COPD, 11:681–688, 2014 ISSN: 1541-2555 print / 1541-2563 online Copyright © Informa Healthcare USA, Inc. DOI: 10.3109/15412555.2014.898048
ORIGINAL RESEARCH
Effect of Rehabilitation Program on Endocrinological Parameters in Patients with COPD and in Healthy Subjects
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Wajdi Mkacher, Zouhair Tabka, Faten Chaieb, Meriem Gueddes, Monia Zaouali, Chirine Aouichaoui, Abdelkrim Zbidi, and Yassine Trabelsi Department of Physiology and Lung Function Testing, Faculty of Medicine of Sousse, University of Sousse, Tunisia
Abstract Background: Skeletal muscle wasting commonly occurs in patients with chronic obstructive pulmonary disease (COPD) and has been associated with the presence of systemic inflammation and endocrinological disturbance. The aim of this study is to analyze the effect of rehabilitation program on the balance of anabolic versus catabolic hormone in patients with COPD and in healthy subjects. Methods: Nineteen patients with COPD and 16 age-matched healthy subjects undertooked exercise training 3 days/week for 8 weeks. Before and after the training program the concentration of growth hormone (GH), Insulin-Like Growth Factor-1 (IGF-1), Insulin-like Growth Factor-Binding Protein 3 (IGF-BP3), testosterone and cortisol in serum were determined. The exercise measurements included a 6-Minute Walking Test (6MWT). Results: After 8 weeks, there was no significant change in lung function in patients with COPD and healthy subjects. Growth hormone, Insulin-like Growth Factor-1 and Insulin-like Growth Factor-Binding Protein 3 increased significantly after rehabilitation training (p < 0.01). The rehabilitation program improves the testosterone/cortisol ratio (T/C ratio) in both groups. There is a significant improvement in the 6-Minute Walking distance (6MWD) in both groups (p < 0.01). Dyspnea and heart rate at rest and at the peak of the 6-Minute Walking Test (6MWT) decreased significantly after training program (p < 0.01). Conclusion: Pulmonary rehabilitation induces an improvement of the anabolic process and reduces proteine distruction by the modifications in endocrinological factors regulating skeletal muscle in patients with COPD.
Introduction
Keywords: Chronic obstructive pulmonary disease, GH/IGF-1/IGF-BP3 axis, pulmonary rehabilitation, Testosterone/Cortisol ratio Correspondence to: Wajdi Mkacher, Department of Physiology and Lung Testing, Faculty of Medicine, PB 126, 4002 Sousse, Tunisia, phone : +216-22 875172, +216-73-466-894, email: wajdi_mkacher@ yahoo.fr
Chronic Obstructive Pulmonary Disease (COPD) is a global health problem and is predicted to be the third most common cause of death worldwide by 2020 (1). Furthermore, the WHO (World Health Organization) predicts COPD to rank fifth as a worldwide burden of disease and chronic disability by 2020 (2). The role of rehabilitation in the management of patients disabled by Chronic Obstructive Pulmonary Disease has been the subject of much interest. It has been shown to decrease the perception of dyspnea (3, 4) to enhance functional exercise tolerance (6-minutes walking distance) (5, 6) to reduce health care resource utilization (7, 8) and to improve health status,the quality of life and rates of hospitalization (9). COPD is considered as a disease with systemic complications (10). Muscle weakness (or more precisely the loss of muscle mass) and the decrease in lean body mass become important indicators of the severity of this respiratory disease (11). Physical fitness, measured by the 6-minute walking test, the use of health care and life expectancy are correlated with muscle weakness 681
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or decreased muscle mass regardless of lung function (11, 12). COPD patients are in a hyper metabolic state with an increase in resting energy expenditure (10%) accompanied by an increased oxidation of proteins (13). This decrease in protein synthesis is often associated with a disturbance of endocrine system (altered somatotropic, gonadotropic and corticotropic axis) (14). Similarly, other studies have shown that muscle weakness is associated with hypogonadism (15). The use of systemic corticosteroids and increased production of inflammatory cytokines (Interleukin-6, TNF-α.) seem to be the main factors of these endocrine disturbances seen an increase in cortisol, a hyposecretion of growth hormone and hypogonadism (14). However, little is known about the effect of pulmonary rehabilitation on serum concentrations of anabolic and catabolic hormones in COPD patients. Therefore, the purpose of this study was to analyze the effect of rehabilitation program on the somatotropic axis Growth hormone / Insulin-like Growth Factor 1 / Insulin-like growth factor-binding protein 3 and Testosterone/ Cortisol ratio in patients suffering from Chronic Obstructive Pulmonary Disease and in healthy subjects.
Methods Study subjects Nineteen COPD men from the department of physiology of the Academic Hospital of Sousse, Tunisia, and 16 healthy volunteers’ subjects were recruited for this study that lasted 8 weeks. The subjects were selected according to the inclusion criteria defined as follows: age of 55 years or older: (1) COPD diagnosed by pulmonary function; (2) Stable clinical condition; they received regular treatment with inhaled bronchodilators but they did not inhale glucocorticoides for a duration of 4.3 ± 0.6 yrs; (3) Absence of other obstructive disease (asthma, bronchiectasis...) (4) Lack of diabetes, respiratory failure and recent cardiac or neuromuscular pathologies. Individuals who smoke and those who run significant response to bronchodilators, defined as an increase in FEV1 over 12% were excluded from our study. On the basis of these criteria, 3 subjects from 22 were excluded. Finally, 19 patients were included in subsequent analysis. The 16 healthy subjects were males, all nonsmokers, and had no significant cardiovascular, metabolic, and musculoskeletal disorders that could limit exercise capacity. Prior to the study, the subjects had been fully informed of the aim of the research, the protocol and the procedure of the investigation before signing a written consent, which was in accordance with legal
requirements and the Declaration of Helsinki, and was approved by the Research Ethics Committee of Farhat Hached Hospital (Sousse).
Study design Subjects were evaluated on 2 days at baseline and at the end of the 8-weeks training program. On the first day of the study, subjects were informed about the purpose of the study and had agreed to participate in pulmonary function test using a body plethysmograph and blood sampling was performed. On the second day, patients were assessed using a standard 6-minute walk test. All these measures were repeated after 8 weeks of training. Pulmonary function test All subjects underwent a pulmonary function test with determination of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Their measurement was performed using a constant volume plethysmograph (ZAN 500 Body II Meßgreräte ZAN GmbH, Germany) according to the “European Respiratory Society” recommendations (16). Six-minute walking test The 6MWT was performed before and after the rehabilitation program. It was conducted in accordance with international recommendations (17). Reference values were calculated using Tunisian equations (18). Subjects were instructed to walk at their own maximal pace along a hospital corridor, which is 40 m long as far as possible for 6 minutes. No encouragement was given, and subjects were informed each minute of the time remaining. The subjects were allowed to stop, but they could start again, if possible. Chairs were placed along the corridor. Dyspnea was measured using Borg scale before the start of 6MWT and at the end of the test. Heart rate (HR) and Oxygen saturation (SO2) were measured for the first minute at baseline, and during the first minute of recovery by a pulse oximeter. At the end of the 6MWT, the total covered distance was recorded. Hormonal balance Morning blood samples are taken both sitting on the chair, through a venous catheter, at baseline and after the 2 months of rehabilitation. The hormonal assessment includes the determination of growth hormone, insulin-like growth factor 1, Insulin-Like Growth Factor Binding Protein 3, testosterone and cortisol. Serum concentrations of GH, IGF-1 and IGF-BP3 were conducted by Immunoradiometric assay (IRMA), those of testosterone and cortisol by Radioimmunoassay (RIA). IRMA of GH The immunoradiometric assay of GH is a sandwichtype assay. The kit utilizes mouse monoclonal antibodies recognize the 22kDa monomer, the dimer and GH bound to its binding protein. Sample and calibrator are Copyright © 2014 Informa Healthcare USA, Inc
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incubated in a tube, coated with the first monoclonal antibody, with a second 125I-labeled monoclonal antibody. The liquid contents of the tubes are aspirated after incubation and bound radioactivity is measured. Values are calculated by interpolation from the standard curve. The radioactivity bound is directly proportional to the concentration of GH in the sample.
