Durabolin

Study objectives: Skeletal muscle weakness commonly occurs in patients with COPD. Long-term use of systemic glucocorticosteroids further contributes to muscle weakness. Anabolic steroids could be an additional mode of intervention to improve outcome of pulmonary rehabilitation by increasing physiologic functioning, possibly mediated by increasing erythropoietic function. Patients and methods: We randomly assigned 63 male patients with COPD to receive on days 1 15, 29, and 43 a deep IM injection of 50 mg of nandrolone decanoate (ND) [Deca-Durabolin; N.V Organon; Oss, The Netherlands] in 1 mL of arachis oil, of 1 mL of arachis oil alone (placebo) in a double-blind design. All patients participated in a standardized pulmonary rehabilitation program. Outcome measures were body composition by deuterium and bromide dilution respiratory and peripheral muscle function, incremental exercise testing, and health status by the St. George's Respiratory Questionnaire.

Results: Treatment with ND relative to placebo resulted in higher increases in fat-free mass (FFM; mean, 1.7 kg [SD, 2.5] vs 0.3 kg [SD, 1.9]; p = 0.015) owing to a rise in intracellular mass (mean, 1.8 kg [SD, 3.1] vs - 0.5 kg [SD, 3.1]; p = 0.002). Muscle function, exercise capacity, and health status improved in both groups to the same extent. Only after ND were increases it erythropoietic parameters seen (erythropoietin: mean, 2.08 U/L [SD, 5.56], p = 0.067; hemoglobin: mean, 0.29 mmol/L [SD, 0.73], p = 0.055). In the total group, the changes in maximal inspiratory mouth pressure (PImax) and peak workload were positively correlated with the change in hemoglobin (r = 0.30, p = 0.032, and r = 0.34, p = 0.016, respectively), whereas the change in isokinetic leg work was correlated with the change in erythropoietin (r = 0.38 p = 0.613). In the patients receiving maintenance treatment with low-dose oral glucocorticosteroids (31 of 63 patients; mean, 7.5 mg/24 h [SD, 2.4]), greater improvements in PImax (mean 6.0 cm [H.sub.2]O [SD, 8.82] vs - 2.18 cm [H.sub.2]O [SD, 11.08], p = 0.046), and peak workload (mean, 20.47 W [SD, 19.82] vs 4.80 W [SD, 7.74], p = 0.023) were seen after 8 weeks of treatment with ND w, placebo.

Conclusions: In conclusion, a short-term course of ND had an overall positive effect relative to placebo on FFM without expanding extracellular water in patients with COPD. In the total group the improvements in muscle function and exercise capacity were associated with improvement, in erythropoietic parameters. The use of low-dose oral glucocorticosteroids as maintenance medication significantly impaired the response to pulmonary rehabilitation with respect to respiratory muscle function and exercise capacity, which could be restored by ND treatment.

Key words: anabolic steroids; body composition; COPD: erythropoietin; exercise capacity; health status; muscle Function; nandrolone decanoate: oral glucocorticosteroids; testosterone

Abbreviations: ECM = extracellular mass: ECW = extracellular water; ESR = erythrocyte sedimentation rate FFM = fat-free mass; FM = fat mass; ICM = intracellular mass; LDH = lactate dehydrogenase; ND = nandrolone decanoate; PImax = maximal inspiratory mouth pressure: SGRQ = St. George's Respiratory Questionnaire SHBG = sex hormone binding globulin: V[O.sub.2] = oxygen consumption

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At present, medical treatment of COPD is pre dominantly focused on the primary organ dysfunction, Despite optimal medication, there is a weak relationship between the primary organ impairment and disability/experienced handicap. The most important complaints of patients with COPD are dyspnea (1) and an impaired exercise performance, of which the latter is clearly related to the diminished muscle function. (2)

Diminished muscle function is in part the result of the commonly occurring muscle wasting in patients with COPD, its prevalence increasing from 20% in clinically stable outpatients (3) up to 35% in patients eligible for pulmonary rehabilitation. (4) Decreased anabolic hormones may also impair the anabolic response needed for skeletal muscle performance. Kamischke et al (5) reported low levels of testosterone in male patients with COPD, especially in those receiving maintenance oral glucocorticosteroid therapy. Systemic glucocorticosteroids are indeed known to contribute to respiratory as well as peripheral muscle weakness in patients with COPD, (6) independently of the extent of muscle wasting. (7)

