Hypogonadism, Quadriceps Weakness, and Exercise Intolerance in Chronic Obstructive Pulmonary Disease
http://www.100md.com
《美国呼吸和危急护理医学》
Respiratory Rehabilitation and Respiratory Division, University Hospital Gasthuisberg
Department of Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences
Laboratories of Pneumology, Experimental Immunology, and Experimental Medicine and Endocrinology (LEGENDO), Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
ABSTRACT
Rationale: Circulating levels of testosterone and gonadotrophins of patients with chronic obstructive pulmonary disease (COPD) have never been compared with those of elderly men with normal pulmonary function. Moreover, the relationship of hypogonadism with quadriceps muscle weakness and exercise intolerance has been studied scarcely in men with COPD.
Objectives: To compare circulating levels of hormones of the pituitary–gonadotrophic axis of men with COPD with those of age-matched control subjects. Moreover, to study the relationship of hypogonadism with quadriceps muscle force, 6-min walking distance, and systemic markers of inflammation in the patients.
Methods and Measurements: Circulating levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and sex homone–binding globulin were determined, and free testosterone was calculated in 78 patients (FEV1: 44 ± 17% of the predicted values) and 21 control subjects. Moreover, quadriceps muscle force, 6-min walking distance, number of pack-yr, and systemic inflammation were determined.
Main Results: Follicle-stimulating hormone and luteinizing hormone were higher in the patients, whereas testosterone was lower (p 0.05). The latter finding was also present in 48 non–steroid-using patients with normal blood gases. Low androgen status was significantly related to quadriceps muscle weakness (r = 0.48) and C-reactive protein (r = –0.39) in the patients, but not to exercise intolerance, the number of pack-yr, or increased circulating levels of interleukin 8 or soluble receptors of tumor necrosis factor .
Conclusions: In contrast to exercise intolerance, quadriceps muscle weakness is related to low circulating levels of testosterone in men with COPD.
Key Words: follicle-stimulating hormone luteinizing hormone quadriceps muscle strength sex hormone–binding globulin testosterone
The role of physical inactivity in the development and/or maintenance of quadriceps muscle weakness in patients with advanced chronic obstructive pulmonary disease (COPD) is well established. A reduction in weight-bearing activities has been observed in these patients (1), and quadriceps muscle weakness is closely related to upper leg muscle atrophy (2). Moreover, resistance training and transcutaneous neuromuscular electrical stimulation have been able to improve quadriceps muscle force and to facilitate ambulation in patients with COPD (3–9). Unfortunately, the recovery of quadriceps muscle force is incomplete even after 6 mo of exercise training (7). Therefore, besides physical inactivity, other factors may contribute to the development and/or presence of quadriceps muscle weakness in patients with COPD (10, 11).
In healthy elderly men, age-related decline in quadriceps muscle force has been related to the reduced circulating levels of testosterone (12), which is able to stimulate muscle protein anabolism and motor neuron size (13). Nevertheless, the relationship between testosterone and quadriceps muscle force does not appear to be straightforward. For example, a 20-wk suppression of the endogenous testosterone production in eugonadal, healthy elderly men resulted in reduced circulating testosterone concentrations (mean, 176 ng/dl) without changes in leg-press strength (14).
Uncertainty on the role of testosterone in the development and/or maintenance of quadriceps muscle weakness also remains in male patients with COPD. Laghi and colleagues (15) did not find a significant difference in quadriceps muscle force between 10 eugonadal and 10 hypogonadal male patients with COPD. By way of contrast, Casaburi and colleagues (16) reported significant improvements in quadriceps muscle force after 10 wk of testosterone injections in male patients with COPD who were selected as a result of low baseline circulating levels of testosterone (mean, 320 ng/dl). Moreover, 10 wk of testosterone injections combined with resistance training resulted in greater improvements in quadriceps muscle force than resistance training alone (16). Therefore, it is still reasonable to hypothesize that quadriceps muscle weakness is, at least in part, related to low circulating testosterone concentrations in male patients with advanced COPD.
In the past, increased systemic inflammation (17), a higher dose of oral corticosteroids (18), and hypoxemia have been related to low circulating testosterone concentrations in male patients with COPD (19, 20). The latter two observations, however, could not be substantiated by three recent studies and remain a matter of debate (16, 17, 21).
A dysfunctioning hypothalamic–pituitary–gonadal axis has been found in COPD (15, 16, 20, 21). For example, hypogonadotrophic hypogonadism has been reported in male patients with COPD (16, 20). Others have shown that hypogonadal patients with COPD may have significantly higher serum gonadotrophins than eugonadal patients (15). Moreover, a decreased response to administered gonadotrophin-releasing hormone has been found in hypoxemic patients with chronic airway diseases (20). Nonetheless, there has never been a direct comparison of circulating gonadotrophin concentrations in male patients with COPD and elderly control subjects with normal pulmonary function.
A cross-sectional study was designed to answer the following questions:
Are the systemic markers of the pituitary–gonadotrophic axis in men with COPD significantly different from those of elderly men with normal pulmonary function
What is the relationship between a low androgen status, clinical outcomes, and systemic markers of inflammation in men with COPD
Some of the results of this study have been previously reported in the form of two abstracts (22, 23).
METHODS
Additional details on the methods for making the measurements as described below are provided in an online supplement.
Patients
A total of 259 consecutive patients who attended the COPD outpatient clinic were asked to participate. Of these, 157 patients were reluctant to participate or were excluded (Figure E1 in the online supplement). Consenting patients with COPD had similar clinical characteristics as those who were not included, except for age (Table E1).
The remaining 102 patients with clinically stable COPD (78 men) voluntarily consented to partake in the present study. For obvious reasons, only the results of the male patients were taken into account to answer the aforementioned questions.
The results of the 78 men with COPD were compared with those of 21 men with normal pulmonary function and similar age distribution (Table 1), except for the results of circulating levels of the inflammatory markers, which were only determined in the male patients with COPD to answer the aforementioned second question.
All participants had to come for one morning to the outpatient clinic to perform the tests as described below and in the online supplement. The Medical Ethical Board of the University Hospitals Leuven approved this cross-sectional comparative study. All participants were white and gave informed consent. Seventeen control subjects were part of a previous publication about physical activity level in patients with COPD (1).
Blood Analyses
Venous blood samples were analyzed for C-reactive protein, soluble TNF receptors (sTNFR) p55 and p75 (24), interleukin 8 (IL-8) (11), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sex hormone–binding globulin (SHBG). Moreover, circulating levels of free testosterone were calculated.
Functional Measurements
Pulmonary function, quadriceps peak torque, and the distance walked in 6 min (6MWD) were assessed as described previously (6, 25).
Comorbidities
Comorbid conditions have been classified using the Charlson index, which is a simple weighted index that takes into account the number and the seriousness of comorbid disease (26). In addition, the scores on the age–comorbidity index (Charlson index II) were calculated (27).
Statistical Analyses
See the online supplement.
RESULTS
Cross-sectional Comparisons
Characteristics.
Patients with COPD had significantly worse pulmonary function, quadriceps muscle force, 6MWD, and scores on the Charlson comorbidity and age–comorbidity indexes than the control group (Table 1 and Table E2).
Hormones of the pituitary–gonadotrophic axis.
Patients with COPD had significantly higher circulating levels of FSH and LH and significantly lower circulating levels of testosterone and free testosterone than the control group. Moreover, circulating levels of SHBG tended to be higher in the patients with COPD (Table 1 and Figure 1).
The prevalence of low circulating testosterone concentrations in patients with COPD was significantly higher than in the control group, whereas the prevalence of low circulating free testosterone concentrations tended to be higher in the patients (Table 1 and Figure E2). Hypogonadal patients had circulating FSH and LH concentrations above the lower limit of normal or even above the upper limit of normal (Figure E3).
Stratification for current use of corticosteroids and PaO2 in COPD.
No significant differences were found between median circulating levels of FSH, LH, testosterone, free testosterone, and SHBG in the patients who had been stratified according to the current use of oral corticosteroids ("yes" or "no") and for the PaO2 (< or 70 mm Hg; Figure E4).
Systemic inflammatory markers in COPD.
Median (interquartile range) circulating levels of C-reactive protein (4.2 mg/L [1.8–9.1]), IL-8 (2.8 pg/ml [2.2–3.8]), sTNFR-p55 (2.4 ng/ml [2.0–2.8]), and sTNFR-p75 (5.1 ng/ml [4.2–6.2]) of the patients with COPD were comparable to previous findings in patients with clinically stable COPD (28) and higher than values obtained in healthy middle-aged adults (24) and elderly individuals (29).
Correlations
For correlations between hormones of the pituitary–gonadotrophic axis in COPD, see the online supplement.
Correlations between hormones of the pituitary–gonadotrophic axis and clinical outcomes in COPD.
In the patients with COPD, the impaired FEV1 did not correlate with the observed changes in the pituitary–gonadotrophic axis (Figure E5). Body mass index was inversely related to the circulating levels of testosterone (rs = –0.44, p = 0.0001), free testosterone (rs = –0.24, p = 0.037), and SHBG (rs = –0.48, p = 0.0001).
