levels in men: cross-sectional data from a healthy male cohort. Clin Endocrinol (Oxf) 2000;53:689–695.|
|6.||Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350:482–492.|
|7.||Spencer S, Calverley PM, Sherwood BP, Jones PW. Health status deterioration in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:122–128.|
|8.||Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997;155:1283–1289.|
|9.||Moy ML, Ingenito EP, Mentzer SJ, Evans RB, Reilly JJ Jr. Health-related quality of life improves following pulmonary rehabilitation and lung volume reduction surgery. Chest 1999;115:383–389.|
|10.||Casaburi R, Goren S, Bhasin S. Substantial prevalence of low anabolic hormone levels in COPD patients undergoing rehabilitation [abstract]. Am J Respir Crit Care Med 1996;153:A128.|
|11.||Kamischke A, Kemper DE, Castel MA, Luthke M, Rolf C, Behre HM, Magnussen H, Nieschlag E. Testosterone levels in men with chronic obstructive pulmonary disease with or without glucocorticoid therapy. Eur Respir J 1998;11:41–45.|
|12.||Gosney JR. Atrophy of Leydig cells in the testes of men with longstanding chronic bronchitis and emphysema. Thorax 1987;42:615–619.|
|13.||Aasebo U, Gyltnes A, Bremnes RM, Aakvaag A, Slordal L. Reversal of sexual impotence in male patients with chronic obstructive pulmonary disease and hypoxemia with long-term oxygen therapy. J Steroid Biochem Mol Biol 1993;46:799–803.|
|14.||Morley JE, Perry HM III. Androgen treatment of male hypogonadism in older males. J Steroid Biochem Mol Biol 2003;85:367–373.|
|15.||Laghi F, Langbein WE, Antonescu-Turcu A, Jubran A, Bammert C, Tobin MJ. Respiratory and skeletal muscles in hypogonadal men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;171:598–605.|
|16.||Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321–1327.|
|17.||Larson JL, Covey MK, Wirtz SE, Berry JK, Alex CG, Langbein WE, Edwards L. Cycle ergometer and inspiratory muscle training in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:500–507.|
|18.||Segal JM, Antonescu-Turcu A, Tobin DE, Collins E, Bhorade S, Laghi F. Impact of hypogonadism on physical and mental health in patients with chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2001;163:A912.|
|19.||Antonescu-Turcu A, Segal JM, Tobin DE, Malik I, Langbein WE, Laghi F. Does hypogonadism impact respiratory symptoms and exercise performance in patients with chronic obstructive pulmonary disease [abstract]? Am J Respir Crit Care Med 2001;163:A911.|
|20.||Kazis LE, Ren XS, Lee A, Skinner K, Rogers W, Clark J, Miller DR. Health status in VA patients: results from the Veterans Health Study. Am J Med Qual 1999;14:28–38.|
|21.||Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Med Care 1992;30:473–483.|
|22.||Perlin J, Kazis LE, Skinner KM, Ren XS, Lee A, Rogers W, Spiro A III, Selim A, Miller D. Health status and outcomes of veterans: physical and mental component summary scores Veterans SF-36. 1999 large health survey of veteran enrollees. Executive report. Washington, DC: Office of Quality and Performance, Department of Veterans Affairs; 2000.|
|23.||Butland RJ, Pang J, Gross ER, Woodcock AA, Geddes DM. Two-, six-, and 12-minute walking tests in respiratory disease. Br Med J (Clin Res Ed) 1982;284:1607–1608.|
|24.||Ferrer M, Alonso J, Morera J, Marrades RM, Khalaf A, Aguar MC, Plaza V, Prieto L, Anto JM. Chronic obstructive pulmonary disease stage and health-related quality of life. The Quality of Life of Chronic Obstructive Pulmonary Disease Study Group. Ann Intern Med 1997;127:1072–1079.|
|25.||Antonelli-Incalzi R, Imperiale C, Bellia V, Catalano F, Scichilone N, Pistelli R, Rengo F. Do GOLD stages of COPD severity really correspond to differences in health status? Eur Respir J 2003;22:444–449.|
|26.||Ferrer M, Villasante C, Alonso J, Sobradillo V, Gabriel R, Vilagut G, Masa JF, Viejo JL, Jimenez-Ruiz CA, Miravitlles M. Interpretation of quality of life scores from the St George's Respiratory Questionnaire. Eur Respir J 2002;19:405–413.|
|27.||Selim AJ, Ren XS, Fincke G, Rogers W, Lee A, Kazis L. A symptom-based measure of the severity of chronic lung disease: results from the Veterans Health Study. Chest 1997;111:1607–1614.|
|28.||Mahler DA, Mackowiak JI. Evaluation of the short-form 36-item questionnaire to measure health-related quality of life in patients with COPD. Chest 1995;107:1585–1589.|
|29.||Sant'Anna CA, Stelmach R, Zanetti Feltrin MI, Filho WJ, Chiba T, Cukier A. Evaluation of health-related quality of life in low-income patients with COPD receiving long-term oxygen therapy. Chest 2003;123:136–141.|