To improve muscle function and exercise capacity in patients with COPD, pulmonary rehabilitation is currently accepted as evidence-based intervention strategy. (8) Anabolic steroids could be an additional mode of intervention to enhance the response to pulmonary rehabilitation. Until now, only a few controlled studies (9, 10) on anabolic steroid supplementation have been performed in patients with COPD, reporting positive effects on fat-free mass (FFM) in underweight patients with COPD. However, the effects on physical performance and health status are still to be precisely defined.

The mechanism behind the supposed physiologic effects of anabolic steroids is still unknown. It can be hypothesized that improvements in function are mediated by an increase in muscle mass and/or muscle oxidative metabolism. (11) In addition, the erythropoietic effects of anabolic steroids-among others, an increase in the hormone erythropoietin (12)--might playa role. As another application, anabolic steroids might be particularly effective in patients receiving oral glucocorticosteroids as maintenance medication. In experimental animal models, nandrolone decanoate (ND) [Deca-Durabolin; N.V. Organon; Oss, the Netherlands] veas able to reverse the diaphragmatic muscle weakness specifically induced by systemically administered glucocorticosteroids. (13,14)

The present study aimed to investigate the effects of ND treatment on body composition, respiratory and peripheral muscle function, exercise performance, health status, and erythropoietic parameters in male patients with COPD. The treatment consisted of 50 mg of ND in 1 mL arachis oil, or 1 mL of arachis oil alone (placebo) administered 1M every 2 weeks in a randomized, double-blind study design. All patients participated in an 8-week standardized pulmonary rehabilitation program. The patients were post hoc stratified by maintenance oral glucocorticosteroid use in order to investigate if the patients receiving oral glucocorticosteroids would benefit more from the ND treatment.

MATERIALS AND METHODS

Patients

The patients were consecutively admitted to a pulmonary rehabilitation center and were included if they fulfilled the criteria for COPD according to the American Thoracie Society guidelines. (15) The FE[V.sub.1] had to be < 70% of the reference value, and the increase in FE[V.sub.1] after inhalation of a [[beta].sup.2]-agonist < 10% of the reference value. Patients had to be in a clinically stable condition (not suffering from a recent respiratory tract infection). Exclusion criteria were as follows: obesity (body mass index > 30), malignancies, cardiac failure, chronic hypoxemia at rest requiring continuous oxygen support (Pa[O.sub.2] < 7.3 kPa), GI inflammatory disorders, and insulin-dependent diabetes mellitus. The final intent-to treat study group consisted of 63 male patients (mean age, 66 years [SD, 66]) with moderate to-severe COPD (FE[V.sub.1], 36% predicted [SD, 141). The study was approved by the medical ethical committee of the University Hospital Maastricht, in accordance with the Helsinki Declaration of 1975, as revised in 1983. All subjects gave their informed consent in writing.

Measurements

Lung Function: At baseline, FE[V.sub.1] and inspiratory vital capacity were calculated from the flow-volume curve using a spirometer (Masterlab; Jaeger; Wurzburg, Germany). Diffusing capacity for carbon monoxide divided by alveolar volume was determined using the single-breath method (Masterlab; Jaeger). Lung function parameters were expressed as percentage of reference values. (16) Blood was drawn from the brachial artery with the patients breathing room air. Pa[O.sub.2] and PaC[O.sub.2] were analyzed on a blood gas analyzer (ABL 330); Radiometer; Copenhagen, Denmark). Before and after 8 weeks of treatment, measurements of body composition, muscle function, exercise capacity, health status, erythropoietic parameters, laboratory parameters, and physical examination were performed as described below.