IRMA of IGF-1 The immunoradiometric assay of GH is a sandwich type assay. mouse monoclonal antibodies directed against two different epitope of IGF-1 and hence not competing are used. To release IGF-1 from its binding protein, a prior dissociation step is necessary. Samples and calibrators are incubated in a tube, coated with the first monoclonal antibody, with a second 125I-labeled monoclonal antibody. After incubation, the content of the tube is removed and bound radioactivity is measured. Unknown values are determined by interpolation from the standard curve. The radioactivity bound is directly proportional to the concentration of IGF-1 in the sample. IRMA of IGF-BP3 The IRMA of IGF-BP3 is a sandwich-type assay. In the kit, goat polyclonal antibodies are used. Samples and calibrators are incubated in a tube, coated with the first monoclonal antibody, with a second 125I-labeled monoclonal antibody. After incubation, unbound reagents are removed by washing the tubes. The amount of 125 I-labeled anti IGF-BP3 bound to the tube is directly proportional to the concentration of IGF-BP3 in the sample. A standard curve is constructed and unknown IGF-BP3 values are obtained from the curve by interpolation. RIA of testosterone The RIA of testosterone is a competition assay. Serum and calibrator are incubated in antibody-coated tube with 125I-labeled cortisol tracer. The liquid contents of the tubes are aspirated after incubation and bound radioactivity is measured. A calibration curve is established and unknown values are determined by interpolation from the standard curve. RIA of cortisol The RIA of cortisol is a competition assay. Serum and calibrator are incubated in an antibody-coated tube with 125 I-labeled cortisol tracer. The liquid contents of the tubes are aspirated after incubation and bound radioactivity is measured. A calibration curve is established and unknown values are determined by interpolation from the standard curve. Training program All the subjects were required to participate in the rehabilitation program 3 days per week during 8 weeks. The program was monitored by health professionals. It involves setting the intensity of effort on a target heart www.copdjournal.com
rate corresponding to 60-70% of maximum heart rate reached during the 6-minute walking test. This intensity of training does not lead to excessive symptoms of dyspnea and fatigue. During the sessions, the subject can monitor the intensity of training by means of a cardiofrequency meter (Polar, S810) where alarms are set to ± 5 beats per minute around the target heart rate. The training consists of a 5-minute warm-up followed by 10 minutes of work (cycling or walking on a treadmill) and 5 minutes of active recovery, repeated over a 45-minute session. Then, the subjects performed strength exercises (legs and arms) for 30 minutes; the resistance training included 3 sets per session of each of the following: seated leg press, seated leg curl, seated leg extension, standing calf raise, and seated ankle dorsiflexion. Training intensity was set at 60% of the pretraining one-repetition maximum for the first 4 weeks and increased as tolerated thereafter to 80% of the new one-repetition maximum obtained after 4 weeks of training, for each exercise. Finally, the session ends with relaxation exercises and stretching. The patients also received a therapeutic education program of two sessions of 30 minutes/week of seminars and discussions covering the following topics: relaxation, disease education, benefits advice, energy conversation, medication advice, chest clearance, and breathing control techniques. No pharmacological, hormonal or nutritional interventions were made during the training period.
Statistical analysis The results of the study are presented as mean ± standard deviation (SD). The nonparametric Mann–Whitney U-test was used to compare baseline characteristics and training related changes in patients with COPD and healthy subjects, Wilcoxon’s matched pairs test was used to assess the effect of training within the group. The statistical program Statistica was used for the analysis (Statistica Kernel Version 6; Stat Soft, France). The level of significance was set as p < 0.05.
Results Anthropometric characteristics and pulmonary function parameters of patients with COPD and healthy subjects before and after the rehabilitation program are provided in Table 1. Age and body mass index (BMI) were similar in both groups. The main differences were observed in pulmonary function where the patients with COPD showed moderate to very severe airflow obstruction. There was no significant change in FEV1 and FVC in the two groups after rehabilitation program. Serum concentrations of somatotropic hormones, testosterone and cortisol are shown in Table 2. GH, IGF-1 and IGF-BP3 increased significantly after the period of rehabilitation training in both groups. Relative (%) changes in COPD patients and healthy subjects
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Table 1. Anthropometric characteristics and pulmonary function parameters of healthy subjects and patients with chronic obstructive pulmonary disease before and after rehabilitation program Healthy subjects (n = 16) Before RP
Before RP
After RP
58 ± 7
–
58.6 ± 0.8
–
BMI, kg.m−2
26.52 ± 1.78
25.19 ± 2.13
24 ± 1.4
23.8 ± 0.9
FEV1 ,L
2.94 ± 0.45
2.97 ± 0.56
1.11 ± 0.08***
1.24 ± 0.08†††
FEV1, % Predicted
88.66 ± 9.1
92.50 ± 5.17
37.11 ± 1.62***
38.88 ± 4.12†††
FVC, L
3.16 ± 0.57
3.27 ± 0.51
1.96 ± 0.12***
2.19 ± 0.52†††
82.75 ± 13.29
85.49 ± 9.41
49.67 ± 3.58***
55.72 ± 12.59†††
82.81 ± 9.5
84.27 ± 10.75
55.3 ± 3.9***
57.7 ± 13.8†††
Age, years
FVC, % Predicted FEV/FVC ratio
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Patients with COPD (n = 19) After RP
Unit: Mean ± SD. Notes: Comparisons between patients with COPD and healthy subjects before rehabilitation program: ***p < 0.001; Comparisons between patients with COPD and healthy subjects after rehabilitation program: †††p < 0.001. Abbreviations: COPD, chronic obstructive pulmonary disease; BMI, body mass index; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; RP, rehabilitation program.
were: GH: 40% vs 10%, IGF-1: 24% vs 2%, IGF-BP3: 5% vs 4%, respectively. A significant increase in the T/C ratio was shown in both groups (p < 0.001) (COPD: 42%, healthy 27%). This increase results from decreased cortisol (COPD: 17%, healthy 11%) and increased testosterone levels (COPD: 30%, healthy: 18%) after rehabilitation program. The 6MWD increased significantly after the rehabilitation program in both groups (p < 0.01), as shown in Table 3. The dyspnea and heart rate at the peak of 6MWT decreased significantly after the rehabilitation program (p < 0.05). Any change in SO2% was marked at the peak of 6MWT in both groups compared with values before the rehabilitation program.