In contrast to the 6MWD (rs = 0.18, p = 0.12; Figure 2), quadriceps muscle force was positively related to circulating testosterone concentrations (rs = 0.48, p = 0.0001; Figure 3) and circulating free testosterone concentrations (rs = 0.37, p = 0.0012). Only circulating free testosterone concentrations tended to be inversely related to the number of pack-yr (rs = –0.22, p = 0.052), whereas circulating testosterone concentrations tended to be inversely related to the mean daily dose of oral corticosteroids (rs = –0.22, p = 0.058).
Correlations between hormones of the pituitary–gonadotrophic axis and systemic inflammation in COPD.
Circulating levels of IL-8 and the sTNFR-p55 were positively related to the circulating levels of FSH (rs = 0.27, p = 0.021, and rs = 0.23, p = 0.045, respectively) and LH (rs = 0.29, p = 0.012, and rs = 0.22, p = 0.054, respectively). Moreover, circulating C-reactive protein concentrations showed inverse relationships with the circulating levels of testosterone (rs = –0.39, p = 0.0004), free testosterone (rs = –0.28, p = 0.014), and SHBG (rs = –0.22, p = 0.057). Other systemic markers of the pituitary–gonadotrophic axis did not relate to the circulating levels of systemic inflammation in the patients with COPD (p 0.17).
DISCUSSION
The present study has found significant differences in circulating levels of hormones of the pituitary–gonadotrophic axis between male patients with COPD and elderly men with normal pulmonary function. In addition, low circulating levels of testosterone were positively related to quadriceps muscle weakness, but not to reduced functional exercise capacity in patients with COPD. Hypogonadism occurred also in non–steroid-using male patients with COPD who had normal arterial blood gases. Low-grade systemic inflammation and smoking did not appear to be the main determinants of hypogonadism in male patients with COPD. In fact, hypogonadism appeared, at least in part, to be caused by a primary testicular dysfunction and/or a hypofunctioning of the hypothalamic–pituitary–gonadal axis.
Prevalence of Hypogonadism
Although results were borderline, male patients with COPD had a higher prevalence of hypogonadism than control subjects (Table 1). Interestingly, the prevalence of hypogonadism was 13% higher than the values reported by Laghi and colleagues (21), even though the patients had similar age, FEV1, and PaO2, and a similar prevalence of oral corticosteroid use in the hypogonadal patients. The difference in prevalence may therefore be explained by the absence of comorbidities (30) or the presence of ethnic differences (31). Unfortunately, Laghi and colleagues (21) did not give details on these variables.
Hypogonadism was also present in about one-third of the control group. The present observation, although somewhat surprising, is in line with previous unrelated data in healthy, elderly Belgian men (32, 33).
Possible Causes of Hypogonadism in COPD
Hypothalamic–pituitary–testicular axis.
The present authors reasoned a priori that low circulating levels of FSH and LH may be responsible for low circulating testosterone concentrations in male patients with COPD, as seen previously (16, 20). In the present study, however, all hypogonadal patients with COPD (e.g., circulating levels of testosterone 300 ng/dl) showed circulating FSH and LH concentrations above the lower limit of normal (Figure E3). Some hypogonadal patients even had circulating FSH and LH concentrations above the upper limit of normal. Considering the role of FSH and LH in the biosynthesis of testosterone, hypergonadotrophism represents a compensatory mechanism of the hypothalamic–pituitary axis to correct for the low circulating testosterone concentrations in patients with COPD. In fact, a decrease in circulating testosterone concentrations and a compensatory increase in the circulating gonadotrophin concentrations have been reported in healthy elderly men (32, 34, 35) and in patients with COPD (15). These findings suggest that hypogonadism can be due to a primary testiscular dysfunction in COPD.
The remaining hypogonadal patients showed no increase in the circulating levels of LH and FSH on low circulating testosterone concentrations. In addition, a decreased response to administered gonadotrophin-releasing hormone has been found in hypoxemic patients with chronic airway diseases (20). Whether this is due to an impaired periodic release of gonadotrophin-releasing hormone, an impaired function of the gonadotropes, an impaired feedback action of the testes exerted through secretion of steroids or peptides, or a combination thereof remains to be determined (36–38). These findings, however, suggest that hypogonadism can also due to a hypofunctioning of the hypothalamic–pituitary–gonadal axis in COPD.
SHBG.
A somewhat unexpected increase of approximately 30% in the circulating levels of SHBG has been found in subjects with COPD as compared with control subjects, which obviously has affected the circulating free testosterone concentrations (Figure 1). Although aging has been shown to be responsible for increased circulating SHBG concentrations ( 1.1%/yr) (39), the present patients and control subjects were of similar age (Table 1). The biosynthesis of SHBG by the liver has been shown to be regulated by triiodothyronine (40), which, in turn, has been shown to be significantly higher in patients with COPD as compared with healthy control subjects (41). It can therefore be reasoned that hyperthyroidism may, at least in part, be responsible for the observed differences in SHBG and indirectly for a low androgen status in male patients with COPD. Unfortunately, thyroid function was not assessed in the present study. Moreover, the increased circulating SHBG concentrations may be a response to the increased circulating levels of FSH and LH (as shown by the positive relationships), which in turn may be a result of low circulating testosterone concentrations.
Current corticosteroid use, hypoxemia, and smoking.
Median circulating levels of testosterone and free testosterone of 48 non–steroid-using patients with COPD with normal arterial oxygen tension were low: 275 and 4.94 ng/dl, respectively (Figure E4). Moreover, Laghi and colleagues (21) found similar PaO2 and the same prevalence of oral corticosteroid users in hypogonadal and eugonadal patients with COPD. Therefore, the role of oral corticosteroid use and hypoxemia in the development of hypogonadism in COPD appears to be less prominent as suggested previously (18–20).
Smoking has been shown to cause hypogonadism (42, 43). In fact, fewer Leydig cells and degeneration of the remaining cells were found in the testes of men with longstanding chronic bronchitis and emphysema without changes in the circulating gonadotrophin concentrations (44). Nevertheless, the number of pack-yr was only weakly related to the circulating levels of free testosterone in the present patients with COPD. On the other hand, in 48 non–steroid-using patients with COPD with normal PaO2 ( 70 mm Hg), an a posteriori analysis revealed stronger relationships between the number of pack-yr and the circulating levels of free testosterone (r = –0.40, p = 0.0043) and testosterone (r = –0.30, p = 0.0418).
Systemic inflammation.
Systemic inflammation has been suggested as a possible cause of low circulating testosterone concentrations in male patients with COPD (45). To date, only a weak but significant inverse relationship between the circulating levels of IL-6 and bioavailable testosterone has been found in men with COPD (r = –0.33) (17). In the present study, circulating levels of IL-8, sTNFR-p55, and sTNFR-p75 did not correlate with the low circulating levels of testosterone in the male patients with COPD. This is in line with data from Debigare and colleagues (17). Nevertheless, weak inverse relationships were found between circulating levels of testosterone and free testosterone with acute-phase C-reactive protein. It would therefore be interesting to study the possible consequences of transiently increased systemic inflammation (11), together with an increased dose of systemic corticosteroids (46), on the low androgen status in men with COPD during an acute exacerbation.
Some markers of systemic inflammation showed positive relationships with FSH and LH. This may indicate an indirect compensatory reaction of the endocrine system against the presence of a chronic catabolic environment in men with COPD (e.g., low-grade systemic inflammation).
Hypogonadism and Quadriceps Muscle Weakness in COPD
Quadriceps muscle weakness has been related to physical disuse (1, 2), the insertion allele of the angiotensin-converting enzyme gene polymorphism (47), and low systemic levels of insulin-like growth factor I, and to chronic low-grade systemic inflammation in men with COPD (11, 17, 48). The present study is the first to find a weak but significant positive relationship between low androgen status and quadriceps muscle weakness in male patients with clinically stable but advanced COPD.
Recently, no significant differences were found between the mean maximal voluntary quadriceps muscle contraction of 10 eugonadal and 10 hypogondal men with COPD (15). Nevertheless, by using the same cut-off value as Laghi and colleagues (circulating free testosterone concentrations > or 5 ng/dl) (15), the present authors did find a significant difference in isometric quadriceps peak torque between 38 eugonadal (median [interquartile range] circulating free testosterone concentrations: 6.0 ng/dl [5.5–8.3]; mean ± SD quadriceps peak torque: 81 ± 19% predicted) and 40 hypogonadal men with COPD (free testosterone: 3.9 ng/dl [2.8–4.4], p = 0.0001; quadriceps peak torque: 68 ± 19% predicted, p = 0.0057) without a significantly different median score on the Charlson comorbidity index (p = 0.24). Currently, a clear explanation for these discrepant results is lacking. In fact, the present patients had comparable characteristics as those studied by Laghi and colleagues (15). Nevertheless, the number of patients studied by these authors was most probably too low to exclude a type II error. Moreover, the present results are in line with previous findings in healthy elderly individuals (49, 50) and the present control subjects had comparable results (see online supplement). Then again, circulating levels of bioavailable testosterone were similar between a group of patients with COPD with and without upper leg muscle atrophy (17). The mean circulating testosterone concentrations of the patients with COPD, however, were equal to those obtained in healthy elderly control subjects (17). Moreover, circulating testosterone concentrations have shown to be independent of daily physical activity level in healthy subjects and in patients with chronic pulmonary or cardiac disease (16, 21, 32). Therefore, the most straightforward suggestion is that patients with COPD with the lowest midthigh cross-sectional area probably had the lowest levels of daily physical activities (17). Unfortunately, the present study and others (15, 17) did not explicitly study the levels of daily physical activity using a validated activity monitor (51, 52).