Body Composition: Body height was determined to the nearest 0.5 cm (WM 715: Lameris; Breukelen, The Netherlands) with subjects standing barefoot. Body weight was assessed with a beam scale to the nearest 0.1 kg (SECA; Hamburg, Germany) with subjects standing barefoot and in light clothing. Total and extracellular water values (ECW) were measured using the deuterium and bromide dilution method according to the Maastricht protocol. (17) Intracellular water was calculated by subtracting ECW from total body water. FFM, extracellular mass (ECM), and intracellular mass (ICM) were calculated assuming a hydration factor of 0.73. Fat mass (FM) was calculated by subtracting FFM from body weight.

Muscle Function: Maximal inspiratory mouth pressure (PImax) was measured according to the method of Black and Hyatt. (18) The device was fabricated by the technical department of our hospital. We used a calibrated leak to prevent the facial muscles from producing significant pressures. PImax results were noted us positive values, and the best of three attempts was taken for analysis.

With use of a Harpenden handgrip dynamometer (Yamar; Preston; Jackson, MI), the maximally developed strength of the flexors of the fingers of both hands was determined. The mean of the highest of three attempts per hand was used in the analysis. Isometric extension strength of the lower extremities was measured with a "multijoint" dynamometer device (Aristokin; Lode; Groningen, the Netherlands). The feet were attached against a fixed support while seated with knees bent at a 120[degrees] angle. The patients generated their maximal isometric force of the legs against an applied resistance of 2,200 N while the seat was fixed. The best of three performed repetitions was used in the analysis, Using the same equipment, linear isokinetic muscle function of the lower limbs was assessed. While seated with knees bent at a 90[degrees] angle, the feet were attached against a fixed support, leaving the ankles free to rotate. The patients performed maximal isokinetic extension of the legs. The rate a which the seat shifted backwards was set at 20 cm/s (preload, 150 N during 0.3 s). The highest work value from five repetitive attempts was taken for analysis. During all muscle function tests, the patients were encouraged.

Exercise Capacity: An incremental bicycle ergometry test was performed on an electromagnetic braked ergometer (Corival 400; Lode) to investigate maximal leg exercise capacity. After a 2-min resting period and 1-min unloaded cycling, power was increased every minute by 10 W. The load cycled was unknown to the patients who were encouraged to cycle for as long as possible. Peak workload was compared with the predicted values. (19) During the exercise test, heart rate was monitored (Sport-tester; Polar Electro Cy; Kempele, Finland). Oxygen consumption (V[O.sub.2]) was measured and calculated from breath-by-breath analysis using a breathing mask (Oxycon; Jaeger). The equipment was calibrated before the tests, and the accuracy of the system was regularly assessed using a methanol combustion test. Immediately before and 2 min after reaching the peak workload, a venous blood sample was taken to measure the concentration of lactate. The blood samples were stored on ice (4[degrees]C) and centrifuged for 5 min at 3,000 revolutions per minute (Sigma 2-15; Lameris; Breukelen, the Netherlands). Plasma lactate was determined enzymatically using an automated system (Cobas Mira; Roche; Basel, Switzerland). Peak workload, peak V[O.sub.2] the ratio between peak V[O.sub.2] and peak heart rate (peak oxygen pulse), and the ratio between peak lactate and peak workload (peak lactate/peak workload ratio; un indirect measure of oxidative capacity) were used in the analyses. A high serum lactate at a given workload was considered as unfavorable, and thus a decrease in peak lactate/ peak workload ratio was considered us an improvement. (20)

Health Status: Health status was measured by the St. George's Respiratory Questionnaire (SGRQ), a standardized, sensitive, and reproducible questionnaire specific for patients with lung diseases. (21) The SGRQ consists of 76 items and is designed to allow direct comparisons of the health gain to be obtained with different types of interventions. After the questionnaire was filled out by the patients themselves, subscores ranging from 0 to 100 points for the categories symptoms (distress due to respiratory symptoms), activity (disturbance of physical activity), and impact (overall impact on daily life and well-being) were calculated, as well us the total score (mean of the three scores). A high score means greater impairment in health status; thus, a reduction in score implies an improvement in health status. A change from baseline score of four points or more after treatment is considered us clinically significant. (21)

