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Exercise Training Benefits Growth Hormone (GH)-Deficient Adults in the Absence or Presence of GH Treatment

Faculty of Physical Education and Health (S.G.T., J.G.E.) and Faculty of Medicine (S.G.T., J.G.E., S.E.), The University of Toronto, Toronto, Ontario M5S 2W6, Canada

Address all correspondence and requests for reprints to: Dr. Scott Thomas, Faculty of Physical Education and Health, University of Toronto, 55 Harbord Street, Toronto, Ontario M5S 2W6 Canada. E-mail:scott.thomas{at}utoronto.ca.

	Abstract

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Reduced aerobic capacity is a prominent manifestation among patients with GH deficiency (GHD). Exercise training may improve the physiological capacity to undertake aerobic activity. The ability of patients with GHD to participate in and benefit from a structured program of aerobic exercise with or without replacement recombinant human GH (rhGH) was investigated. We examined the effect of aerobic training on cycle ergometers in a double-blind crossover trial. Ten patients with GHD trained for 3 months with rhGH (6 µg/kg·d) or placebo, stopped both exercise and drug for 2 months, and resumed training for another 3 months with the other agent. Peak oxygen uptake (VO₂peak) and ventilation threshold (VeT) were measured during a progressive cycle ergometer test to fatigue or symptom-limited maximum. Serum IGF-I levels were monitored to assess compliance with GH treatment. VO₂peak was low at the two baseline measures (B1, 19.3 ± 5.5; B2, 19.9 ± 6.9 ml/kg·min; normal, 30 ml/kg·min) as was VeT (B1, 11.6 ± 2.2 ml/kg·min; B2, 11.7 ± 2.6 ml/kg·min; normal, 16 ml/kg·min). Exercise training increased VeT with (8.6%) or without (9.4%) rhGH treatment. Similarly, exercise training resulted in significant reduction in submaximal heart rate in the presence (–5 ± 4 beats per minute; P < 0.05) or absence of rhGH treatment (–4 ± 4 beats per minute; P < 0.05). Peak oxygen uptake was not significantly affected by training with or without rhGH treatment.

Our findings suggest that exercise training is a feasible intervention in GH-deficient adults that can measurably improve their submaximal responses to exercise. The beneficial effects of exercise can mimic and are not additive to the effects of GH treatment alone.

	Introduction

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SINCE ITS INTRODUCTION more than a decade ago, recombinant human GH (rhGH) therapy in adults has gained widespread popularity (1). The potential therapeutic effects have been explored with variable responses in age-related and non-age-related catabolic conditions including those associated with HIV, burns, infections, and nutritional disorders (1).

Acquired hypopituitarism due to pituitary disease provides a relatively more homogenous population to study the effects of GH in adults. Indeed, a diminished sense of wellbeing (2, 3, 4) and reduced physical performance (5, 6, 7) represent prominent features in adults with acquired GH deficiency (GHD).

Treatment of GH-deficient adults with GH has measurable effects on physical function and perception of fatigue (5, 6, 7, 8). Yet, many patients treated with GH continue to suffer from diminished physical capacity and heightened sense of fatigue.

We have previously shown that measures of effort-independent submaximal aerobic performance can be used to objectively determine functional impairment and perception of fatigue (5). These measures can be used to evaluate and predict an individual’s response to GH treatment. GH treatment improves responses to submaximal exercise, physical and perceived function (5).

Aerobic training has proven efficacy in numerous populations (9). Change in maximal aerobic capacity occurs when the ability to deliver or consume oxygen is altered. Change in response to submaximal exercise may occur for diverse reasons including change in autonomic function, energy metabolism, and muscle recruitment. Although GHD impairs, aerobic exercise training positively influences maximal aerobic power (10, 11), oxygen-carrying capacity (12), cardiac function (8), autonomic function (13), and energy metabolism (8). Surprisingly, there is very limited information on the effect of aerobic exercise training for patients with GHD.

The ability of patients with GHD to participate in regular aerobic exercise has not been evaluated. Low- to moderate-intensity exercise is recommended for individuals with low aerobic capacity (14). Exercise training of patients may be facilitated by concurrent rhGH treatment. rhGH might increase the compliance with exercise by reducing fatigue and permit GH-dependent cardiorespiratory system adaptations. We hypothesized that treatment with a structured low- to moderate-intensity exercise program would enhance physical capacity even in GH-deficient subjects and that GH treatment may further enhance the response to exercise training.