Discussion The objective of this study was to analyze the effect of rehabilitation program on the somatotropic axis GH/ IGF-1/IGF-BP3 and T/C ratio in patients with Chronic Obstructive Pulmonary Disease and in healthy subjects. Given the paucity of studies that investigate the effect of
training on hormonal parameters in COPD patients, we have compared briefly our results to those observed in healthy elderly subjects or with other diseases. The major finding of this study showed an increase in anabolic hormone levels (somatotropic hormones and testosterone) after a training program against a decrease in cortisol, one of the important catabolic hormones. An increase in T/C ratio after physical training was also observed in both groups. The rehabilitation program that we used was well tolerated by most patients. Its benefits on dyspnea, exercise tolerance and quality-of-life of COPD patients have been clearly shown (19). No adverse effects were noted during the training program. The 6MWT is easy to perform, reproducible, well standardized and patients with COPD walk at a speed close to their maximum capacity (20). The 6MWT and the incremental cardiopulmonary exercise test (also used in COPD evaluation in many studies) are not interchangeable exercise tests from a physiological point of view. However, from the clinical point of view, when the 6MWT is performed in a standardised manner and verbal incentive is used, it
Table 2. Serum levels of anabolic and catabolic factors before and after rehabilitation program in healthy subjects and in patients with COPD Healthy subjects (n = 16)
Patients with COPD (n = 19)
Before RP
After RP
1.74 ± 0,48
1.94 ± 0.42*
143.67 ± 8,86
147.78 ± 9.87*
98.72 ± 6.60‡‡‡
3166.44 ± 148.4
3305.78 ± 117.06*
2988.91 ± 187.13
2.32 ± 0.33
2.82 ± 0.2***
1.76 ± 0.57‡‡‡
2.51 ± 0.52†††§
Cortisol, ng/mL
219.33 ± 22.78
194.89 ± 14.48**
260.11 ± 20.44‡‡‡
215.37 ± 22.59†††§
T/C ratio, 10−3
10.66 ± 1.77
14.57 ± 1.72***
6.98 ± 1.83‡‡‡
12.1 ± 2.07‡‡‡§§
GH, ng/Ml IGF-1, ng/mL IGF-BP3, ng/mL Testosterone, ng/mL
Before RP 0.55 ± 0.31
After RP 0.91 ± 0.21†††§§§
‡‡‡
131,00 ± 12.81†††§§§ ‡‡
3121,18 ± 142,24†††§§
Unit: Mean ± SD. Notes: Comparison in healthy subjects with values before and after rehabilitation program, *p < 0.05, **p < 0.01, ***p < 0.001; Comparison in patients with COPD with values before and after rehabilitation program, †††p < 0.001; Comparison between patients with COPD and healthy subjects before rehabilitation program; ‡‡‡p < 0.001;Comparison between patients with COPD and healthy subjects after rehabilitation program, §p < 0.05, §§p < 0.01, §§§p < 0.001. Abbreviations: GH, Growth hormone; IGF-1, Insulin-Like Growth Factor 1; IGF-BP3, Insulin-Like Growth Factor Binding Protein 3; T\C ratio, Testosterone\Cortisol ratio; RP, rehabilitation program.
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Table 3. Six-minute walking test parameters before and after rehabilitation program in healthy subjects and in patients with COPD Healthy subjects (n = 16)
Patients with COPD (n = 19)
Before RP
After RP
Before RP
6MWD, m
After RP
600 ± 28.28
789 ± 19.07**
518.7 ± 23.2
581.2 ± 22.0††§§§
6MWD, %
86 ± 4
113 ± 3**
69.8 ± 2.4
77.6 ± 3.8†§§§
Rest
96.9 ± 1.13
96.72 ± 1.1
Peak
96.27 ± 1.1
95.45 ± 1.8
Rest
0.18 ± 0.4
0.91 ± 0.3*
2.9 ± 0.2‡‡
1.1 ± 0.9†§§§
Peak
1.72 ± 1.48
0.36 ± 0.5*
4.7 ± 1.6‡‡‡
2.8 ± 1.1†§§§
Rest
73.72 ± 8.9
65 ± 4.07
75.2 ± 2.5‡‡
73.5 ± 1.3†§§
Peak
87.8 ± 12.1
82.27 ± 27.7*
126.2 ± 3.8‡‡
122.4 ± 4.4†§§§
‡‡‡
‡‡‡
SO2, % 96.7 ± 1.6 91.8 ± 1.4
‡‡‡
95.1 ± 1,1 89.2 ± 2.7§§
Dyspnea
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HR
Unit: Mean ± SD. Notes: Comparison in healthy subjects with values before and after rehabilitation program, *p < 0.05, **p < 0.01; Comparison in patients with COPD with values before and after rehabilitation program, †p < 0.05, ††p < 0.01; Comparison between patients with COPD and healthy subjects before rehabilitation program; ‡‡p < 0.01, ‡‡‡p < 0.001; Comparison between patients with COPD and healthy subjects after rehabilitation program, §p < 0.05, §§p < 0.01, §§§p < 0.001. Abbreviations: 6MWD, 6-minute walking distance; HR, heart rate; SO2, oxygen saturation; RP, rehabilitation program.
shows the maximum sustainable exercise capacity and efficiently reflects the maximum capacity obtained from the cycle ergometer (21). Our results showed no significant change in weight and body mass index in both groups. The short duration of the protocol can explain this stability. Studies that use long periods of training (over 6 months) indicated a decrease in the weight of obese subjects COPD (22). As demonstrated in other studies (23), no significant modification of pulmonary function was marked after a training program. Our results showed decreased levels of serum GH, IGF-1 and IGF-BP3 in COPD patients compared to healthy subjects before training program. These results are consistent with previous studies that reported that growth hormone tends to decline in COPD patient (24). These hormones are considered as key regulators of muscle mass, it is also clear that the IGF-1 exerts its actions independent of GH (25). IGF-1 stimulates protein synthesis and muscle hypertrophy and inhibits protein catabolism through the Phosphatidylinositol 3-kinase (PI3K) (26). Aging, poor nutrition, inactivity and the administration of glucocorticoids are associated with poorly regulating hormones of the somatotropic axis (15). After the training period, serum concentrations of GH, IGF-1 and IGF-BP3 have been increased significantly in both groups but the ranges of change are heigher in COPD patients than healthy subjects (GH: 40% vs 10%, IGF-1: 24% vs 2%, IGF-BP3: 5% vs 4%), these results are consistent with the work of Lafranco, who found that alteration of the somatotropic axis associated to age can be regulated by physical activity (27). A previous study of Koziris et al. (28) showed that endurance training increased the IGF-1 with a significant increase www.copdjournal.com
in IGF-BP3, which is considered as an important marker of physical activity. In healthy elderly subjects, the concentration of IGF-I is positively correlated with maximal aerobic capacity and time spent in physical activity and negatively correlated with adiposity (29.30). Singh et al. (31) showed an increased production of IGF-1 intramuscular after strength training. This type of training meets the objective to complete the endurance training by practices that may induce anabolic effects, in order to fight against muscle atrophy (32). Lafranco et al. (27) showed the role of physical activity as a regulator of the GH / IGF-1 axis function considering the effect of the restoration of GH and circulating IGF-1 Levels on physical performance and body composition. Similarly, Craig et al. (33) showed that strength training can induce testosterone and growth hormone release in elderly people. Growth hormone released by the anterior pituitary is controlled by a hypothalamic factor pituitary: the CH-RH. Many other factors control the release of growth hormone; dopamine, serotonin and catecholamine. The elevation of these factors under the influence of muscular exercise is probably responsible for the increased concentrations of growth hormone (27). Before the rehabilitation program, COPD patients presented decreased level of serum testosterone compared to healthy subjects (p < 0.001). Some authors (34, 35) showed that increased systemic inflammation, administration of corticosteroids and hypoxemia have been correlated with decreased testosterone levels in patients with COPD. Several factors are involved in causing hypogonadism in patients with COPD like decreasing levels of FSH and LH and smoking (36). Debigaré et al. (34) showed a significant correlation