Erythropoietic and Anabolic Parameters: Blood was collected for the assessment of erythropoietin and also for total and free testosterone, since anabolic steroids are known to decrease testosterone levels. (22) For the calculation of free testosterone, albumin and sex hormone-binding globulin (SHBG) were assessed, An evacuated tube containing ethylenediaminetetra-acetic acid (Sherwood Medical; St Louis, MO) was used for the collection of blood when patients were in the fasting state for at least 10 h at approximately 9 AM. Plasma was separated from blood cells by centrifugation at 1,000g for 10 min at 4[degrees]C within 2 h after collection. Separated plasma was again centrifuged at 1,000g for 10 min at 4[degrees]C. Plasma samples were stored at -70[degrees]C until analysis, erythropoietin, total testosterone, SHBG, and albumin were analyzed using an AutuDelfia automatic analyzer (Perkin-Elmer; Norwalk, CT). In our laboratory, the detection limit of plasma total testosterone was 0.7 mnol/L. Plasma free testosterone was calculated from total testosterone, SHBG, and albumin according to the method of Swinkels et al. (23,24) In whole blood, the hematologic parameters erythrocyte count, hemoglobin, and hematocrit were measured (Cobas Micro; Hoffman-La Roche; Nutley, NJ).

Laboratory Parameters: For the assessment of laboratory parameters, blood was collected in un evacuated tube when the patients were in the fasting state for at least 10 h at approximately 9 AM. The following parameters of biochemistry were measured by spectrophotometric analysis (Cobas Mira; Hoffmann-La Roche): serum creatinine, glucose, aspartate aminotransferase, alanine aminotransferase, [gamma]-glutamyl transpeptidase, total bilirubin, total protein, albumin, urea, and lactate dehydrogenase (LDH). In whole blood, leukocyte and thrombocyte counts were measured (Cobas Micro; Hoffman-La Roche). Also, the erythrocyte sedimentation rate (ESR) was assessed.

Physical Examination: Before and after 8 weeks of treatment, the following potential side effects were checked: androgenic effects, BP, and fluid retention.

Study Design and Intervention

After patients were consecutively admitted to the pulmonary rehabilitation center, fulfilled all inclusion and exclusion criteria, and had given written informed consent, they were randomly allocated to receive ND of placebo. The study medication was numbered beginning with No. 001. A coded list with the randomization number and the matching treatment (ND or placebo) was stored in a sealed envelope that only could be opened in case of an emergency. The study was double blinded by using the same packaging and labeling fur ampules with ND and the ampules with placebo. All ampules contained arachis oil: only in the treatment ampules was ND added. Neither the investigator nor the patient could see any difference between arachis oil alone and arachis oil with ND. The patients received on day 1, day 15, day 29, and day 43 a deep IM injection in the gluteus maximus muscle with 50 mg ND in 1 mL arachis oil or 1 mL arachis oil alone (placebo).

Patients were post hoc stratified by maintenance oral glucocorticosteroid use. In approximately half of the patients, the use of oral glucocorticosteroids was prescribed as maintenance medication regime by the chest physician. Post hoc stratification of oral glucocorticosteroid use was introduced after 8 weeks of assigned treatment (ND or placebo); the patients were classified into two groups: patients with no oral glucocorticosteroids as maintenance medication (n = 32), and patients receiving oral glucocorticosteroids as maintenance medication (n = 31). These two groups were further subdivided: (1) no oral glucocorticosteroids plus placebo (n = 18), (2) no oral glucocorticosteroids plus ND (n = 14), (3) oral glucocorticosteroids plus placebo (n = 12), and (4) oral glucocorticosteroids plus ND (n = 19). Because we wanted to investigate the interaction between the maintenance use of oral glucocorticosteroids and ND, only the groups oral glucocorticosteroids plus placebo and oral glucocorticosteroids plus ND were compared in the post hoc analysis.