	Subjects and Methods

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Subjects

Twelve patients (24–72 yr) with GHD were enrolled. GHD was documented by a peak GH of 3 µg/liter during an insulin tolerance test with adequate hypoglycemia. All participants had adult-onset GHD due to pituitary tumor lesions, had no other concurrent systemic illnesses, and had not received exogenous GH within the previous 6 months. Replacement of other pituitary-controlled hormones was stabilized for at least 6 months before study entry.

Study design

The study and the consent process received ethics approval from the University of Toronto. Participants who gave written informed consent were studied in a double-blind, placebo-controlled crossover fashion. The two-period, two-group trial was an A/B B/A design. After a 1-month single-blind run-in on placebo, participants were randomized to receive either drug A, active treatment with rhGH (Humatrope, 6.0 µg/kg lean body mass), or drug B, placebo for 3 months (period 1) daily. After a 2-month washout, participants crossed over to the alternative treatment for 3 months (period 2). All measures were performed at baseline and after each treatment period. Sample size estimation was based on a paired t test comparison of change in ventilation threshold (VeT) with a 1 ± 1.1ml/kg·min greater change with exercise combined with rhGH compared with rhGH treatment alone (5).

Serum levels of GH (Quest, San Juan Capistrano, CA) and IGF-I (Diagnostic Systems Laboratories, Inc., Webster, TX) were measured using immunoassays according to manufacturers’ protocols as previously described (5).

Aerobic training intervention

Study participants followed a home cycle ergometer training program. Frequency was set at three sessions per week, and intensity was progressed from 50% to 70% of measured maximum heart rate (HRmax) over the 3-month program. Training intensity was increased from 50% to 60% of HRmax over the first 2 wk and then progressed to 70% HRmax. Participants increased session duration from 15 to 30 min of cycling during the first month of training. Heart rate (Polar Heart Rate Monitor, Kempele, Finland) and actual duration and frequency of training were recorded in diaries that were monitored for exercise compliance during monthly visits. This training regimen was selected in view of the limited physical capacity and high prevalence of fatigue in GH-deficient adults (5, 14).

Aerobic fitness

Respiratory gas exchange was measured during a continuous, progressive, pseudo-ramp (small step increases) cycle ergometer protocol to symptom-limited peak (14). The initial power output, based on the level of physical activity and fitness of each subject, was set low to ensure accurate estimation of VeT. Measures included peak oxygen uptake (VO₂peak) and VeT. VO₂peak was the highest oxygen uptake achieved. Objective criteria for ascertaining VO₂peak were that VO₂ and heart rate plateaued despite further increases in work rate. Day-to-day variation in VO₂peak with healthy volunteers and patients in our laboratory (6%) is similar to published values (5%) (14).

A noninvasive method was used to estimate VeT from ventilatory equivalents for oxygen (V_E/VO₂) and carbon dioxide (V_E/VCO₂) as previously described (15, 16). VeT was identified as VO₂ at the point of inflection where V_E/VO₂ was lowest then increased progressively with further increments in cycle power output whereas V_E/VCO₂ plateaued or declined. The modified V-slope method where VCO₂ was plotted against VO₂ (17) was used to support the estimate of VeT by ventilatory equivalents. Two investigators blinded to treatment and data of the study were able to clearly identify VeT at each of the four time points. Discrepancy in VeT between investigators was less than 10% in all cases, and the mean value was recorded.

Patients performed 6 min of constant-load cycle ergometer exercise at 60 ± 2.3 and 78 ± 2.5% of their peak capacity at baseline. Values from the last 2 min of exercise were averaged to assess HR and perceived exertion (10-point Borg scale) (18) responses to training.

Fatigue

The self-report profile of mood states (POMS) questionnaire has been validated for use with exercise interventions (18) as well as GHD (5, 19). It evaluates six domains of mood state: tension, depression, anger, vigor, fatigue, and confusion. Subjects rated "how they had been feeling during the previous week during their normal daily activities" on a four-point scale to each of 65 words/phrases that describe feelings. Responses were summed for each domain (20).

Statistical analyses

Descriptive statistics included means, SDs, and SEM were calculated (SigmaStat, Jandel Scientific, San Rafael, CA). Within-subjects repeated measures ANOVA was used to examine differences from baseline to 3 months of active treatment or placebo. Carryover effects were assessed by comparing the two baseline measures (paired t test). Post hoc comparisons were made using Student-Newman-Keuls. Level of significance was P < 0.05.