|30.||Lindholm E, Brevinge H, Bergh CH, Korner U, Lundholm K. Relationships between self-reported health related quality of life and measures of standardized exercise capacity and metabolic efficiency in a middle-aged and aged healthy population. Qual Life Res 2003;12:575–582.|
|31.||Jenkinson C, Coulter A, Wright L. Short form 36 (SF36) health survey questionnaire: normative data for adults of working age. BMJ 1993;306:1437–1440.|
|32.||Kazis LE, Lee AF, Spiro A III, Miller DR, Rogers W, Ren XS. Zhang M. HOS/VA (Veterans Administration) comparison project part 2: test of reliability and validity at the scale level for Medicare HOS SF-36 (R) and VA Veterans SF-36. Available from:(Accessed January 14, 2004).|
|33.||Morley JE, Patrick P, Perry HM III. Evaluation of assays available to measure free testosterone. Metabolism 2002;51:554–559.|
|34.||Debigare R, Marquis K, Cote CH, Tremblay RR, Michaud A, LeBlanc P, Maltais F. Catabolic/anabolic balance and muscle wasting in patients with COPD. Chest 2003;124:83–89.|
|35.||Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991;73:1016–1025.|
|36.||Semple PD, Beastall GH, Watson WS, Hume R. Serum testosterone depression associated with hypoxia in respiratory failure. Clin Sci (Lond) 1980;58:105–106.|
|37.||Strain GW, Zumoff B, Miller LK, Rosner W. Sex difference in the effect of obesity on 24-hour mean serum gonadotropin levels. Horm Metab Res 2003;35:362–366.|
|38.||MacAdams MR, White RH, Chipps BE. Reduction of serum testosterone levels during chronic glucocorticoid therapy. Ann Intern Med 1986;104:648–651.|
|39.||Bjorntorp P. The regulation of adipose tissue distribution in humans. Int J Obes Relat Metab Disord 1996;20:291–302.|
|40.||Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21:697–738.|
|41.||Jockenhovel F, Blum WF, Vogel E, Englaro P, Muller-Wieland D, Reinwein D, Rascher W, Krone W. Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. J Clin Endocrinol Metab 1997;82:2510–2513.|
|42.||Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M, Mori K, Tamura N, Hosoda K, Yoshimasa Y, et al. Human obese gene expression: adipocyte-specific expression and regional differences in the adipose tissue. Diabetes 1995;44:855–858.|
|43.||Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546–549.|
|44.||Mealy K, Robinson B, Millette CF, Majzoub J, Wilmore DW. The testicular effects of tumor necrosis factor. Ann Surg 1990;211:470–475.|
|45.||Cover PO, Baanah-Jones F, John CD, Buckingham JC. Annexin 1 (lipocortin 1) mimics inhibitory effects of glucocorticoids on testosterone secretion and enhances effects of interleukin-1beta. Endocrine 2002;18:33–39.|
|46.||Gao HB, Tong MH, Hu YQ, You HY, Guo QS, Ge RS, Hardy MP. Mechanisms of glucocorticoid-induced Leydig cell apoptosis. Mol Cell Endocrinol 2003;199:153–163.|
|47.||Domingo-Salvany A, Lamarca R, Ferrer M, Garcia-Aymerich J, Alonso J, Felez M, Khalaf A, Marrades RM, Monso E, Serra-Batlles J, et al. Health-related quality of life and mortality in male patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:680–685.|
|48.||Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of the factors related to mortality in chronic obstructive pulmonary disease: role of exercise capacity and health status. Am J Respir Crit Care Med 2003;167:544–549.|
|49.||Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med 1998;158:1384–1387.|
|50.||Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. J Clin Endocrinol Metab 1999;84:573–577.|
|51.||Berwick DM, Murphy JM, Goldman PA, Ware JE Jr, Barsky AJ, Weinstein MC. Performance of a five-item mental health screening test. Med Care 1991;29:169–176.|
|52.||Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, Dlewati A, Staley J, Santanna J, Kapoor SC, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999;84:1966–1972.|
|53.||Osman IM, Godden DJ, Friend JA, Legge JS, Douglas JG. Quality of life and hospital re-admission in patients with chronic obstructive pulmonary disease. Thorax 1997;52:67–71.|
|54.||Bhasin S, Bagatell CJ, Bremner WJ, Plymate SR, Tenover JL, Korenman SG, Nieschlag E. Issues in testosterone replacement in older men. J Clin Endocrinol Metab 1998;83:3435–3448.|
|55.||Bagatell CJ, Bremner WJ. Androgens in men–uses and abuses. N Engl J Med 1996;334:707–714.|
|56.||Storer TW, Magliano L, Woodhouse L, Lee ML, Dzekov C, Dzekov J, Casaburi R, Bhasin S. Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. J Clin Endocrinol Metab 2003;88:1478–1485.|
|57.||Snyder PJ. Hypogonadism in elderly men—what to do until the evidence comes. N Engl J Med 2004;350:440–442.|