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between systemic inflammation (IL-6 levels, an important inflammatory cytokine) and decreased concentrations of testosterone known as a stimulator of protein anabolism (37). The decrease in PaO2 and atrophy of Leydig cells are also important causes of hypogonadism in COPD (38, 39). Our results showed increased level of cortisol in COPD patient compared to healthy subject (p < 0.001). A study of Schoorlemmer et al. (40) showed that cortisol tends to increase with chronic lung disease. It is associated with a high risk of mortality and hypertension in the elderly. Similarly, Debigaré et al. showed the prevalence of catabolic hormone in patients with COPD (34). The same study showed an increase in catabolic factors like IL6 and TNF alpha, with the fact that muscle atrophy detected in these patients was associated with a disturbance in the anabolic and catabolic functions and not with the decrease of the lung function. The testosterone level increased significantly in both groups after RP, we found that the range of change was higher in COPD patients compared to healthy subjects (30% vs 18%). similarly, a recent study demonstrated that growth hormone and testosterone concentration increased with 8 weeks moderate intensity resistance training (41). Increased testosterone can increase anabolic activity and thus an increase in muscle mass. Vogiatzis et al. (42). demonstrated that endurance exercise training in COPD induces peripheral muscle adaptations that are accompanied by upregulation of factors regulating skeletal muscle hypertrophy and regeneration. The results of our study are in contradiction with those found by Casaburi et al. (43) and Creutzberg et al. (44), who reported no changes in testosterone levels or IGF-1 in the training groups that received placebo supplement. The decrease in cortisol after the rehabilitation period was significant in both groups with higher range of change in COPD patients (17% vs 11%); this showed that the anabolic process increased in our patients with a decline in catabolic function which was shown by the increase in the T/C ratio after training. The increase in the testosterone/cortisol ratio is partly explained by lower levels of the stress hormone. A previous study of Kraemer et al. (45) found a decrease in cortisol levels after training period. The T/C ratio has been proposed to be useful indicator of the balance anabolism/catabolism (40). The ratio T/C known to be related to muscle strength was used to track workouts (46). Hakkinen et al. (47) showed that serum testosterone levels and the T/C were positively correlated with muscle strength during a period of strength training in elderly subjects. The increase in T/C ratio, which was higher in COPD patients (42% vs 27%) increases the synthesis and muscle strength probably partly through the total production of IGE-1 (48). The 6-minute walking test results showed a significant increase in walking distance after the rehabilitation period. Some of studies have shown that the distance
covered in six minutes increased after a program of rehabilitation training, the recent study of Ben Cheikh et al. (5) clearly showed an increase in this distance in Tunisian COPD patients after pulmonary rehabilitation program. The effect of individualized training on dyspnea peak and the maximal heart rate after 6MWT, after rehabilitation program, was significantly important. This could be explained, firstly by improved physical conditions and by very good response to exercise, which supports a decreased sensation of dyspnea (19). Secondly, by some physiological changes, such as better cardiac adaptation, decrease in lactic acid production and reduction in metabolic cost of exercise (49). This study presents a number of important limitations. Initially, we did not measure the level of thyroid hormones. Dysthyroidism have been associated with a decline in respiratory muscle function and exercise capacity (50). Similarly muscle mass/strength is not assessed, and we do not define the basal PaO2 and PaCO2 of COPD patients. GH and testosterone levels can be influenced by both hypoxemia (51) and hypercapnia (52).
Conclusion In conclusion, the findings of this study demonstrate that combined strength and endurance training improves the anabolic processes in COPD patients by increasing serum concentrations of growth hormone GH/IGF-1 and the T/C ratio and consequently reduce protein destruction and improve muscle strength which presents a major obstacle in practical life of those patients. The present study can serve to make health administrators aware of the benefits of pulmonary rehabilitation in patients with COPD, promoting the development of public policies related to such treatment. Similar study is required to support the potential similar effects of training in women with COPD.
Acknowledgments The authors thank the participants for their co-operative attitude and dedicated performance.
Declaration of Interest Statement The authors report no conflicts of interest in this work. The authors alone are responsible for the content and writing of the paper.
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test in cycloergometer in chronic obstructive pulmonary disease. Are the physiological demands equivalent? Arch Bronconeumol 2010; 46(6):294–301. Derom E, Marchand E, Troosters T . Réhabilitation du malade atteint de bronchopneumopathie chronique obstructive. Annales de Réadaptation et de Médecine Physique 2007; 50(7):602–614. Zwick RH, Burghuber OC, Dovjak N, Hartl S, Kössler W, Lichtenschopf A, Müller R, Zwick H. The effect of one year outpatient pulmonary rehabilitation on patients with COPD. Wien Klin Wochenschr 2009; 121(5–6):189–195. Scalvini S, Volterrani M, Vitacca M, et al. Plasma hormone levels and haemodynamics in patients with chronic obstructive lung disease. Monaldi Arch Chest Dis 1996 Oct;51(5):380– 386. Crul T, Spruit MA, Gayan-Ramirez G, et al. Markers of inflammation and disuse in vastus lateralis of chronic obstructive pulmonary disease patients. Eur J Clin Invest 2007; 37(11):897–904. Sacheck JM, Ohtsuka A, McLary SC, Goldberg AL. IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am J Physiol Endocrinol Metab 2004; 287(4):E591–601. Lafranco F, Gianotti L, Giordano R, Pellegrino M, Maccario M, Arvat E. Aging, growth hormone and physical performance. J Endocrinol Invest 2003; 26(9): 861–872. Koziris LP, Hickson RC, Chatterton RT Jr, et al. Serum levels of total and free IGF-I and IGFBP-3 are increased and maintained in long-term training. J Appl Physiol 1999; 86(4):1436–1442. Poehlman ET, Copeland KC. Influence of physical activity on insulinlike growth factor-I in healthy younger and older men. J Clin Endocrinol Metab 1990; 35:1468–1473. Manetta J, Brun JF, Maimoun L, Callis A, Préfaut C, Mercier J. Effect of training on the GH/IGF-I axis during exercise in middle-aged men: relationship to glucose homeostasis. Am J Physiol Endocrinol Metab 2002; 283(5):E929–36. Singh MA, Ding W, Manfredi TJ, et al. Insulin-like growth factor I in skeletal muscle after weight-lifting exercise in frail elders. Am J Physiol 1999; 277(1 Pt 1):E135–143. Whittom F, Jobin J, Simard PM, et al. Histochemical and morphological characteristics of the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. Med Sci Sports Exerc 1998; 30(10):1467–1474. Craig BW, Brown R, Everhart J. Effects of progressive resistance training on growth hormone and testosterone levels in young and elderly subjects. Mech Ageing Dev 1989; 49(2):159–169. Debigaré R, Marquis K, Côté CH, et al. Catabolic/anabolic balance and muscle wasting in patients with COPD. Chest 2003; 124(1):83–89. Kamischke A, Kemper DE, Castel MA, Lüthke 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(1):41–45. Creutzberg EC, Casaburi R. Endocrinological disturbances in chronic obstructive pulmonary disease. Eur Respir J Suppl 2003; 46:76s–80s. Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care 2004; 7(3):271–277. Review. Semple PD, Beastall GH, Watson WS, Hume R. Hypothalamicpituitary dysfunction in respiratory hypoxia. Thorax 1981; 36(8):605–609. Gosney JR. Atrophy of Leydig cells in the testes of men with long standing chronic bronchitis and emphysema. Thorax 1987; 42(8):615–619. Schoorlemmer RM, Peeters GM, van Schoor NM, Lips P. Relationship between cortisol level, mortality and chronic diseases in older persons. Clin Endocrinol (Oxf ) 2009; 71(6):779–786.