	Results

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Patient characteristics

Twelve subjects (three males and nine females; mean age, 47.7 yr) were included. No adverse events resulted in withdrawal from the study. Two participants (females) withdrew before completion of the 3-month data collection for personal reasons. Body mass was significantly higher than age- and sex-matched population norms (Table 1). Weight and body mass index did not change significantly over either treatment period. One subject smoked and another was under treatment with oral hypoglycemics for diabetes mellitus.

Nine of the ten study participants completed their training logs as requested. One individual verbally reported training but did not complete the written diaries. The reporting study participants completed 88.0 ± 6.5% of prescribed sessions while receiving rhGH and 94.4 ± 2.3% of the sessions during treatment with placebo. With (100.2 ± 1.6%) or without (102.3 ± 1.7%) rhGH, study participants trained very near their prescribed heart rate intensity.

Biochemical changes

A significant (P < 0.02) increase in circulating IGF-I (mean change ± SEM; 155.4 ± 38.0 µg/l) followed 3 months of rhGH, confirming compliance with this treatment. Treatment with placebo did not alter IGF-I, or its binding proteins, confirming that exercise training was insufficient to induce circulating IGF-I levels in these patients with severe hypopituitarism (see Table 1). There was no significant change in IGF-I levels from baseline 1 to baseline 2.

Aerobic performance

At baseline the VO₂peak relative to body weight was lower than normative values (normal = 31 ml/kg·min; patients = 19.3 ± 5.5 ml/kg·min; P < 0.05) (21) and less than values measured in our laboratory for healthy volunteers of the same gender and similar age (mean value 40 ml/kg·min). The measured VeT of our sample at baseline (VeT = 11.6 ± 2.3 ml/kg·min) was significantly (P < 0.05) less than predicted for healthy sedentary adults of the same, age and gender (14.2 ± 3.0 ml/kg·min) (22).

Three months of aerobic training significantly (P < 0.05) increased VeT in the presence (8.6%) or absence (9.4%) of rhGH treatment (Fig. 1). VeT as a percentage of VO₂peak was 60 ± 6% (normal = 55%) at baseline and was not significantly changed after aerobic training (63 ± 7%).

View larger version (44K): [in this window] [in a new window]   FIG. 1. Effect of exercise training and rhGH or placebo on VeT in patients with GHD. Values illustrated are mean ± SD; *, significant (P < 0.05) change with respect to baseline.

Response to constant load exercise

The HR response to exercise was reduced after exercise training with or without rhGH treatment. HR at 60% of the baseline peak capacity significantly decreased by 5 beats per minute with exercise training and rhGH and by 4 beats per minute with exercise training and placebo (Fig. 2). Similar responses were observed with exercise at 80% of peak capacity with 4- and 6-beat-per-minute declines with exercise training plus rhGH and exercise training plus placebo, respectively. The perceived exertion at either constant power output was reduced by the exercise intervention.

View larger version (42K): [in this window] [in a new window]   FIG. 2. HR response to constant-load exercise equivalent to 60% (solid bar) and 80% (hatched bar) of baseline maximal aerobic capacity before and after aerobic training by patients with GHD. Values illustrated are mean ± SD; *, significant (P < 0.05) change with respect to baseline.

Although there was a trend for improvements in the POMS subscales with exercise training, these scores did not achieve statistical significance. The mean vigor score increased from 14.6 ± 6.2 to 17.4 ± 6.2 (P < 0.069) after 3 months of exercise and rhGH treatment. Interestingly, the vigor score after 3 months of exercise in the absence of rhGH treatment did not appreciably increase (15.7 ± 4.2). For comparison purposes, it should be noted that the expected vigor score for a mixed sample of men and women is 19.5 ± 6.6 (20).

	Discussion

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Exercise training is an important component of treatment plans for diverse pathologies (9). The reduced cardiorespiratory capacity and excess fatigue are common features evident in patients with GHD. Irrespective of GH replacement status, we show that exercise training was associated with a reduced HR response to submaximal exercise and increased VeT. These changes are of sufficient magnitude to reduce the physiological strain of performing activities of daily living (23). Moreover, the exercise training-associated increase in VeT (9%) is similar to the response that occurred with GH treatment of GH-deficient adults (12%) (5). The hyperbolic relation between exercise intensity and time to fatigue (24) would imply that this magnitude (10%) of increase in VeT is sufficient to allow patients to exercise twice as long before reaching a fatigue limit when working at an intensity equivalent to their baseline VeT (25).