Testosterone replacement therapy has not always been effective to improve quadriceps muscle strength in healthy elderly men (53). Moreover, improvements in skeletal muscle mass and leg-press strength in healthy elderly men receiving a combination of 600 mg testosterone enanthate injections (once every wk for 20 wk) together with 7.5 mg Lupron depot (a long-acting gonadotrophin agonist, once monthly for 20 wk) were not significantly different from those who received 125 or 300 mg testosterone enanthate injections together with 7.5 mg Lupron depot (14). Nevertheless, the relationship of quadriceps muscle weakness with physical disuse (2) and hypogonadism may provide a rationale to combine structured exercise programs with testosterone replacement therapy in highly selected hypogonadal patients with COPD. Actually, weekly injections of testosterone enanthate have shown to result in significant increases in bodyweight, lean body mass, and quadriceps muscle function, but not in respiratory muscle function or exercise capacity in male patients with COPD with low baseline circulating levels of testosterone (16). This dose (100 mg/wk) for this duration (10 wk) did not result in adverse effects in male patients with COPD who had low baseline androgen status (16). Nevertheless, additional safety and feasibility studies are necessary before testosterone supplements may be added to the management of highly selected patients with severe COPD (54).
Hypogonadism and Exercise Intolerance in COPD
Exercise capacity was not affected by the gonadal status in patients with COPD (Figure 2), corroborating previous findings (15, 16, 21). In fact, quadriceps muscle endurance was similar between eugonadal and hypogonadal patients with COPD (15). This seems reasonable considering the fact that quadriceps muscle endurance has shown to be related to the proportion of type I muscle fibers, citrate synthase activity (55), physical inactivity (56), and exercise-induced muscle oxidative stress (57).
Methodologic and Statistical Considerations
The present study has been performed in a tertiary care setting, and may therefore have led to a bias in the selection of males with only advanced COPD. Hence, external validity of the current findings is limited to this subgroup. Nevertheless, patients with Global Initiative for Chronic Obstructive Lung Disease stage II disease (58) also had low median circulating levels of testosterone and free testosterone (336 and 4.6 ng/dl, respectively), and this finding can therefore also be expected in male patients with COPD in primary and secondary care settings.
A relatively high number of the present patients used oral corticosteroids (29%), which may have biased the results. Nonetheless, previous studies reported a similar prevalence (15, 21).
Patients had a significantly higher score on the Charlson comorbidity index than control subjects (Table 1), which may have affected the circulating free testosterone concentrations. Nevertheless, circulating testosterone concentrations did not change significantly in elderly patients (mean age, 70 yr) directly or 3 mo after an acute myocardial infarction (32). In the present study, the circulating free testosterone concentrations remained significantly different between 52 patients (5.22 ng/dl [4.12–6.11]) and 20 control subjects (6.57 ng/dl [5.14–9.03], p = 0.03) after excluding 26 patients with COPD and one control subject with comorbidities. Moreover, hypogonadal patients with COPD had a similar median score on the Charlson comorbidity index as eugonadal patients.
At the time of the study, the present authors did not have access to a magnetic stimulator, which has been shown to be a painless, supramaximal method of assessing quadriceps force independent of the maximality of the effort made during the test by the participants (59). Nevertheless, the variability of maximal voluntary quadriceps femoris muscle contraction was found to be similar to measurements by magnetic stimulation (59), and a supramaximal twitch during a maximal voluntary contraction did not result in a significantly higher peak force (60). The present authors therefore believe that a maximal voluntary contraction is a valid technique to measure peak force of the femoral quadriceps muscles of patients with COPD.
Currently, a minimal clinically important difference for quadriceps peak torque has not been determined in COPD. Nonetheless, a mean difference of 13% of the predicted value for quadriceps peak torque between hypo- and eugonadal patients appears to be clinically relevant, in particular because quadriceps muscle force increased significantly with a mean of 7% of the predicted values after 3 mo of high-intensity progressive resistance and endurance training in 65 patients with advanced COPD (6).
Significant correlations do not necessarily imply causal relationships. Moreover, statistically significant differences between groups need to be interpreted in the light of the number of comparisons that were made in the present study. Nonetheless, the current statistical procedures have been used to test predefined hypotheses. Moreover, according to Perneger (61), "Bonferoni adjustments are at best, unnecessary and, at worst, deleterious to sound statistical inference."
Future Research
Although reduced quality of life was not related to the gonadal status of patients with COPD (21), endocrinological changes (i.e., hyposomatotrophism [11], hypogonadism [15, 21], hyperthyroidism [41], and elevated plasma ghrelin levels [62]) may still be of clinical importance for patients with advanced COPD. In the present study, the clinically relevant quadriceps muscle weakness (25, 63–66) was positively related to reduced circulating levels of testosterone. Other clinically important complaints of patients with COPD may also be, at least in part, due to low testosterone levels. For example, reduced libido and erectile dysfunction have been reported in approximately 67% of the male patients with COPD with chronic respiratory failure on long-term oxygen therapy (67). Sex hormone replacement therapy has already shown to result in an improved erectile function and overall sexual quality of life in male patients with COPD (68).
The possible role of the increased circulating levels of SHBG (Figure 1) in the loss of bone mineral density (69) may also be worthy of study. Indeed, in middle-aged men with idiopathic or secondary osteoporosis, the increased circulating levels of SHBG were related to the bone mineral density of the hip and spine (70).
Conclusions
About 50% of the male outpatients with clinically stable COPD have a low androgen status, which can be caused by a combination of factors. In the present study, a primary testicular dysfunction and/or a hypofunctioning of the hypothalamic–pituitary–gonadal axis appeared to be the main underlying mechanisms of hypogonadism in male patients with COPD. Moreover, low circulating levels of testosterone were positively related to quadriceps muscle weakness but not to exercise intolerance in these patients.
Acknowledgments
The authors thank physiotherapists Veronica Barbier, Iris Coosemans, and Vanessa Probst for assessing the functional outcomes in the present study.
FOOTNOTES
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Conflict of Interest Statement: M.V.V. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. M.A.S. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. G.V. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. A.K. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. E.V.H. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. F.P. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. R.B. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. M.D. has received an unrestricted grant from AstraZeneca to pay the salary of M.V.V. and has received $40,000 from AstraZeneca Belgium between 9/1/2003 and 8/31/2004.
These authors contributed equally to this study.
REFERENCES
Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:972–977.
Bernard S, LeBlanc P, Whittom F, Carrier G, Jobin J, Belleau R, Maltais F. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:629–634.
Ortega F, Toral J, Cejudo P, Villagomez R, Sanchez H, Castillo J, Montemayor T. Comparison of effects of strength and endurance training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:669–674.
Spruit MA, Gosselink R, Troosters T, De Paepe K, Decramer M. Resistance versus endurance training in patients with COPD and peripheral muscle weakness. Eur Respir J 2002;19:1072–1078.
Spruit MA, Troosters T, Trappenburg JCA, Decramer M, Gosselink R. Exercise training during rehabilitation of patients with COPD: a current perspective. Patient Educ Couns 2004;52:243–248.
Spruit MA, Gosselink R, Troosters T, Kasran A, Van Vliet M, Decramer M. Low-grade systemic inflammation and the response to exercise training in patients with advanced COPD. Chest (In press)
Troosters T, Gosselink R, Decramer M. Short- and long-term effects of outpatient rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. Am J Med 2000;109:207–212.
Troosters T, Casaburi R, Gosselink R, Decramer M. Pulmonary rehabilitation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:19–38.
Zanotti E, Felicetti G, Maini M, Fracchia C. Peripheral muscle strength training in bed-bound patients with COPD receiving mechanical ventilation: effect of electrical stimulation. Chest 2003;124:292–296.
Debigare R, Cote CH, Maltais F. Peripheral muscle wasting in chronic obstructive pulmonary disease: clinical relevance and mechanisms. Am J Respir Crit Care Med 2001;164:1712–1717.
Spruit MA, Gosselink R, Troosters T, Kasran A, Gayan-Ramirez G, Bogaerts P, Bouillon R, Decramer M. Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I. Thorax 2003;58:752–756.
van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 2000;85:3276–3282.
Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care 2004;7:271–277.
Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-Hikim I, Dzekov C, Dzekov J, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005;90:678–688.
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 2005;171:598–605.
Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis MI, Fournier M, Storer TW. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:870–878.