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Mkacher et al. 41. Arazi H, Damirchi A, Asadi A. Age-related hormonal adaptations, muscle circumference and strength development with 8 weeks moderate intensity resistance training. Ann Endocrinol (Paris) 2013; 74(1):30–35. 42. Vogiatzis I, Stratakos G, Simoes DC, Terzis G, Georgiadou O, Roussos C, Zakynthinos S. Effects of rehabilitative exercise on peripheral muscle TNFalpha, IL-6, IGF-I and MyoDexpression in patients with COPD. Thorax 2007; 62(11):950–956. 43. 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(8):870–878. 44. Creutzberg EC, Wouters EF, Mostert R, Pluymers RJ, Schols AM. A role for anabolic steroids in the rehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial. Chest. 2003; 124(5):1733–1742. 45. Kraemer WJ, Patton J, Gordon SE, et al. Compatibility of high intensity strength and endurance training on hormonal and skeletal muscle adaptations. J Appl Physiol 1995; 7 8:976–989. 46. Alén M, Pakarinen A, Häkkinen K, Komi PV. Responses of serum androgenic-anabolic and catabolic hormones to prolonged strength training. Int J Sports Med 1988; 9(3):229–233.
47. Häkkinen K, Pakarinen A. Serum hormones and strength development during strength training in middle-aged and elderly males and females. Acta Physiol Scand 1994; 150(2):211–219. 48. Urban RJ, Bodenburg YH, Gilkison C, et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol 1995; 269(5 Pt 1):E820–826. 49. Casaburi R, Patessio A, Ioli F, et al. Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am Rev Respir Dis 1991; 143:9–18. 50. Siafakas NM, Salesiotou V, Filaditaki V, Tzanakis N, Thalassinos N, Bouros D. Respiratory muscle strength in hypothyroidism. Chest 1992; 102(1):189–194. 51. Benso A, Broglio F, Aimaretti G, Lucatello B, Lanfranco F, Ghigo E, Grottoli S. Endocrine and metabolic responses to extreme altitude and physical exercise in climbers. Eur J Endocrinol 2007; 157(6):733–740. 52. Leach RM, Forsling ML. The effect of changes in arterial PCO2 on neuroendocrine function in man. Exp Physiol 2004; 89(3):287–292.
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ORIGINAL RESEARCH
Effect of Rehabilitation Program on Endocrinological Parameters in Patients with COPD and in Healthy Subjects
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Wajdi Mkacher, Zouhair Tabka, Faten Chaieb, Meriem Gueddes, Monia Zaouali, Chirine Aouichaoui, Abdelkrim Zbidi, and Yassine Trabelsi Department of Physiology and Lung Function Testing, Faculty of Medicine of Sousse, University of Sousse, Tunisia
Abstract Background: Skeletal muscle wasting commonly occurs in patients with chronic obstructive pulmonary disease (COPD) and has been associated with the presence of systemic inflammation and endocrinological disturbance. The aim of this study is to analyze the effect of rehabilitation program on the balance of anabolic versus catabolic hormone in patients with COPD and in healthy subjects. Methods: Nineteen patients with COPD and 16 age-matched healthy subjects undertooked exercise training 3 days/week for 8 weeks. Before and after the training program the concentration of growth hormone (GH), Insulin-Like Growth Factor-1 (IGF-1), Insulin-like Growth Factor-Binding Protein 3 (IGF-BP3), testosterone and cortisol in serum were determined. The exercise measurements included a 6-Minute Walking Test (6MWT). Results: After 8 weeks, there was no significant change in lung function in patients with COPD and healthy subjects. Growth hormone, Insulin-like Growth Factor-1 and Insulin-like Growth Factor-Binding Protein 3 increased significantly after rehabilitation training (p < 0.01). The rehabilitation program improves the testosterone/cortisol ratio (T/C ratio) in both groups. There is a significant improvement in the 6-Minute Walking distance (6MWD) in both groups (p < 0.01). Dyspnea and heart rate at rest and at the peak of the 6-Minute Walking Test (6MWT) decreased significantly after training program (p < 0.01). Conclusion: Pulmonary rehabilitation induces an improvement of the anabolic process and reduces proteine distruction by the modifications in endocrinological factors regulating skeletal muscle in patients with COPD.
Introduction
Keywords: Chronic obstructive pulmonary disease, GH/IGF-1/IGF-BP3 axis, pulmonary rehabilitation, Testosterone/Cortisol ratio Correspondence to: Wajdi Mkacher, Department of Physiology and Lung Testing, Faculty of Medicine, PB 126, 4002 Sousse, Tunisia, phone : +216-22 875172, +216-73-466-894, email: wajdi_mkacher@ yahoo.fr
Chronic Obstructive Pulmonary Disease (COPD) is a global health problem and is predicted to be the third most common cause of death worldwide by 2020 (1). Furthermore, the WHO (World Health Organization) predicts COPD to rank fifth as a worldwide burden of disease and chronic disability by 2020 (2). The role of rehabilitation in the management of patients disabled by Chronic Obstructive Pulmonary Disease has been the subject of much interest. It has been shown to decrease the perception of dyspnea (3, 4) to enhance functional exercise tolerance (6-minutes walking distance) (5, 6) to reduce health care resource utilization (7, 8) and to improve health status,the quality of life and rates of hospitalization (9). COPD is considered as a disease with systemic complications (10). Muscle weakness (or more precisely the loss of muscle mass) and the decrease in lean body mass become important indicators of the severity of this respiratory disease (11). Physical fitness, measured by the 6-minute walking test, the use of health care and life expectancy are correlated with muscle weakness 681
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or decreased muscle mass regardless of lung function (11, 12). COPD patients are in a hyper metabolic state with an increase in resting energy expenditure (10%) accompanied by an increased oxidation of proteins (13). This decrease in protein synthesis is often associated with a disturbance of endocrine system (altered somatotropic, gonadotropic and corticotropic axis) (14). Similarly, other studies have shown that muscle weakness is associated with hypogonadism (15). The use of systemic corticosteroids and increased production of inflammatory cytokines (Interleukin-6, TNF-α.) seem to be the main factors of these endocrine disturbances seen an increase in cortisol, a hyposecretion of growth hormone and hypogonadism (14). However, little is known about the effect of pulmonary rehabilitation on serum concentrations of anabolic and catabolic hormones in COPD patients. Therefore, the purpose of this study was to analyze the effect of rehabilitation program on the somatotropic axis Growth hormone / Insulin-like Growth Factor 1 / Insulin-like growth factor-binding protein 3 and Testosterone/ Cortisol ratio in patients suffering from Chronic Obstructive Pulmonary Disease and in healthy subjects.
