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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.
Correspondence to: Eva C. Creutzberg, PhD, Department of Pulmonology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands; e-mail: E.Creutzberg{at}PUL.Unimaas.NL
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Abstract |
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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, or 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 in 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 = 0.013). 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 H2O [SD, 8.82] vs – 2.18 cm H2O [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 vs 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 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.
Key Words: anabolic steroids • body composition • COPD • erythropoietin • exercise capacity • health status • muscle function • nandrolone decanoate • oral glucocorticosteroids • testosterone
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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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 outpatients3 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 al5 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 studies9 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 erythropoietin12 – might play a 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] was 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 IM 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.
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Materials and Methods |
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Measurements
Lung Function:
At baseline, FEV1 and inspiratory vital capacity were calculated from the flow-volume curve using a spirometer (Masterlab; Jaeger; Würzburg, 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. PaO2 and PaCO2 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 as 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° 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° 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 at 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 (
O2) 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°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 O2, the ratio between peak O2 and peak heart rate (peak oxygen pulse), and the ratio between peak lactate and peak workload (peak lactate/peak workload ratio; an 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 as 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 as 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 as 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°C within 2 h after collection. Separated plasma was again centrifuged at 1,000g for 10 min at 4°C. Plasma samples were stored at - 70°C until analysis. erythropoietin, total testosterone, SHBG, and albumin were analyzed using an AutoDelfia automatic analyzer (Perkin-Elmer; Norwalk, CT). In our laboratory, the detection limit of plasma total testosterone was 0.7 nmol/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; Hoffmann-La Roche; Nutley, NJ).
Laboratory Parameters:
For the assessment of laboratory parameters, blood was collected in an 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, 
-glutamyl transpeptidase, total bilirubin, total protein, albumin, urea, and lactate dehydrogenase (LDH). In whole blood, leukocyte and thrombocyte counts were measured (Cobas Micro; Hoffmann-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 or 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 for 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, inpatient pulmonary rehabilitation program, consisting of 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 three meals per day with the same caloric 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 
16 kg/m2; 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 study9
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
).
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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).
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O2 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) .
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-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.
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Discussion |
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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 Studies31 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 al10 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 study33 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 erythropoietic 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, cross-over 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 score, 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 induced by long-term, low-dose methylprednisolone administration.13
A subsequent study14
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 or 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 al45 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 al9 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
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Footnotes |
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O2 = oxygen consumption The study was supported by NV Organon, Oss, The Netherlands.
The study was performed at Asthma Center Hornerheide, Horn, The Netherlands.
Received for publication April 22, 2002. Accepted for publication June 23, 2003.
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