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.
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.
Semple PD, Beastall GH, Watson WS, Hume R. Serum testosterone depression associated with hypoxia in respiratory failure. Clin Sci (Lond) 1980;58:105–106.
Semple PD, Beastall GH, Watson WS, Hume R. Hypothalamic-pituitary dysfunction in respiratory hypoxia. Thorax 1981;36:605–609.
Laghi F, Antonescu-Turcu A, Collins E, Segal J, Tobin DE, Jubran A, Tobin MJ. Hypogonadism in men with chronic obstructive pulmonary disease: prevalence and quality of life. Am J Respir Crit Care Med 2005;171:728–733.
Van Vliet M, Spruit MA, Verleden G, Decramer M. Hypogonadism is related to skeletal muscle weakness in male patients with COPD . Eur Respir J 2004;24:256s.
Van Vliet M, Spruit MA, Verleden G, Decramer M. Low circulating levels of testosterone in male patients with chronic obstructive pulmonary disease (COPD) . Proc Am Thorac Soc 2005;2:A530.
Spruit MA, Thomeer MJ, Gosselink R, Troosters T, Kasran A, Debrock AJ, Demedts MG, Decramer M. Skeletal muscle weakness in patients with sarcoidosis and its relationship with exercise intolerance and reduced health status. Thorax 2005;60:32–38.
Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 1996;153:976–980.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–383.
Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994;47:1245–1251.
Vernooy JH, Kucukaycan M, Jacobs JA, Chavannes NH, Buurman WA, Dentener MA, Wouters EF. Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. Am J Respir Crit Care Med 2002;166:1218–1224.
Bruunsgaard H, Bjerregaard E, Schroll M, Pedersen BK. Muscle strength after resistance training is inversely correlated with baseline levels of soluble tumor necrosis factor receptors in the oldest old. J Am Geriatr Soc 2004;52:237–241.
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.
Ellis L, Nyborg H. Racial/ethnic variations in male testosterone levels: a probable contributor to group differences in health. Steroids 1992;57:72–75.
Deslypere JP, Vermeulen A. Leydig cell function in normal men: effect of age, life-style, residence, diet, and activity. J Clin Endocrinol Metab 1984;59:955–962.
van den Berghe G, Weekers F, Baxter RC, Wouters P, Iranmanesh A, Bouillon R, Veldhuis JD. Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. J Clin Endocrinol Metab 2001;86:3217–3226.
Winters SJ, Troen P. Episodic luteinizing hormone (LH) secretion and the response of LH and follicle-stimulating hormone to LH-releasing hormone in aged men: evidence for coexistent primary testicular insufficiency and an impairment in gonadotropin secretion. J Clin Endocrinol Metab 1982;55:560–565.
Morley JE, Kaiser FE, Perry HM III, Patrick P, Morley PM, Stauber PM, Vellas B, Baumgartner RN, Garry PJ. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997;46:410–413.
Deslypere JP, Kaufman JM, Vermeulen T, Vogelaers D, Vandalem JL, Vermeulen A. Influence of age on pulsatile luteinizing hormone release and responsiveness of the gonadotrophs to sex hormone feedback in men. J Clin Endocrinol Metab 1987;64:68–73.
Kaufman JM, Deslypere JP, Giri M, Vermeulen A. Neuroendocrine regulation of pulsatile luteinizing hormone secretion in elderly men. J Steroid Biochem Mol Biol 1990;37:421–430.
Kaufman JM, Giri M, Deslypere JM, Thomas G, Vermeulen A. Influence of age on the responsiveness of the gonadotrophs to luteinizing hormone-releasing hormone in males. J Clin Endocrinol Metab 1991;72:1255–1260.
Muller M, den Tonkelaar I, Thijssen JH, Grobbee DE, van der Schouw YT. Endogenous sex hormones in men aged 40–80 years. Eur J Endocrinol 2003;149:583–589.
Raggatt LE, Blok RB, Hamblin PS, Barlow JW. Effects of thyroid hormone on sex hormone-binding globulin gene expression in human cells. J Clin Endocrinol Metab 1992;75:116–120.
Okutan O, Kartaloglu Z, Onde ME, Bozkanat E, Kunter E. Pulmonary function tests and thyroid hormone concentrations in patients with chronic obstructive pulmonary disease. Med Princ Pract 2004;13:126–128.
Vermeulen A, Kaufman JM. Ageing of the hypothalamo-pituitary-testicular axis in men. Horm Res 1995;43:25–28.
Yardimci S, Atan A, Delibasi T, Sunguroglu K, Guven MC. Long-term effects of cigarette-smoke exposure on plasma testosterone, luteinizing hormone and follicle-stimulating hormone levels in male rats. Br J Urol 1997;79:66–69.
Gosney JR. Atrophy of Leydig cells in the testes of men with longstanding chronic bronchitis and emphysema. Thorax 1987;42:615–619.
Creutzberg EC, Casaburi R. Endocrinological disturbances in chronic obstructive pulmonary disease. Eur Respir J Suppl 2003;46:76s–80s.
Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994;150:11–16.
Hopkinson NS, Nickol AH, Payne J, Hawe E, Man WD, Moxham J, Montgomery H, Polkey MI. Angiotensin converting enzyme genotype and strength in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:395–399.
Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, Shale DJ. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1414–1418.
Liu PY, Swerdloff RS, Veldhuis JD. Clinical review 171: the rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations. J Clin Endocrinol Metab 2004;89:4789–4796.
Szulc P, Duboeuf F, Marchand F, Delmas PD. Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study. Am J Clin Nutr 2004;80:496–503.
Pitta F, Troosters T, Spruit MA, Decramer M, Gosselink R. Validation of a triaxial accelerometer to assess various activities in COPD patients . Am J Respir Crit Care Med 2004;169:A594.
Pitta F, Troosters T, Spruit MA, Decramer M, Gosselink R. Activity monitoring for assessment of physical activities in daily life in patients with COPD. Arch Phys Med Rehabil (In press)
Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003;58:618–625.
Wouters EF. Management of severe COPD. Lancet 2004;364:883–895.
Allaire J, Maltais F, Doyon JF, Noel M, LeBlanc P, Carrier G, Simard C, Jobin J. Peripheral muscle endurance and the oxidative profile of the quadriceps in patients with COPD. Thorax 2004;59:673–678.
Serres I, Gautier V, Varray A, Prefaut C. Impaired skeletal muscle endurance related to physical inactivity and altered lung function in COPD patients. Chest 1998;113:900–905.
Couillard A, Maltais F, Saey D, Debigare R, Michaud A, Koechlin C, LeBlanc P, Prefaut C. Exercise-induced quadriceps oxidative stress and peripheral muscle dysfunction in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167:1664–1669.
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med 2001;163:1256–1276.
Polkey MI, Kyroussis D, Hamnegard CH, Mills GH, Green M, Moxham J. Quadriceps strength and fatigue assessed by magnetic stimulation of the femoral nerve in man. Muscle Nerve 1996;19:549–555.
Hopkinson NS, Man WD, Dayer MJ, Ross ET, Nickol AH, Hart N, Moxham J, Polkey MI. Acute effect of oral steroids on muscle function in chronic obstructive pulmonary disease. Eur Respir J 2004;24:137–142.
Perneger TV. What's wrong with Bonferroni adjustments. BMJ 1998;316:1236–1238.
Itoh T, Nagaya N, Yoshikawa M, Fukuoka A, Takenaka H, Shimizu Y, Haruta Y, Oya H, Yamagishi M, Hosoda H, et al. Elevated plasma ghrelin level in underweight patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:879–882.
Decramer M, de Bock V, Dom R. Functional and histologic picture of steroid-induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153:1958–1964.
Decramer M, Gosselink R, Troosters T, Verschueren M, Evers G. Muscle weakness is related to utilization of health care resources in COPD patients. Eur Respir J 1997;10:417–423.
Man WD, Soliman MG, Gearing J, Radford SG, Rafferty GF, Gray BJ, Polkey MI, Moxham J. Symptoms and quadriceps fatigability after walking and cycling in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168:562–567.
Saey D, Debigare R, LeBlanc P, Mador MJ, Cote CH, Jobin J, Maltais F. Contractile leg fatigue after cycle exercise: a factor limiting exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168:425–430.
Ibanez M, Aguilar JJ, Maderal MA, Prats E, Farrero E, Font A, Escarrabill J. Sexuality in chronic respiratory failure: coincidences and divergences between patient and primary caregiver. Respir Med 2001;95:975–979.
Svartberg J, Aasebo U, Hjalmarsen A, Sundsfjord J, Jorde R. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial. Respir Med 2004;98:906–913.
Bolton CE, Ionescu AA, Shiels KM, Pettit RJ, Edwards PH, Stone MD, Nixon LS, Evans WD, Griffiths TL, Shale DJ. Associated loss of fat-free mass and bone mineral density in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:1286–1293.