The intervention was incorporated into an 8-week, standardized, impatient pulmonary rehabilitation program, consisting in general physical training with particular attention to exercise in relation to daily activities, cycle ergometry (load depending on the maximal load during an incremental bicycle ergometry test) treadmill walking, swimming, sports, and games. No respiratory or peripheral muscle strength training was given. The exercise program was spread over the day; therefore, the free unstructured exercise activity was limited The diet that was offered to the patients could be standardized to an 8-week menu cycle because of the inpatient setting. All patients received throe meals per day with the same calorie and macronutritional content. The total protein content of the diet was more than enough to ensure optimal protein synthesis (1.5 g protein per kilogram body weight per 24 h). (25) Patients who were depleted in FFM (FFM index [less than or equal to] 16, kg/[m.sup.2]; 18 of 30 patients in the placebo group and 24 of 33 patients in the ND group) received in addition two to three oral nutritional supplements (Nutridrink, Fortimel, Ensini, Fortipudding; Nutricia Nederland B.V.; Zoetermeer, the Netherlands) per day, with a total energy amount of 500 to 750 kilocalories per 24 h.

Data Handling

Power analysis was based on the effects of ND on FFM and PImax in the previous study (9) of our group in a comparable set-up In this previous study, (9) some of the parameters studied in the present study were also evaluated, including FFM and PImax. Based on the t test comparing groups pairwise, with respect to changes from baseline, the detectable difference can be determined assuming 30 patients per group are included in the analyses (Table 1).

The intent-to-treat group consisted of 63 subjects (ND, n = 33; placebo, n = 30). One patient in the ND-treated group discontinued because he accidentally received an ampoule with ND instead of study medication, one patient was not willing to cooperate further with the study (placebo group), one patient resigned from the rehabilitation center because of family problems (placebo group), and one patient was too weak to fulfill the exercise tests anymore (ND treated group). Three patients in the ND-treated group discontinued, as judged by an independent chest physician, because of intubation for mechanical ventilation due to respiratory insufficiency. Two of them died. All of the above-mentioned seven subjects were excluded from the per-protocol group. The per-protocol group is defined as all subjects who had at least one postbaseline assessment of at least one of the primary efficacy parameters (n = 56; ND, n = 28; placebo, n = 28). Fifty six patients completed the study.

Statistical Analysis

Statistical analysis on the efficacy parameters was performed in the per-protocol group (n = 56). Differences between the groups at baseline were analyzed by the Student t test for independent samples. Changes within the groups between baseline and week 8 were tested by the t test for dependent samples. Differences in the treatment response after 8 weeks of ND or placebo were tested using analysis of variance, with treatment (ND or placebo) as fixed factor and the respective baseline value as covariate. Also, theophylline use was taken as covariate since a higher proportion of patients in the ND group compared to the placebo group were receiving theophylline as maintenance medication. To investigate if the changes in physiologic functioning were associated with the changes in erythropoietic parameters after the intervention, a Pearson correlation analysis was performed. Subsequently, partial correlation analysis was done in order to correct the hypothesized relationship between changes in physiologic functioning and changes in erythropoietic parameters for the possible influence of changes in body composition after the therapy. Significance was determined at the level of 5%. Data are expressed as mean (SD) in the text and as mean (SEM) in the bar graphs. Data were analyzed according to the guidelines of Altman et al, (26) using SPSS/PC+ (Statistical Package for the Social Sciences, Version 9.0 for Windows; SPSS; Chicago, IL).

RESULTS

Baseline Characteristics

The baseline characteristics of the intent-to-treat group are shown in Table 2. Lung function and exercise capacity were severely impaired when compared with the predicted values. Thirty-one of 63 patients were receiving oral glucocorticosteroids as maintenance medication (mean, 7.5 mg/24 h [SD, 2.4]), 19 of 33 patients in the ND-treated group (mean, 7.6 mg/d [SD, 2.4]), and 12 of 30 patients in the placebo group (mean, 7.3 mg/d [SD, 2.5D. Other maintenance respiratory medication included [[beta].sub.2]-sympathomimetics (32 of 33 patients in the ND-treated group and 29 of 30 patients in the placebo group, p > 0.99), theophylline (26 of 33 patients and 16 of 30 patients, respectively; p = 0.047), ipratropium bromide (30 of 33 patients and 26 of 30 patients, respectively; p = 0.69), and inhaled glucocorticosteroids (28 of 33 patients and 23 of 30 patients, respectively; p = 0.28). No differences in (safety or efficacy) parameters at baseline were seen between the patients treated with ND vs placebo, nor between patients who were receiving oral glucocorticosteroids vs patients who were not, nor between the per-protocol group and the patients dropping out from the study.