Methods Study subjects Nineteen COPD men from the department of physiology of the Academic Hospital of Sousse, Tunisia, and 16 healthy volunteers’ subjects were recruited for this study that lasted 8 weeks. The subjects were selected according to the inclusion criteria defined as follows: age of 55 years or older: (1) COPD diagnosed by pulmonary function; (2) Stable clinical condition; they received regular treatment with inhaled bronchodilators but they did not inhale glucocorticoides for a duration of 4.3 ± 0.6 yrs; (3) Absence of other obstructive disease (asthma, bronchiectasis...) (4) Lack of diabetes, respiratory failure and recent cardiac or neuromuscular pathologies. Individuals who smoke and those who run significant response to bronchodilators, defined as an increase in FEV1 over 12% were excluded from our study. On the basis of these criteria, 3 subjects from 22 were excluded. Finally, 19 patients were included in subsequent analysis. The 16 healthy subjects were males, all nonsmokers, and had no significant cardiovascular, metabolic, and musculoskeletal disorders that could limit exercise capacity. Prior to the study, the subjects had been fully informed of the aim of the research, the protocol and the procedure of the investigation before signing a written consent, which was in accordance with legal
requirements and the Declaration of Helsinki, and was approved by the Research Ethics Committee of Farhat Hached Hospital (Sousse).
Study design Subjects were evaluated on 2 days at baseline and at the end of the 8-weeks training program. On the first day of the study, subjects were informed about the purpose of the study and had agreed to participate in pulmonary function test using a body plethysmograph and blood sampling was performed. On the second day, patients were assessed using a standard 6-minute walk test. All these measures were repeated after 8 weeks of training. Pulmonary function test All subjects underwent a pulmonary function test with determination of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Their measurement was performed using a constant volume plethysmograph (ZAN 500 Body II Meßgreräte ZAN GmbH, Germany) according to the “European Respiratory Society” recommendations (16). Six-minute walking test The 6MWT was performed before and after the rehabilitation program. It was conducted in accordance with international recommendations (17). Reference values were calculated using Tunisian equations (18). Subjects were instructed to walk at their own maximal pace along a hospital corridor, which is 40 m long as far as possible for 6 minutes. No encouragement was given, and subjects were informed each minute of the time remaining. The subjects were allowed to stop, but they could start again, if possible. Chairs were placed along the corridor. Dyspnea was measured using Borg scale before the start of 6MWT and at the end of the test. Heart rate (HR) and Oxygen saturation (SO2) were measured for the first minute at baseline, and during the first minute of recovery by a pulse oximeter. At the end of the 6MWT, the total covered distance was recorded. Hormonal balance Morning blood samples are taken both sitting on the chair, through a venous catheter, at baseline and after the 2 months of rehabilitation. The hormonal assessment includes the determination of growth hormone, insulin-like growth factor 1, Insulin-Like Growth Factor Binding Protein 3, testosterone and cortisol. Serum concentrations of GH, IGF-1 and IGF-BP3 were conducted by Immunoradiometric assay (IRMA), those of testosterone and cortisol by Radioimmunoassay (RIA). IRMA of GH The immunoradiometric assay of GH is a sandwichtype assay. The kit utilizes mouse monoclonal antibodies recognize the 22kDa monomer, the dimer and GH bound to its binding protein. Sample and calibrator are Copyright © 2014 Informa Healthcare USA, Inc
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incubated in a tube, coated with the first monoclonal antibody, with a second 125I-labeled monoclonal antibody. The liquid contents of the tubes are aspirated after incubation and bound radioactivity is measured. Values are calculated by interpolation from the standard curve. The radioactivity bound is directly proportional to the concentration of GH in the sample.
IRMA of IGF-1 The immunoradiometric assay of GH is a sandwich type assay. mouse monoclonal antibodies directed against two different epitope of IGF-1 and hence not competing are used. To release IGF-1 from its binding protein, a prior dissociation step is necessary. Samples and calibrators are incubated in a tube, coated with the first monoclonal antibody, with a second 125I-labeled monoclonal antibody. After incubation, the content of the tube is removed and bound radioactivity is measured. Unknown values are determined by interpolation from the standard curve. The radioactivity bound is directly proportional to the concentration of IGF-1 in the sample. IRMA of IGF-BP3 The IRMA of IGF-BP3 is a sandwich-type assay. In the kit, goat polyclonal antibodies are used. Samples and calibrators are incubated in a tube, coated with the first monoclonal antibody, with a second 125I-labeled monoclonal antibody. After incubation, unbound reagents are removed by washing the tubes. The amount of 125 I-labeled anti IGF-BP3 bound to the tube is directly proportional to the concentration of IGF-BP3 in the sample. A standard curve is constructed and unknown IGF-BP3 values are obtained from the curve by interpolation. RIA of testosterone The RIA of testosterone is a competition assay. Serum and calibrator are incubated in antibody-coated tube with 125I-labeled cortisol tracer. The liquid contents of the tubes are aspirated after incubation and bound radioactivity is measured. A calibration curve is established and unknown values are determined by interpolation from the standard curve. RIA of cortisol The RIA of cortisol is a competition assay. Serum and calibrator are incubated in an antibody-coated tube with 125 I-labeled cortisol tracer. The liquid contents of the tubes are aspirated after incubation and bound radioactivity is measured. A calibration curve is established and unknown values are determined by interpolation from the standard curve. Training program All the subjects were required to participate in the rehabilitation program 3 days per week during 8 weeks. The program was monitored by health professionals. It involves setting the intensity of effort on a target heart www.copdjournal.com
rate corresponding to 60-70% of maximum heart rate reached during the 6-minute walking test. This intensity of training does not lead to excessive symptoms of dyspnea and fatigue. During the sessions, the subject can monitor the intensity of training by means of a cardiofrequency meter (Polar, S810) where alarms are set to ± 5 beats per minute around the target heart rate. The training consists of a 5-minute warm-up followed by 10 minutes of work (cycling or walking on a treadmill) and 5 minutes of active recovery, repeated over a 45-minute session. Then, the subjects performed strength exercises (legs and arms) for 30 minutes; the resistance training included 3 sets per session of each of the following: seated leg press, seated leg curl, seated leg extension, standing calf raise, and seated ankle dorsiflexion. Training intensity was set at 60% of the pretraining one-repetition maximum for the first 4 weeks and increased as tolerated thereafter to 80% of the new one-repetition maximum obtained after 4 weeks of training, for each exercise. Finally, the session ends with relaxation exercises and stretching. The patients also received a therapeutic education program of two sessions of 30 minutes/week of seminars and discussions covering the following topics: relaxation, disease education, benefits advice, energy conversation, medication advice, chest clearance, and breathing control techniques. No pharmacological, hormonal or nutritional interventions were made during the training period.
Statistical analysis The results of the study are presented as mean ± standard deviation (SD). The nonparametric Mann–Whitney U-test was used to compare baseline characteristics and training related changes in patients with COPD and healthy subjects, Wilcoxon’s matched pairs test was used to assess the effect of training within the group. The statistical program Statistica was used for the analysis (Statistica Kernel Version 6; Stat Soft, France). The level of significance was set as p < 0.05.