Lormeau C, Soudan B, d'Herbomez M, Pigny P, Duquesnoy B, Cortet B. Sex hormone-binding globulin, estradiol, and bone turnover markers in male osteoporosis. Bone 2004;34:933–939.(Monique Van Vliet, Martijn A. Spruit, Ge)
Department of Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences
Laboratories of Pneumology, Experimental Immunology, and Experimental Medicine and Endocrinology (LEGENDO), Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
ABSTRACT
Rationale: Circulating levels of testosterone and gonadotrophins of patients with chronic obstructive pulmonary disease (COPD) have never been compared with those of elderly men with normal pulmonary function. Moreover, the relationship of hypogonadism with quadriceps muscle weakness and exercise intolerance has been studied scarcely in men with COPD.
Objectives: To compare circulating levels of hormones of the pituitary–gonadotrophic axis of men with COPD with those of age-matched control subjects. Moreover, to study the relationship of hypogonadism with quadriceps muscle force, 6-min walking distance, and systemic markers of inflammation in the patients.
Methods and Measurements: Circulating levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and sex homone–binding globulin were determined, and free testosterone was calculated in 78 patients (FEV1: 44 ± 17% of the predicted values) and 21 control subjects. Moreover, quadriceps muscle force, 6-min walking distance, number of pack-yr, and systemic inflammation were determined.
Main Results: Follicle-stimulating hormone and luteinizing hormone were higher in the patients, whereas testosterone was lower (p 0.05). The latter finding was also present in 48 non–steroid-using patients with normal blood gases. Low androgen status was significantly related to quadriceps muscle weakness (r = 0.48) and C-reactive protein (r = –0.39) in the patients, but not to exercise intolerance, the number of pack-yr, or increased circulating levels of interleukin 8 or soluble receptors of tumor necrosis factor .
Conclusions: In contrast to exercise intolerance, quadriceps muscle weakness is related to low circulating levels of testosterone in men with COPD.
Key Words: follicle-stimulating hormone luteinizing hormone quadriceps muscle strength sex hormone–binding globulin testosterone
The role of physical inactivity in the development and/or maintenance of quadriceps muscle weakness in patients with advanced chronic obstructive pulmonary disease (COPD) is well established. A reduction in weight-bearing activities has been observed in these patients (1), and quadriceps muscle weakness is closely related to upper leg muscle atrophy (2). Moreover, resistance training and transcutaneous neuromuscular electrical stimulation have been able to improve quadriceps muscle force and to facilitate ambulation in patients with COPD (3–9). Unfortunately, the recovery of quadriceps muscle force is incomplete even after 6 mo of exercise training (7). Therefore, besides physical inactivity, other factors may contribute to the development and/or presence of quadriceps muscle weakness in patients with COPD (10, 11).
In healthy elderly men, age-related decline in quadriceps muscle force has been related to the reduced circulating levels of testosterone (12), which is able to stimulate muscle protein anabolism and motor neuron size (13). Nevertheless, the relationship between testosterone and quadriceps muscle force does not appear to be straightforward. For example, a 20-wk suppression of the endogenous testosterone production in eugonadal, healthy elderly men resulted in reduced circulating testosterone concentrations (mean, 176 ng/dl) without changes in leg-press strength (14).
Uncertainty on the role of testosterone in the development and/or maintenance of quadriceps muscle weakness also remains in male patients with COPD. Laghi and colleagues (15) did not find a significant difference in quadriceps muscle force between 10 eugonadal and 10 hypogonadal male patients with COPD. By way of contrast, Casaburi and colleagues (16) reported significant improvements in quadriceps muscle force after 10 wk of testosterone injections in male patients with COPD who were selected as a result of low baseline circulating levels of testosterone (mean, 320 ng/dl). Moreover, 10 wk of testosterone injections combined with resistance training resulted in greater improvements in quadriceps muscle force than resistance training alone (16). Therefore, it is still reasonable to hypothesize that quadriceps muscle weakness is, at least in part, related to low circulating testosterone concentrations in male patients with advanced COPD.
In the past, increased systemic inflammation (17), a higher dose of oral corticosteroids (18), and hypoxemia have been related to low circulating testosterone concentrations in male patients with COPD (19, 20). The latter two observations, however, could not be substantiated by three recent studies and remain a matter of debate (16, 17, 21).
A dysfunctioning hypothalamic–pituitary–gonadal axis has been found in COPD (15, 16, 20, 21). For example, hypogonadotrophic hypogonadism has been reported in male patients with COPD (16, 20). Others have shown that hypogonadal patients with COPD may have significantly higher serum gonadotrophins than eugonadal patients (15). Moreover, a decreased response to administered gonadotrophin-releasing hormone has been found in hypoxemic patients with chronic airway diseases (20). Nonetheless, there has never been a direct comparison of circulating gonadotrophin concentrations in male patients with COPD and elderly control subjects with normal pulmonary function.
A cross-sectional study was designed to answer the following questions:
Are the systemic markers of the pituitary–gonadotrophic axis in men with COPD significantly different from those of elderly men with normal pulmonary function
What is the relationship between a low androgen status, clinical outcomes, and systemic markers of inflammation in men with COPD
Some of the results of this study have been previously reported in the form of two abstracts (22, 23).
METHODS
Additional details on the methods for making the measurements as described below are provided in an online supplement.
Patients
A total of 259 consecutive patients who attended the COPD outpatient clinic were asked to participate. Of these, 157 patients were reluctant to participate or were excluded (Figure E1 in the online supplement). Consenting patients with COPD had similar clinical characteristics as those who were not included, except for age (Table E1).
The remaining 102 patients with clinically stable COPD (78 men) voluntarily consented to partake in the present study. For obvious reasons, only the results of the male patients were taken into account to answer the aforementioned questions.
The results of the 78 men with COPD were compared with those of 21 men with normal pulmonary function and similar age distribution (Table 1), except for the results of circulating levels of the inflammatory markers, which were only determined in the male patients with COPD to answer the aforementioned second question.
All participants had to come for one morning to the outpatient clinic to perform the tests as described below and in the online supplement. The Medical Ethical Board of the University Hospitals Leuven approved this cross-sectional comparative study. All participants were white and gave informed consent. Seventeen control subjects were part of a previous publication about physical activity level in patients with COPD (1).
Blood Analyses
Venous blood samples were analyzed for C-reactive protein, soluble TNF receptors (sTNFR) p55 and p75 (24), interleukin 8 (IL-8) (11), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sex hormone–binding globulin (SHBG). Moreover, circulating levels of free testosterone were calculated.
Functional Measurements
Pulmonary function, quadriceps peak torque, and the distance walked in 6 min (6MWD) were assessed as described previously (6, 25).
Comorbidities
Comorbid conditions have been classified using the Charlson index, which is a simple weighted index that takes into account the number and the seriousness of comorbid disease (26). In addition, the scores on the age–comorbidity index (Charlson index II) were calculated (27).
Statistical Analyses
See the online supplement.
RESULTS
Cross-sectional Comparisons
Characteristics.
Patients with COPD had significantly worse pulmonary function, quadriceps muscle force, 6MWD, and scores on the Charlson comorbidity and age–comorbidity indexes than the control group (Table 1 and Table E2).
Hormones of the pituitary–gonadotrophic axis.
Patients with COPD had significantly higher circulating levels of FSH and LH and significantly lower circulating levels of testosterone and free testosterone than the control group. Moreover, circulating levels of SHBG tended to be higher in the patients with COPD (Table 1 and Figure 1).
The prevalence of low circulating testosterone concentrations in patients with COPD was significantly higher than in the control group, whereas the prevalence of low circulating free testosterone concentrations tended to be higher in the patients (Table 1 and Figure E2). Hypogonadal patients had circulating FSH and LH concentrations above the lower limit of normal or even above the upper limit of normal (Figure E3).
Stratification for current use of corticosteroids and PaO2 in COPD.
No significant differences were found between median circulating levels of FSH, LH, testosterone, free testosterone, and SHBG in the patients who had been stratified according to the current use of oral corticosteroids ("yes" or "no") and for the PaO2 (< or 70 mm Hg; Figure E4).
Systemic inflammatory markers in COPD.
Median (interquartile range) circulating levels of C-reactive protein (4.2 mg/L [1.8–9.1]), IL-8 (2.8 pg/ml [2.2–3.8]), sTNFR-p55 (2.4 ng/ml [2.0–2.8]), and sTNFR-p75 (5.1 ng/ml [4.2–6.2]) of the patients with COPD were comparable to previous findings in patients with clinically stable COPD (28) and higher than values obtained in healthy middle-aged adults (24) and elderly individuals (29).
Correlations
For correlations between hormones of the pituitary–gonadotrophic axis in COPD, see the online supplement.
Correlations between hormones of the pituitary–gonadotrophic axis and clinical outcomes in COPD.
In the patients with COPD, the impaired FEV1 did not correlate with the observed changes in the pituitary–gonadotrophic axis (Figure E5). Body mass index was inversely related to the circulating levels of testosterone (rs = –0.44, p = 0.0001), free testosterone (rs = –0.24, p = 0.037), and SHBG (rs = –0.48, p = 0.0001).