Efficacy of ND

Body Composition: Treatment with ND resulted in a significantly higher rise in FFM and ICM compared with placebo (Fig 1). No expansion of ECM was noted in either group. FM increased only in the placebo group (Fig 1).

[FIGURE 1 OMITTED]

Muscle Function and Exercise Capacity: In Table 3, the effects of treatment with ND vs placebo on muscle function and exercise capacity are presented. In both ND- and placebo-treated patients, maximal isometric handgrip strength, maximal isometric strength of the lower extremities, peak workload, and peak V[O.sub.2] increased significantly. Significant improvements in PImax, maximal isokinetic work of the lower extremities, peak lactate/peak workload ratio, and peak oxygen pulse were revealed only in the patients treated with ND. No influence of the higher prevalence of maintenance treatment with theophylline in the ND-treated group was seen on the changes in muscle function and exercise capacity after ND or placebo.

Health Status: The treatment response in the different domains of the SGRQ was not significantly different between the groups. However, only after treatment with ND were symptom score and total score improved (Table 3).

Erythropoietic and Anabolic Parameters: In Table 4, the changes in erythropoietic and anabolic parameters after treatment with ND vs placebo are shown. In the ND-treated group, a significant in crease was seen in erythrocyte count accompanied by a tendency toward increases in hematocrit, hemoglobin, and erythropoietin. Total as well as free testosterone dropped significantly more after ND compared to placebo. In the placebo group, no changes were seen. The magnitude of therapy response after ND was not influenced by baseline concentrations of total or free testosterone.

In the total group, the change in PImax was significantly associated with the change in hemoglobin (Fig 2, top), as well as after correction for the change in FFM (r = 0.29, p = 0.039). The change in peak workload was associated with the change in hemoglobin (Fig 2, middle), independently of the change in FFM (r = 0.33, p = 0.019). Furthermore, a significant correlation coefficient was seen between the change in work of the lower extremities at 20 cm/s and the change in erythropoietin (Fig 2, bottom), as well as after correction for the change in FFM (r = 0.37, p = 0.015). No differences in treatment response were seen between the nondepleted patients and the nutritionally depleted patients (18 of 29 patients in the placebo group and 21 of 30 patients in the ND group).

[FIGURE 2 OMITTED]

Efficacy of ND in Patients Receiving Oral Glucocorticosteroids

In Figure 3, the treatment responses after ND vs placebo in patients receiving of oral glucocorticosteroids are presented. In these patients, the improvement in PImax was higher after ND compared to placebo (Fig 3, top). Furthermore, peak workload improved to a higher extent after treatment with ND vs placebo (Fig 3, bottom).

[FIGURE 3 OMITTED]

Safety of ND

Laboratory Parameters: Shifts in laboratory parameters from baseline until week 8 after treatment with ND or placebo are given in Table 4. The drop in ESR and the rise in LDH were significantly greater after ND compared to placebo. Serum [gamma]-glutamyl transpeptidase, glucose, albumin, and protein did not significantly change in either group.

Physical Examination: No changes in BP were seen in either group, and no androgenic effects or fluid retention were noted after ND treatment or placebo.

DISCUSSION

Efficacy of ND

The increase in FFM after ND treatment was in agreement with the results of previous studies (9,10) in depleted patients with COPD. Our group previously investigated the effects of ND plus nutritional supplementation vs placebo plus nutrition vs placebo alone in depleted male and female patients, who all participated in an 8-week pulmonary rehabilitation program. Both placebo plus nutrition and ND plus nutrition resulted in improvements in body weight, FFM, and PImax; but only in the ND plus nutrition-treated group were rises in FFM and PImax greater compared to placebo. (9) Besides this short-term study, (9) others (10) have evaluated the effects of 6 months of oral stanozolol treatment combined with inspiratory muscle training and cycling in underweight patients with COPD and a low PImax. Body weight, lean body mass, and arm muscle and thigh circumference increased, but the changes in PImax and exercise capacity were not different from those in the control group. (10)