Results Anthropometric characteristics and pulmonary function parameters of patients with COPD and healthy subjects before and after the rehabilitation program are provided in Table 1. Age and body mass index (BMI) were similar in both groups. The main differences were observed in pulmonary function where the patients with COPD showed moderate to very severe airflow obstruction. There was no significant change in FEV1 and FVC in the two groups after rehabilitation program. Serum concentrations of somatotropic hormones, testosterone and cortisol are shown in Table 2. GH, IGF-1 and IGF-BP3 increased significantly after the period of rehabilitation training in both groups. Relative (%) changes in COPD patients and healthy subjects
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Table 1. Anthropometric characteristics and pulmonary function parameters of healthy subjects and patients with chronic obstructive pulmonary disease before and after rehabilitation program Healthy subjects (n = 16) Before RP
Before RP
After RP
58 ± 7
–
58.6 ± 0.8
–
BMI, kg.m−2
26.52 ± 1.78
25.19 ± 2.13
24 ± 1.4
23.8 ± 0.9
FEV1 ,L
2.94 ± 0.45
2.97 ± 0.56
1.11 ± 0.08***
1.24 ± 0.08†††
FEV1, % Predicted
88.66 ± 9.1
92.50 ± 5.17
37.11 ± 1.62***
38.88 ± 4.12†††
FVC, L
3.16 ± 0.57
3.27 ± 0.51
1.96 ± 0.12***
2.19 ± 0.52†††
82.75 ± 13.29
85.49 ± 9.41
49.67 ± 3.58***
55.72 ± 12.59†††
82.81 ± 9.5
84.27 ± 10.75
55.3 ± 3.9***
57.7 ± 13.8†††
Age, years
FVC, % Predicted FEV/FVC ratio
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Patients with COPD (n = 19) After RP
Unit: Mean ± SD. Notes: Comparisons between patients with COPD and healthy subjects before rehabilitation program: ***p < 0.001; Comparisons between patients with COPD and healthy subjects after rehabilitation program: †††p < 0.001. Abbreviations: COPD, chronic obstructive pulmonary disease; BMI, body mass index; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; RP, rehabilitation program.
were: GH: 40% vs 10%, IGF-1: 24% vs 2%, IGF-BP3: 5% vs 4%, respectively. A significant increase in the T/C ratio was shown in both groups (p < 0.001) (COPD: 42%, healthy 27%). This increase results from decreased cortisol (COPD: 17%, healthy 11%) and increased testosterone levels (COPD: 30%, healthy: 18%) after rehabilitation program. The 6MWD increased significantly after the rehabilitation program in both groups (p < 0.01), as shown in Table 3. The dyspnea and heart rate at the peak of 6MWT decreased significantly after the rehabilitation program (p < 0.05). Any change in SO2% was marked at the peak of 6MWT in both groups compared with values before the rehabilitation program.
Discussion The objective of this study was to analyze the effect of rehabilitation program on the somatotropic axis GH/ IGF-1/IGF-BP3 and T/C ratio in patients with Chronic Obstructive Pulmonary Disease and in healthy subjects. Given the paucity of studies that investigate the effect of
training on hormonal parameters in COPD patients, we have compared briefly our results to those observed in healthy elderly subjects or with other diseases. The major finding of this study showed an increase in anabolic hormone levels (somatotropic hormones and testosterone) after a training program against a decrease in cortisol, one of the important catabolic hormones. An increase in T/C ratio after physical training was also observed in both groups. The rehabilitation program that we used was well tolerated by most patients. Its benefits on dyspnea, exercise tolerance and quality-of-life of COPD patients have been clearly shown (19). No adverse effects were noted during the training program. The 6MWT is easy to perform, reproducible, well standardized and patients with COPD walk at a speed close to their maximum capacity (20). The 6MWT and the incremental cardiopulmonary exercise test (also used in COPD evaluation in many studies) are not interchangeable exercise tests from a physiological point of view. However, from the clinical point of view, when the 6MWT is performed in a standardised manner and verbal incentive is used, it
Table 2. Serum levels of anabolic and catabolic factors before and after rehabilitation program in healthy subjects and in patients with COPD Healthy subjects (n = 16)
Patients with COPD (n = 19)
Before RP
After RP
1.74 ± 0,48
1.94 ± 0.42*
143.67 ± 8,86
147.78 ± 9.87*
98.72 ± 6.60‡‡‡
3166.44 ± 148.4
3305.78 ± 117.06*
2988.91 ± 187.13
2.32 ± 0.33
2.82 ± 0.2***
1.76 ± 0.57‡‡‡
2.51 ± 0.52†††§
Cortisol, ng/mL
219.33 ± 22.78
194.89 ± 14.48**
260.11 ± 20.44‡‡‡
215.37 ± 22.59†††§
T/C ratio, 10−3
10.66 ± 1.77
14.57 ± 1.72***
6.98 ± 1.83‡‡‡
12.1 ± 2.07‡‡‡§§
GH, ng/Ml IGF-1, ng/mL IGF-BP3, ng/mL Testosterone, ng/mL
Before RP 0.55 ± 0.31
After RP 0.91 ± 0.21†††§§§
‡‡‡
131,00 ± 12.81†††§§§ ‡‡
3121,18 ± 142,24†††§§
Unit: Mean ± SD. Notes: Comparison in healthy subjects with values before and after rehabilitation program, *p < 0.05, **p < 0.01, ***p < 0.001; Comparison in patients with COPD with values before and after rehabilitation program, †††p < 0.001; Comparison between patients with COPD and healthy subjects before rehabilitation program; ‡‡‡p < 0.001;Comparison between patients with COPD and healthy subjects after rehabilitation program, §p < 0.05, §§p < 0.01, §§§p < 0.001. Abbreviations: GH, Growth hormone; IGF-1, Insulin-Like Growth Factor 1; IGF-BP3, Insulin-Like Growth Factor Binding Protein 3; T\C ratio, Testosterone\Cortisol ratio; RP, rehabilitation program.
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Table 3. Six-minute walking test parameters before and after rehabilitation program in healthy subjects and in patients with COPD Healthy subjects (n = 16)
Patients with COPD (n = 19)
Before RP
After RP
Before RP
6MWD, m
After RP
600 ± 28.28
789 ± 19.07**
518.7 ± 23.2
581.2 ± 22.0††§§§
6MWD, %
86 ± 4
113 ± 3**
69.8 ± 2.4
77.6 ± 3.8†§§§
Rest
96.9 ± 1.13
96.72 ± 1.1
Peak
96.27 ± 1.1
95.45 ± 1.8
Rest
0.18 ± 0.4
0.91 ± 0.3*
2.9 ± 0.2‡‡
1.1 ± 0.9†§§§
Peak
1.72 ± 1.48
0.36 ± 0.5*
4.7 ± 1.6‡‡‡
2.8 ± 1.1†§§§
Rest
73.72 ± 8.9
65 ± 4.07
75.2 ± 2.5‡‡
73.5 ± 1.3†§§
Peak
87.8 ± 12.1
82.27 ± 27.7*
126.2 ± 3.8‡‡
122.4 ± 4.4†§§§
‡‡‡
‡‡‡
SO2, % 96.7 ± 1.6 91.8 ± 1.4
‡‡‡
95.1 ± 1,1 89.2 ± 2.7§§
Dyspnea
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HR
Unit: Mean ± SD. Notes: Comparison in healthy subjects with values before and after rehabilitation program, *p < 0.05, **p < 0.01; Comparison in patients with COPD with values before and after rehabilitation program, †p < 0.05, ††p < 0.01; Comparison between patients with COPD and healthy subjects before rehabilitation program; ‡‡p < 0.01, ‡‡‡p < 0.001; Comparison between patients with COPD and healthy subjects after rehabilitation program, §p < 0.05, §§p < 0.01, §§§p < 0.001. Abbreviations: 6MWD, 6-minute walking distance; HR, heart rate; SO2, oxygen saturation; RP, rehabilitation program.