In contrast to the 6MWD (rs = 0.18, p = 0.12; Figure 2), quadriceps muscle force was positively related to circulating testosterone concentrations (rs = 0.48, p = 0.0001; Figure 3) and circulating free testosterone concentrations (rs = 0.37, p = 0.0012). Only circulating free testosterone concentrations tended to be inversely related to the number of pack-yr (rs = –0.22, p = 0.052), whereas circulating testosterone concentrations tended to be inversely related to the mean daily dose of oral corticosteroids (rs = –0.22, p = 0.058).
Correlations between hormones of the pituitary–gonadotrophic axis and systemic inflammation in COPD.
Circulating levels of IL-8 and the sTNFR-p55 were positively related to the circulating levels of FSH (rs = 0.27, p = 0.021, and rs = 0.23, p = 0.045, respectively) and LH (rs = 0.29, p = 0.012, and rs = 0.22, p = 0.054, respectively). Moreover, circulating C-reactive protein concentrations showed inverse relationships with the circulating levels of testosterone (rs = –0.39, p = 0.0004), free testosterone (rs = –0.28, p = 0.014), and SHBG (rs = –0.22, p = 0.057). Other systemic markers of the pituitary–gonadotrophic axis did not relate to the circulating levels of systemic inflammation in the patients with COPD (p 0.17).
DISCUSSION
The present study has found significant differences in circulating levels of hormones of the pituitary–gonadotrophic axis between male patients with COPD and elderly men with normal pulmonary function. In addition, low circulating levels of testosterone were positively related to quadriceps muscle weakness, but not to reduced functional exercise capacity in patients with COPD. Hypogonadism occurred also in non–steroid-using male patients with COPD who had normal arterial blood gases. Low-grade systemic inflammation and smoking did not appear to be the main determinants of hypogonadism in male patients with COPD. In fact, hypogonadism appeared, at least in part, to be caused by a primary testicular dysfunction and/or a hypofunctioning of the hypothalamic–pituitary–gonadal axis.
Prevalence of Hypogonadism
Although results were borderline, male patients with COPD had a higher prevalence of hypogonadism than control subjects (Table 1). Interestingly, the prevalence of hypogonadism was 13% higher than the values reported by Laghi and colleagues (21), even though the patients had similar age, FEV1, and PaO2, and a similar prevalence of oral corticosteroid use in the hypogonadal patients. The difference in prevalence may therefore be explained by the absence of comorbidities (30) or the presence of ethnic differences (31). Unfortunately, Laghi and colleagues (21) did not give details on these variables.
Hypogonadism was also present in about one-third of the control group. The present observation, although somewhat surprising, is in line with previous unrelated data in healthy, elderly Belgian men (32, 33).
Possible Causes of Hypogonadism in COPD
Hypothalamic–pituitary–testicular axis.
The present authors reasoned a priori that low circulating levels of FSH and LH may be responsible for low circulating testosterone concentrations in male patients with COPD, as seen previously (16, 20). In the present study, however, all hypogonadal patients with COPD (e.g., circulating levels of testosterone 300 ng/dl) showed circulating FSH and LH concentrations above the lower limit of normal (Figure E3). Some hypogonadal patients even had circulating FSH and LH concentrations above the upper limit of normal. Considering the role of FSH and LH in the biosynthesis of testosterone, hypergonadotrophism represents a compensatory mechanism of the hypothalamic–pituitary axis to correct for the low circulating testosterone concentrations in patients with COPD. In fact, a decrease in circulating testosterone concentrations and a compensatory increase in the circulating gonadotrophin concentrations have been reported in healthy elderly men (32, 34, 35) and in patients with COPD (15). These findings suggest that hypogonadism can be due to a primary testiscular dysfunction in COPD.
The remaining hypogonadal patients showed no increase in the circulating levels of LH and FSH on low circulating testosterone concentrations. In addition, a decreased response to administered gonadotrophin-releasing hormone has been found in hypoxemic patients with chronic airway diseases (20). Whether this is due to an impaired periodic release of gonadotrophin-releasing hormone, an impaired function of the gonadotropes, an impaired feedback action of the testes exerted through secretion of steroids or peptides, or a combination thereof remains to be determined (36–38). These findings, however, suggest that hypogonadism can also due to a hypofunctioning of the hypothalamic–pituitary–gonadal axis in COPD.
SHBG.
A somewhat unexpected increase of approximately 30% in the circulating levels of SHBG has been found in subjects with COPD as compared with control subjects, which obviously has affected the circulating free testosterone concentrations (Figure 1). Although aging has been shown to be responsible for increased circulating SHBG concentrations ( 1.1%/yr) (39), the present patients and control subjects were of similar age (Table 1). The biosynthesis of SHBG by the liver has been shown to be regulated by triiodothyronine (40), which, in turn, has been shown to be significantly higher in patients with COPD as compared with healthy control subjects (41). It can therefore be reasoned that hyperthyroidism may, at least in part, be responsible for the observed differences in SHBG and indirectly for a low androgen status in male patients with COPD. Unfortunately, thyroid function was not assessed in the present study. Moreover, the increased circulating SHBG concentrations may be a response to the increased circulating levels of FSH and LH (as shown by the positive relationships), which in turn may be a result of low circulating testosterone concentrations.
Current corticosteroid use, hypoxemia, and smoking.
Median circulating levels of testosterone and free testosterone of 48 non–steroid-using patients with COPD with normal arterial oxygen tension were low: 275 and 4.94 ng/dl, respectively (Figure E4). Moreover, Laghi and colleagues (21) found similar PaO2 and the same prevalence of oral corticosteroid users in hypogonadal and eugonadal patients with COPD. Therefore, the role of oral corticosteroid use and hypoxemia in the development of hypogonadism in COPD appears to be less prominent as suggested previously (18–20).
Smoking has been shown to cause hypogonadism (42, 43). In fact, fewer Leydig cells and degeneration of the remaining cells were found in the testes of men with longstanding chronic bronchitis and emphysema without changes in the circulating gonadotrophin concentrations (44). Nevertheless, the number of pack-yr was only weakly related to the circulating levels of free testosterone in the present patients with COPD. On the other hand, in 48 non–steroid-using patients with COPD with normal PaO2 ( 70 mm Hg), an a posteriori analysis revealed stronger relationships between the number of pack-yr and the circulating levels of free testosterone (r = –0.40, p = 0.0043) and testosterone (r = –0.30, p = 0.0418).
Systemic inflammation.
Systemic inflammation has been suggested as a possible cause of low circulating testosterone concentrations in male patients with COPD (45). To date, only a weak but significant inverse relationship between the circulating levels of IL-6 and bioavailable testosterone has been found in men with COPD (r = –0.33) (17). In the present study, circulating levels of IL-8, sTNFR-p55, and sTNFR-p75 did not correlate with the low circulating levels of testosterone in the male patients with COPD. This is in line with data from Debigare and colleagues (17). Nevertheless, weak inverse relationships were found between circulating levels of testosterone and free testosterone with acute-phase C-reactive protein. It would therefore be interesting to study the possible consequences of transiently increased systemic inflammation (11), together with an increased dose of systemic corticosteroids (46), on the low androgen status in men with COPD during an acute exacerbation.
Some markers of systemic inflammation showed positive relationships with FSH and LH. This may indicate an indirect compensatory reaction of the endocrine system against the presence of a chronic catabolic environment in men with COPD (e.g., low-grade systemic inflammation).
Hypogonadism and Quadriceps Muscle Weakness in COPD
Quadriceps muscle weakness has been related to physical disuse (1, 2), the insertion allele of the angiotensin-converting enzyme gene polymorphism (47), and low systemic levels of insulin-like growth factor I, and to chronic low-grade systemic inflammation in men with COPD (11, 17, 48). The present study is the first to find a weak but significant positive relationship between low androgen status and quadriceps muscle weakness in male patients with clinically stable but advanced COPD.
Recently, no significant differences were found between the mean maximal voluntary quadriceps muscle contraction of 10 eugonadal and 10 hypogondal men with COPD (15). Nevertheless, by using the same cut-off value as Laghi and colleagues (circulating free testosterone concentrations > or 5 ng/dl) (15), the present authors did find a significant difference in isometric quadriceps peak torque between 38 eugonadal (median [interquartile range] circulating free testosterone concentrations: 6.0 ng/dl [5.5–8.3]; mean ± SD quadriceps peak torque: 81 ± 19% predicted) and 40 hypogonadal men with COPD (free testosterone: 3.9 ng/dl [2.8–4.4], p = 0.0001; quadriceps peak torque: 68 ± 19% predicted, p = 0.0057) without a significantly different median score on the Charlson comorbidity index (p = 0.24). Currently, a clear explanation for these discrepant results is lacking. In fact, the present patients had comparable characteristics as those studied by Laghi and colleagues (15). Nevertheless, the number of patients studied by these authors was most probably too low to exclude a type II error. Moreover, the present results are in line with previous findings in healthy elderly individuals (49, 50) and the present control subjects had comparable results (see online supplement). Then again, circulating levels of bioavailable testosterone were similar between a group of patients with COPD with and without upper leg muscle atrophy (17). The mean circulating testosterone concentrations of the patients with COPD, however, were equal to those obtained in healthy elderly control subjects (17). Moreover, circulating testosterone concentrations have shown to be independent of daily physical activity level in healthy subjects and in patients with chronic pulmonary or cardiac disease (16, 21, 32). Therefore, the most straightforward suggestion is that patients with COPD with the lowest midthigh cross-sectional area probably had the lowest levels of daily physical activities (17). Unfortunately, the present study and others (15, 17) did not explicitly study the levels of daily physical activity using a validated activity monitor (51, 52).