Although anabolic steroids may cause water retention, (27) in the present study no expansion of ECM was seen. The increase in FFM was completely attributable to a rise in ICM and thus probably to an increase in muscle mass. The stimulating effects of anabolic steroids on muscle tissue are mediated by the androgen receptor and can be attributed to increases in the fractional synthesis rates of actin and myosin heavy, chains, (28) resulting in fiber hypertrophy. (29) However, inhibition of protein catabolic processes by neutralizing the effects of endogenous glucocorticosteroids via interaction with the glucocorticosteroid receptor is proposed. (30) Studies (31,32) favor the hypothesis of anabolic steroids stimulating skeletal muscle anabolism, in the presence of sufficient amino acids, rather than attenuating muscle protein breakdown.

In the present study, total and free testosterone decreased after ND treatment. Anabolic steroids are indeed known to affect the pituitary-gonadal axis; an inhibitory effect on testicular testosterone secretion is assumed together with inhibition of pituitary follicle-stimulating hormone secretion. (22) Ferreira et al (10) reported, in accordance with our results, a significant decrease in serum testosterone during 6 months of treatment with oral stanozolol.

No differences in improvements in physical functioning were seen between the ND- and placebo-treated patients. Our results were in contrast to the study of Bhasin et al, (11) who revealed higher increases in muscle strength after testosterone therapy on top of strength training alone in healthy weight lifters. Possibly the discrepancy between the higher rise in FFM and the similar rise in muscle function after ND compared to placebo could be explained by regional differences in FFM accumulation after anabolic steroid supplementation, favoring the legs and especially the trunk. (33) The improvements in muscle function in the placebo group, despite no rise in FFM, were quite likely the result of intrinsic alterations in muscle energy metabolism induced by the pulmonary rehabilitation program itself. (34)

Theophylline is known to increase muscle function and exercise capacity. (35) Although more patients in the ND group were receiving maintenance therapy with theophylline, no influence of maintenance treatment with theophylline was seen on the outcome parameters after ND or placebo.

The fact that maximal isokinetic leg work, peak lactate/peak workload ratio, and peak oxygen pulse only improved after ND treatment and not pulmonary rehabilitation alone might be the result of cardiovascular effects. One study (33) on the effects of anabolic steroids on heart morphology and function by echocardiographic assessment did indeed reveal an increase of the posterior wall thickness, intraventricular septum thickness, and/or the left ventricular mass in strength athletes. The improvements in endurance after ND might also reflect an improved oxygen delivery. This was illustrated by the observed rise in the erythropoietic parameters. Anabolic steroids are indeed reported to stimulate erythropoiesis, predominantly by enhancing the activity of erythropoietin, but can also directly act on erythropoiesis. (12,36,37)

The revealed associations between the changes in physiologic function and the changes in eryhropoietic parameters suggest that the improvements in physiologic functioning after ND were mediated by improvements in erythropoiesis and perhaps in oxygen delivery to the tissues. Androgen therapy is known to increase 2,3-diphosphoglycerate in the erythrocytes, a mechanism that increases the oxygen release at a given tissue oxygen tension. Theoretically, this mechanism could improve exercise tolerance. Weekly IM injections of 100 mg of ND for 6 weeks in a double-blind, placebo-controlled, crossover design resulted in an increase in 2,3-diphosphoglycerate accompanied by an increase in stress tolerance, exercise capacity measured by a treadmill test, and a decreased dyspnea sensation in six patients with COPD. (38)

Pulmonary rehabilitation per se results in improvements in health status. (39,40) This is the first study evaluating the effects of anabolic steroids on health status in COPD. The reduction (ie, improvement) in symptom store, reflected in improvement in total score, was however only significant after ND but not after placebo. Since the changes in symptom and total score in the ND-treated group were more than four points, they can be considered as clinically significant improvements. (21) An explanation for the positive, although not significantly different from placebo, effect of ND on health status could be a decreased dyspnea sensation, (41) via a reduction in lung hyperinflation by the increase in respiratory muscle function (PImax). (42) Alternatively, central, adrenergic effects of anabolic steroids, such as better mood and less depression, (43) might have attributed to the improvement in health status in the ND-treated group.

