Hypogonadism

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 (FEV^sub 1^ 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.

Keywords: aging; androgens; exercise tolerance; health status; testosterone

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).

METHODS

Further details on methods are available in the online supplement.

Patients

A total of 101 men with COPD were studied (Table 1). Inclusion criteria were as follows: age of 55 years or older, chronic airway obstruction, and stable clinical condition without recent exacerbation. Exclusion criteria included orchiectomy and current androgen and antiandrogen therapy. Patients with cirrhosis and alcoholism were excluded because these conditions can cause low testosterone concentrations. Appropriate institutional review boards approved the study, and written consent was obtained.

Hormone Studies

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%.

Measurements of Health-related Quality of Life

St. George's Respiratory Questionnaire. 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).

Veterans Short Form-36 health survey. 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.

Six-minute walking distance. 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).

Pulmonary function tests. Lung volumes were measured by plethysmography and timed spirometry. Arterial blood was sampled from the radial artery in 91 patients.

Protocol

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).

Data Analysis

Comparisons between patients with hypogonadism and eugonadism were performed using an unpaired t test and χ^sup 2^ 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.

RESULTS

Patient Characteristics and Hormone Status

Of the 101 participants, 38 were hypogonadal (free testosterone

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 (FEV^sub 1^), air trapping (residual volume), or hyperinflation (total lung capacity).

Measurements of Health-related Quality of Life

Results obtained with the SGRO 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.

DISCUSSION

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).

What Is the Prevalence of Hypogonadism in Men with COPD?

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.

Is Prevalence of Hypogonadism Increased in Men with COPD?

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 testoster-one-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.

Why Is Free Testosterone Decreased in Men with COPD?

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).

Impact of Hypogonadism on Health-related Quality of Life

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

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).

Critique of Methods

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 [51]), 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.

Clinical Implications

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.

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; A.A.-T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.S. received $4,500 in 2003 from Eli Lilly for participating in a multicenter trial and $800 in March 2005 from Glaxo for speaking at a meeting; D.E.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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Franco Laghi, Andreea Antonescu-Turcu, Eileen Collins, Jeremy Segal, Damien E. Tobin, Amal Jubran, and Martin J. Tobin

Division of Pulmonary and Critical Care Medicine, Edward Hines Jr. Veterans Administration Hospital; Stritch School of Medicine, Loyola University of Chicago, Hines, Illinois

(Received in original form April 13, 2004; accepted in final form January 7, 2005)

Supported by grants from the AMVETS and Veterans Administration Research Service. A.A.-T. was supported by the Chest Foundation of the American College of Chest Physicians.

Correspondence and requests for reprints should be addressed to Franco Laghi, M.D., Division of Pulmonary and Critical Care Medicine, Edward Hines Jr. VA Hospital, 11IN 5th Avenue and Roosevelt Road, Hines, IL 60141. E-mail: flaghi@ lumc.edu

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 171. pp 728-733, 2005

Originally Published in Press as DOI: 10.1164/rccm.200501-037OC on January 18, 2005

Internet address: www.atsjournals.org

Copyright American Thoracic Society Apr 1, 2005
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