Testosterone replacement therapy has not always been effective to improve quadriceps muscle strength in healthy elderly men (53). Moreover, improvements in skeletal muscle mass and leg-press strength in healthy elderly men receiving a combination of 600 mg testosterone enanthate injections (once every wk for 20 wk) together with 7.5 mg Lupron depot (a long-acting gonadotrophin agonist, once monthly for 20 wk) were not significantly different from those who received 125 or 300 mg testosterone enanthate injections together with 7.5 mg Lupron depot (14). Nevertheless, the relationship of quadriceps muscle weakness with physical disuse (2) and hypogonadism may provide a rationale to combine structured exercise programs with testosterone replacement therapy in highly selected hypogonadal patients with COPD. Actually, weekly injections of testosterone enanthate have shown to result in significant increases in bodyweight, lean body mass, and quadriceps muscle function, but not in respiratory muscle function or exercise capacity in male patients with COPD with low baseline circulating levels of testosterone (16). This dose (100 mg/wk) for this duration (10 wk) did not result in adverse effects in male patients with COPD who had low baseline androgen status (16). Nevertheless, additional safety and feasibility studies are necessary before testosterone supplements may be added to the management of highly selected patients with severe COPD (54).
Hypogonadism and Exercise Intolerance in COPD
Exercise capacity was not affected by the gonadal status in patients with COPD (Figure 2), corroborating previous findings (15, 16, 21). In fact, quadriceps muscle endurance was similar between eugonadal and hypogonadal patients with COPD (15). This seems reasonable considering the fact that quadriceps muscle endurance has shown to be related to the proportion of type I muscle fibers, citrate synthase activity (55), physical inactivity (56), and exercise-induced muscle oxidative stress (57).
Methodologic and Statistical Considerations
The present study has been performed in a tertiary care setting, and may therefore have led to a bias in the selection of males with only advanced COPD. Hence, external validity of the current findings is limited to this subgroup. Nevertheless, patients with Global Initiative for Chronic Obstructive Lung Disease stage II disease (58) also had low median circulating levels of testosterone and free testosterone (336 and 4.6 ng/dl, respectively), and this finding can therefore also be expected in male patients with COPD in primary and secondary care settings.
A relatively high number of the present patients used oral corticosteroids (29%), which may have biased the results. Nonetheless, previous studies reported a similar prevalence (15, 21).
Patients had a significantly higher score on the Charlson comorbidity index than control subjects (Table 1), which may have affected the circulating free testosterone concentrations. Nevertheless, circulating testosterone concentrations did not change significantly in elderly patients (mean age, 70 yr) directly or 3 mo after an acute myocardial infarction (32). In the present study, the circulating free testosterone concentrations remained significantly different between 52 patients (5.22 ng/dl [4.12–6.11]) and 20 control subjects (6.57 ng/dl [5.14–9.03], p = 0.03) after excluding 26 patients with COPD and one control subject with comorbidities. Moreover, hypogonadal patients with COPD had a similar median score on the Charlson comorbidity index as eugonadal patients.
At the time of the study, the present authors did not have access to a magnetic stimulator, which has been shown to be a painless, supramaximal method of assessing quadriceps force independent of the maximality of the effort made during the test by the participants (59). Nevertheless, the variability of maximal voluntary quadriceps femoris muscle contraction was found to be similar to measurements by magnetic stimulation (59), and a supramaximal twitch during a maximal voluntary contraction did not result in a significantly higher peak force (60). The present authors therefore believe that a maximal voluntary contraction is a valid technique to measure peak force of the femoral quadriceps muscles of patients with COPD.
Currently, a minimal clinically important difference for quadriceps peak torque has not been determined in COPD. Nonetheless, a mean difference of 13% of the predicted value for quadriceps peak torque between hypo- and eugonadal patients appears to be clinically relevant, in particular because quadriceps muscle force increased significantly with a mean of 7% of the predicted values after 3 mo of high-intensity progressive resistance and endurance training in 65 patients with advanced COPD (6).
Significant correlations do not necessarily imply causal relationships. Moreover, statistically significant differences between groups need to be interpreted in the light of the number of comparisons that were made in the present study. Nonetheless, the current statistical procedures have been used to test predefined hypotheses. Moreover, according to Perneger (61), "Bonferoni adjustments are at best, unnecessary and, at worst, deleterious to sound statistical inference."
Future Research
Although reduced quality of life was not related to the gonadal status of patients with COPD (21), endocrinological changes (i.e., hyposomatotrophism [11], hypogonadism [15, 21], hyperthyroidism [41], and elevated plasma ghrelin levels [62]) may still be of clinical importance for patients with advanced COPD. In the present study, the clinically relevant quadriceps muscle weakness (25, 63–66) was positively related to reduced circulating levels of testosterone. Other clinically important complaints of patients with COPD may also be, at least in part, due to low testosterone levels. For example, reduced libido and erectile dysfunction have been reported in approximately 67% of the male patients with COPD with chronic respiratory failure on long-term oxygen therapy (67). Sex hormone replacement therapy has already shown to result in an improved erectile function and overall sexual quality of life in male patients with COPD (68).
The possible role of the increased circulating levels of SHBG (Figure 1) in the loss of bone mineral density (69) may also be worthy of study. Indeed, in middle-aged men with idiopathic or secondary osteoporosis, the increased circulating levels of SHBG were related to the bone mineral density of the hip and spine (70).
Conclusions
About 50% of the male outpatients with clinically stable COPD have a low androgen status, which can be caused by a combination of factors. In the present study, a primary testicular dysfunction and/or a hypofunctioning of the hypothalamic–pituitary–gonadal axis appeared to be the main underlying mechanisms of hypogonadism in male patients with COPD. Moreover, low circulating levels of testosterone were positively related to quadriceps muscle weakness but not to exercise intolerance in these patients.
Acknowledgments
The authors thank physiotherapists Veronica Barbier, Iris Coosemans, and Vanessa Probst for assessing the functional outcomes in the present study.
FOOTNOTES
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Conflict of Interest Statement: M.V.V. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. M.A.S. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. G.V. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. A.K. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. E.V.H. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. F.P. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. R.B. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. M.D. has received an unrestricted grant from AstraZeneca to pay the salary of M.V.V. and has received $40,000 from AstraZeneca Belgium between 9/1/2003 and 8/31/2004.
These authors contributed equally to this study.
REFERENCES
Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:972–977.
Bernard S, LeBlanc P, Whittom F, Carrier G, Jobin J, Belleau R, Maltais F. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:629–634.
Ortega F, Toral J, Cejudo P, Villagomez R, Sanchez H, Castillo J, Montemayor T. Comparison of effects of strength and endurance training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:669–674.
Spruit MA, Gosselink R, Troosters T, De Paepe K, Decramer M. Resistance versus endurance training in patients with COPD and peripheral muscle weakness. Eur Respir J 2002;19:1072–1078.
Spruit MA, Troosters T, Trappenburg JCA, Decramer M, Gosselink R. Exercise training during rehabilitation of patients with COPD: a current perspective. Patient Educ Couns 2004;52:243–248.
Spruit MA, Gosselink R, Troosters T, Kasran A, Van Vliet M, Decramer M. Low-grade systemic inflammation and the response to exercise training in patients with advanced COPD. Chest (In press)
Troosters T, Gosselink R, Decramer M. Short- and long-term effects of outpatient rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. Am J Med 2000;109:207–212.
Troosters T, Casaburi R, Gosselink R, Decramer M. Pulmonary rehabilitation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:19–38.
Zanotti E, Felicetti G, Maini M, Fracchia C. Peripheral muscle strength training in bed-bound patients with COPD receiving mechanical ventilation: effect of electrical stimulation. Chest 2003;124:292–296.
Debigare R, Cote CH, Maltais F. Peripheral muscle wasting in chronic obstructive pulmonary disease: clinical relevance and mechanisms. Am J Respir Crit Care Med 2001;164:1712–1717.
Spruit MA, Gosselink R, Troosters T, Kasran A, Gayan-Ramirez G, Bogaerts P, Bouillon R, Decramer M. Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I. Thorax 2003;58:752–756.
van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 2000;85:3276–3282.
Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care 2004;7:271–277.
Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-Hikim I, Dzekov C, Dzekov J, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005;90:678–688.
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 2005;171:598–605.
Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis MI, Fournier M, Storer TW. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:870–878.
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.
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.
Semple PD, Beastall GH, Watson WS, Hume R. Serum testosterone depression associated with hypoxia in respiratory failure. Clin Sci (Lond) 1980;58:105–106.