shows the maximum sustainable exercise capacity and efficiently reflects the maximum capacity obtained from the cycle ergometer (21). Our results showed no significant change in weight and body mass index in both groups. The short duration of the protocol can explain this stability. Studies that use long periods of training (over 6 months) indicated a decrease in the weight of obese subjects COPD (22). As demonstrated in other studies (23), no significant modification of pulmonary function was marked after a training program. Our results showed decreased levels of serum GH, IGF-1 and IGF-BP3 in COPD patients compared to healthy subjects before training program. These results are consistent with previous studies that reported that growth hormone tends to decline in COPD patient (24). These hormones are considered as key regulators of muscle mass, it is also clear that the IGF-1 exerts its actions independent of GH (25). IGF-1 stimulates protein synthesis and muscle hypertrophy and inhibits protein catabolism through the Phosphatidylinositol 3-kinase (PI3K) (26). Aging, poor nutrition, inactivity and the administration of glucocorticoids are associated with poorly regulating hormones of the somatotropic axis (15). After the training period, serum concentrations of GH, IGF-1 and IGF-BP3 have been increased significantly in both groups but the ranges of change are heigher in COPD patients than healthy subjects (GH: 40% vs 10%, IGF-1: 24% vs 2%, IGF-BP3: 5% vs 4%), these results are consistent with the work of Lafranco, who found that alteration of the somatotropic axis associated to age can be regulated by physical activity (27). A previous study of Koziris et al. (28) showed that endurance training increased the IGF-1 with a significant increase www.copdjournal.com
in IGF-BP3, which is considered as an important marker of physical activity. In healthy elderly subjects, the concentration of IGF-I is positively correlated with maximal aerobic capacity and time spent in physical activity and negatively correlated with adiposity (29.30). Singh et al. (31) showed an increased production of IGF-1 intramuscular after strength training. This type of training meets the objective to complete the endurance training by practices that may induce anabolic effects, in order to fight against muscle atrophy (32). Lafranco et al. (27) showed the role of physical activity as a regulator of the GH / IGF-1 axis function considering the effect of the restoration of GH and circulating IGF-1 Levels on physical performance and body composition. Similarly, Craig et al. (33) showed that strength training can induce testosterone and growth hormone release in elderly people. Growth hormone released by the anterior pituitary is controlled by a hypothalamic factor pituitary: the CH-RH. Many other factors control the release of growth hormone; dopamine, serotonin and catecholamine. The elevation of these factors under the influence of muscular exercise is probably responsible for the increased concentrations of growth hormone (27). Before the rehabilitation program, COPD patients presented decreased level of serum testosterone compared to healthy subjects (p < 0.001). Some authors (34, 35) showed that increased systemic inflammation, administration of corticosteroids and hypoxemia have been correlated with decreased testosterone levels in patients with COPD. Several factors are involved in causing hypogonadism in patients with COPD like decreasing levels of FSH and LH and smoking (36). Debigaré et al. (34) showed a significant correlation
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between systemic inflammation (IL-6 levels, an important inflammatory cytokine) and decreased concentrations of testosterone known as a stimulator of protein anabolism (37). The decrease in PaO2 and atrophy of Leydig cells are also important causes of hypogonadism in COPD (38, 39). Our results showed increased level of cortisol in COPD patient compared to healthy subject (p < 0.001). A study of Schoorlemmer et al. (40) showed that cortisol tends to increase with chronic lung disease. It is associated with a high risk of mortality and hypertension in the elderly. Similarly, Debigaré et al. showed the prevalence of catabolic hormone in patients with COPD (34). The same study showed an increase in catabolic factors like IL6 and TNF alpha, with the fact that muscle atrophy detected in these patients was associated with a disturbance in the anabolic and catabolic functions and not with the decrease of the lung function. The testosterone level increased significantly in both groups after RP, we found that the range of change was higher in COPD patients compared to healthy subjects (30% vs 18%). similarly, a recent study demonstrated that growth hormone and testosterone concentration increased with 8 weeks moderate intensity resistance training (41). Increased testosterone can increase anabolic activity and thus an increase in muscle mass. Vogiatzis et al. (42). demonstrated that endurance exercise training in COPD induces peripheral muscle adaptations that are accompanied by upregulation of factors regulating skeletal muscle hypertrophy and regeneration. The results of our study are in contradiction with those found by Casaburi et al. (43) and Creutzberg et al. (44), who reported no changes in testosterone levels or IGF-1 in the training groups that received placebo supplement. The decrease in cortisol after the rehabilitation period was significant in both groups with higher range of change in COPD patients (17% vs 11%); this showed that the anabolic process increased in our patients with a decline in catabolic function which was shown by the increase in the T/C ratio after training. The increase in the testosterone/cortisol ratio is partly explained by lower levels of the stress hormone. A previous study of Kraemer et al. (45) found a decrease in cortisol levels after training period. The T/C ratio has been proposed to be useful indicator of the balance anabolism/catabolism (40). The ratio T/C known to be related to muscle strength was used to track workouts (46). Hakkinen et al. (47) showed that serum testosterone levels and the T/C were positively correlated with muscle strength during a period of strength training in elderly subjects. The increase in T/C ratio, which was higher in COPD patients (42% vs 27%) increases the synthesis and muscle strength probably partly through the total production of IGE-1 (48). The 6-minute walking test results showed a significant increase in walking distance after the rehabilitation period. Some of studies have shown that the distance
covered in six minutes increased after a program of rehabilitation training, the recent study of Ben Cheikh et al. (5) clearly showed an increase in this distance in Tunisian COPD patients after pulmonary rehabilitation program. The effect of individualized training on dyspnea peak and the maximal heart rate after 6MWT, after rehabilitation program, was significantly important. This could be explained, firstly by improved physical conditions and by very good response to exercise, which supports a decreased sensation of dyspnea (19). Secondly, by some physiological changes, such as better cardiac adaptation, decrease in lactic acid production and reduction in metabolic cost of exercise (49). This study presents a number of important limitations. Initially, we did not measure the level of thyroid hormones. Dysthyroidism have been associated with a decline in respiratory muscle function and exercise capacity (50). Similarly muscle mass/strength is not assessed, and we do not define the basal PaO2 and PaCO2 of COPD patients. GH and testosterone levels can be influenced by both hypoxemia (51) and hypercapnia (52).
Conclusion In conclusion, the findings of this study demonstrate that combined strength and endurance training improves the anabolic processes in COPD patients by increasing serum concentrations of growth hormone GH/IGF-1 and the T/C ratio and consequently reduce protein destruction and improve muscle strength which presents a major obstacle in practical life of those patients. The present study can serve to make health administrators aware of the benefits of pulmonary rehabilitation in patients with COPD, promoting the development of public policies related to such treatment. Similar study is required to support the potential similar effects of training in women with COPD.
Acknowledgments The authors thank the participants for their co-operative attitude and dedicated performance.
Declaration of Interest Statement The authors report no conflicts of interest in this work. The authors alone are responsible for the content and writing of the paper.
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