Efficacy of ND in Patients Receiving of Oral Glucocorticosteroids

In the present study, striking differences were seen in the response to treatment with ND vs placebo in patients to whom maintenance oral glucocorticosteroids were prescribed. The higher effect of ND treatment on PImax compared to placebo in patients receiving oral glucocorticosteroids were in line with two animal experimental studies. (13,14) In a rat model, treatment with ND was able to antagonize the loss of diaphragm force indeed by long-term, low-dose methylprednisolone administration. (13) A subsequent study (14) reported that ND was also able to antagonize the loss of diaphragmatic function in emphysematous hamsters treated with long-term, low-dose methylprednisolone. (14) One of the possible explanations for this phenomenon could be the competitive binding of anabolic steroids with glucocorticosteroids to the glucocorticosteroid receptor, thereby neutralizing the deleterious effects of glucocorticosteroids. (43)

In addition, the combined treatment of ND and pulmonary rehabilitation was more effective than pulmonary rehabilitation 'alone in improving exercise capacity in patients receiving oral glucocorticosteroids. This finding suggests a counteracting effect of ND on the disturbances in intrinsic muscle oxidative capacity induced by the systemic glucocorticosteroids. Of course, it must be stressed that these findings were the result of a post hoc analysis. Only a randomized trial of oral glucocorticosteroids could establish that systemic glucocorticosteroids impair the response to pulmonary rehabilitation.

Safety of ND

Side effects of anabolic steroids are highly dose dependent and only likely to appear after long-term treatment, as in osteoporosis. (43) We found no evidence for androgenic effects, fluid retention or effects on BP of thrombocyte count due to ND. Eventual changes in lipid profile, which we did not measure, include predominantly a reduction in high-density lipoprotein cholesterol and are also dose related. (43) In both groups, changes in laboratory parameters occurred, so it seemed unlikely that they could be attributed to the ND treatment. Anabolic steroids are predominantly excreted by the kidneys; therefore, hepatotoxicity is therefore negligible. (44)

Erythrocytosis or polycythemia can be a complication of anabolic steroid therapy. Hematocrit elevation may be associated with increased blood viscosity, stagnant flow, and vascular occlusion. Drinka et al (45) reported on testosterone replacement during 6 months in 26 hypogonadal, male veterans. In two patients, hematocrit values > 51% developed, which were reversed after testosterone discontinuation. The patients in our study received, however, only four injections of ND during 8 weeks; therefore, it seems unlikely that such a short course of anabolic steroids will result in serious erythrocytosis. We suggested that the erythropoietic action of a short course of ND positively affected exercise capacity in the present investigation as discussed above.

We cannot dismiss the fact that the three patients with respiratory failure, two of whom died, were all in the ND group. However, they did not die from known anabolic steroid-related side effects such as a cardiovascular event. Furthermore, it must be considered that our study group was drawn from a population of severely disabled patients, with low survival time. In the study of Schols et al (9) with a comparable set-up and patient population, 6 of the 217 patients died from respiratory failure, of whom only 2 patients received ND. (9)

CONCLUSIONS

A short-term course of ND had an overall positive efficacy relative to placebo on body composition without expanding ECW in patients with moderate-to-severe COPD. In the total group, the improvements in muscle function and exercise capacity were associated with improvements in erythropoietic parameters. The use of low-dose oral glucocorticosteroids as maintenance medication significantly impaired the response to pulmonary rehabilitation with respect to respiratory muscle function and exercise capacity, which could be restored by ND treatment. Therefore, we conclude that ND has a role in the treatment of patients with COPD, especially in those patients treated long term with low-dose systemic glucocorticosteroids.

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* From the Department of Pulmonology (Drs. Creutzberg, Wouters, and Schols), University Hospital Maastricht, Maastricht; Asthma Center Hornerheide (Dr. Mostert), Horn; and NV Organon (Dr. Pluymers), Oss, The Netherlands.

The study was supported by NV Organon, Oss, The Netherlands. The study was performed at Asthma Center Hornerheide, Horn, The Netherlands.

Manuscript received April 22, 2002; revision accepted June 23, 2003.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Eva C. Creutzberg, PhD, Department of Pulmonology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands; e-mail: E.Creutzberg@PUL.Unimaas.NL

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