Semple PD, Beastall GH, Watson WS, Hume R. Hypothalamic-pituitary dysfunction in respiratory hypoxia. Thorax 1981;36:605–609.
Laghi F, Antonescu-Turcu A, Collins E, Segal J, Tobin DE, Jubran A, Tobin MJ. Hypogonadism in men with chronic obstructive pulmonary disease: prevalence and quality of life. Am J Respir Crit Care Med 2005;171:728–733.
Van Vliet M, Spruit MA, Verleden G, Decramer M. Hypogonadism is related to skeletal muscle weakness in male patients with COPD . Eur Respir J 2004;24:256s.
Van Vliet M, Spruit MA, Verleden G, Decramer M. Low circulating levels of testosterone in male patients with chronic obstructive pulmonary disease (COPD) . Proc Am Thorac Soc 2005;2:A530.
Spruit MA, Thomeer MJ, Gosselink R, Troosters T, Kasran A, Debrock AJ, Demedts MG, Decramer M. Skeletal muscle weakness in patients with sarcoidosis and its relationship with exercise intolerance and reduced health status. Thorax 2005;60:32–38.
Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 1996;153:976–980.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–383.
Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994;47:1245–1251.
Vernooy JH, Kucukaycan M, Jacobs JA, Chavannes NH, Buurman WA, Dentener MA, Wouters EF. Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. Am J Respir Crit Care Med 2002;166:1218–1224.
Bruunsgaard H, Bjerregaard E, Schroll M, Pedersen BK. Muscle strength after resistance training is inversely correlated with baseline levels of soluble tumor necrosis factor receptors in the oldest old. J Am Geriatr Soc 2004;52:237–241.
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.
Ellis L, Nyborg H. Racial/ethnic variations in male testosterone levels: a probable contributor to group differences in health. Steroids 1992;57:72–75.
Deslypere JP, Vermeulen A. Leydig cell function in normal men: effect of age, life-style, residence, diet, and activity. J Clin Endocrinol Metab 1984;59:955–962.
van den Berghe G, Weekers F, Baxter RC, Wouters P, Iranmanesh A, Bouillon R, Veldhuis JD. Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. J Clin Endocrinol Metab 2001;86:3217–3226.
Winters SJ, Troen P. Episodic luteinizing hormone (LH) secretion and the response of LH and follicle-stimulating hormone to LH-releasing hormone in aged men: evidence for coexistent primary testicular insufficiency and an impairment in gonadotropin secretion. J Clin Endocrinol Metab 1982;55:560–565.
Morley JE, Kaiser FE, Perry HM III, Patrick P, Morley PM, Stauber PM, Vellas B, Baumgartner RN, Garry PJ. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997;46:410–413.
Deslypere JP, Kaufman JM, Vermeulen T, Vogelaers D, Vandalem JL, Vermeulen A. Influence of age on pulsatile luteinizing hormone release and responsiveness of the gonadotrophs to sex hormone feedback in men. J Clin Endocrinol Metab 1987;64:68–73.
Kaufman JM, Deslypere JP, Giri M, Vermeulen A. Neuroendocrine regulation of pulsatile luteinizing hormone secretion in elderly men. J Steroid Biochem Mol Biol 1990;37:421–430.
Kaufman JM, Giri M, Deslypere JM, Thomas G, Vermeulen A. Influence of age on the responsiveness of the gonadotrophs to luteinizing hormone-releasing hormone in males. J Clin Endocrinol Metab 1991;72:1255–1260.
Muller M, den Tonkelaar I, Thijssen JH, Grobbee DE, van der Schouw YT. Endogenous sex hormones in men aged 40–80 years. Eur J Endocrinol 2003;149:583–589.
Raggatt LE, Blok RB, Hamblin PS, Barlow JW. Effects of thyroid hormone on sex hormone-binding globulin gene expression in human cells. J Clin Endocrinol Metab 1992;75:116–120.
Okutan O, Kartaloglu Z, Onde ME, Bozkanat E, Kunter E. Pulmonary function tests and thyroid hormone concentrations in patients with chronic obstructive pulmonary disease. Med Princ Pract 2004;13:126–128.
Vermeulen A, Kaufman JM. Ageing of the hypothalamo-pituitary-testicular axis in men. Horm Res 1995;43:25–28.
Yardimci S, Atan A, Delibasi T, Sunguroglu K, Guven MC. Long-term effects of cigarette-smoke exposure on plasma testosterone, luteinizing hormone and follicle-stimulating hormone levels in male rats. Br J Urol 1997;79:66–69.
Gosney JR. Atrophy of Leydig cells in the testes of men with longstanding chronic bronchitis and emphysema. Thorax 1987;42:615–619.
Creutzberg EC, Casaburi R. Endocrinological disturbances in chronic obstructive pulmonary disease. Eur Respir J Suppl 2003;46:76s–80s.
Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994;150:11–16.
Hopkinson NS, Nickol AH, Payne J, Hawe E, Man WD, Moxham J, Montgomery H, Polkey MI. Angiotensin converting enzyme genotype and strength in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:395–399.
Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, Shale DJ. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1414–1418.
Liu PY, Swerdloff RS, Veldhuis JD. Clinical review 171: the rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations. J Clin Endocrinol Metab 2004;89:4789–4796.
Szulc P, Duboeuf F, Marchand F, Delmas PD. Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study. Am J Clin Nutr 2004;80:496–503.
Pitta F, Troosters T, Spruit MA, Decramer M, Gosselink R. Validation of a triaxial accelerometer to assess various activities in COPD patients . Am J Respir Crit Care Med 2004;169:A594.
Pitta F, Troosters T, Spruit MA, Decramer M, Gosselink R. Activity monitoring for assessment of physical activities in daily life in patients with COPD. Arch Phys Med Rehabil (In press)
Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003;58:618–625.
Wouters EF. Management of severe COPD. Lancet 2004;364:883–895.
Allaire J, Maltais F, Doyon JF, Noel M, LeBlanc P, Carrier G, Simard C, Jobin J. Peripheral muscle endurance and the oxidative profile of the quadriceps in patients with COPD. Thorax 2004;59:673–678.
Serres I, Gautier V, Varray A, Prefaut C. Impaired skeletal muscle endurance related to physical inactivity and altered lung function in COPD patients. Chest 1998;113:900–905.
Couillard A, Maltais F, Saey D, Debigare R, Michaud A, Koechlin C, LeBlanc P, Prefaut C. Exercise-induced quadriceps oxidative stress and peripheral muscle dysfunction in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167:1664–1669.
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med 2001;163:1256–1276.
Polkey MI, Kyroussis D, Hamnegard CH, Mills GH, Green M, Moxham J. Quadriceps strength and fatigue assessed by magnetic stimulation of the femoral nerve in man. Muscle Nerve 1996;19:549–555.
Hopkinson NS, Man WD, Dayer MJ, Ross ET, Nickol AH, Hart N, Moxham J, Polkey MI. Acute effect of oral steroids on muscle function in chronic obstructive pulmonary disease. Eur Respir J 2004;24:137–142.
Perneger TV. What's wrong with Bonferroni adjustments. BMJ 1998;316:1236–1238.
Itoh T, Nagaya N, Yoshikawa M, Fukuoka A, Takenaka H, Shimizu Y, Haruta Y, Oya H, Yamagishi M, Hosoda H, et al. Elevated plasma ghrelin level in underweight patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:879–882.
Decramer M, de Bock V, Dom R. Functional and histologic picture of steroid-induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153:1958–1964.
Decramer M, Gosselink R, Troosters T, Verschueren M, Evers G. Muscle weakness is related to utilization of health care resources in COPD patients. Eur Respir J 1997;10:417–423.
Man WD, Soliman MG, Gearing J, Radford SG, Rafferty GF, Gray BJ, Polkey MI, Moxham J. Symptoms and quadriceps fatigability after walking and cycling in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168:562–567.
Saey D, Debigare R, LeBlanc P, Mador MJ, Cote CH, Jobin J, Maltais F. Contractile leg fatigue after cycle exercise: a factor limiting exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168:425–430.
Ibanez M, Aguilar JJ, Maderal MA, Prats E, Farrero E, Font A, Escarrabill J. Sexuality in chronic respiratory failure: coincidences and divergences between patient and primary caregiver. Respir Med 2001;95:975–979.
Svartberg J, Aasebo U, Hjalmarsen A, Sundsfjord J, Jorde R. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial. Respir Med 2004;98:906–913.
Bolton CE, Ionescu AA, Shiels KM, Pettit RJ, Edwards PH, Stone MD, Nixon LS, Evans WD, Griffiths TL, Shale DJ. Associated loss of fat-free mass and bone mineral density in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:1286–1293.
Lormeau C, Soudan B, d'Herbomez M, Pigny P, Duquesnoy B, Cortet B. Sex hormone-binding globulin, estradiol, and bone turnover markers in male osteoporosis. Bone 2004;34:933–939.(Monique Van Vliet, Martijn A. Spruit, Ge)