We did not observe an independent effect of rhGH treatment on participation in exercise training or on exercise capacity. GH replacement in GH-deficient adults has been shown to alleviate fatigue and increase vigor (5) with a similar tendency (although not statistically significant) in the current study. Nevertheless, our patient’s ability to train with cycle ergometers was not influenced by GH treatment. The high level of participation we observed may result from self-selection by patients volunteering for a study that they recognized would involve regular exercise. It is encouraging, however, that GH-deficient patients with markedly reduced physical capacity and complaints of severe fatigue could maintain participation in a training program of moderate intensity. Our data indicate that this low- to moderate- intensity exercise intervention was sufficient in resulting in significant improvements in ventilatory and cardiac responses. More importantly, this approach was associated a high degree of compliance rendering such an exercise regimen a feasible and potentially realistic therapeutic option in this population.

Our study demonstrates that aerobic training improves responses to submaximal exercise. VeT is a useful clinical marker because it is an effort-independent physiological marker of ability to perform submaximal, prolonged activity (26). Working at intensities above VeT results in metabolic acidosis, hyperventilation, and inability to sustain performance.

VeT is reduced in conditions characterized by excessive fatigue, including cardiac failure (27), chronic fatigue syndrome (28), chronic pulmonary disease (29), and acromegaly (16). Exercise training of patients with chronic congestive heart failure increases VeT and improves functional status (30). In this study, treatment of GH-deficient patients with aerobic training alone increased VeT. Although changes in self reported vigor and fatigue did not reach statistical significance, the decrease in self-reported fatigue and increase in VeT supports our hypothesis that fatigue and VeT are physiologically linked (5, 16).

The physiological basis of an increased VeT remains uncertain, but explanations include a decrease in glycolytic anaerobic metabolism (31), increased clearance of lactate (31), or delayed recruitment of muscle fibers with less oxidative capacity (32). Given that exercise training of low to moderate intensity was sufficient in increasing VeT and reducing HR at a fixed power output, our findings suggest that normal circulating GH/IGF-I may not be a prerequisite for cardiorespiratory adaptation. However, rhGH treatment alone does increase VeT in patients with GHD (5, 10). Taken together, these observations suggest that overlapping mechanisms are responsible for cardiorespiratory changes in response to the two stimuli. However, it is possible that a more intense program of exercise would produce additional adaptations in patients with GHD.

Exercise training did not increase VO₂peak in both treatment phases. A previous study from our laboratory found no significant change in VO₂max with rhGH treatment in similar adult patients with GHD (5). In contrast, others observed a mean increase of 4.8 ml/kg·min after 3 months of rhGH treatment, but also a 2.2-ml/kg·min corresponding increase was noted among placebo-receiving patients (10). Moreover, both groups in the latter study demonstrated an increase in maximal HR, suggesting increased effort during the second test by all participants. Our finding of consistency in peak HR and respiratory exchange ratio in maximal exercise testing suggests that our patients reached a physiological limit to aerobic metabolism at both time points.

Aerobic metabolism is dependent on cardiac function, peripheral blood flow, blood flow distribution, and the ability of muscle tissue to take up and use oxygen (33). The absence of change in VO₂ peak with exercise training in the presence or absence of GH treatment in the current study suggests that GH-deficient patients may have an underlying limitation that is not sufficiently alleviated even by combined exercise and rhGH treatment. Alternatively, our low- to moderate-intensity program may not have provided an adequate stimulus to change peak aerobic power. However, studies with healthy participants suggest that change in VO₂peak is more easily provoked in those with low initial values (14).

Previous studies have documented positive effects of structured exercise training in various cardiovascular diseases (14), endocrine disorders such as diabetes mellitus (34), and immunological pathologies such as HIV-associated muscle wasting (35). This is the first study to examine and demonstrate that moderate exercise training can mimic the effects of GH replacement on physical capacity in GH-deficient adults. Our findings suggest that additional studies to explore the interactions between hormone replacement therapies and exercise training on physical performance are warranted.

	Acknowledgments

 
The generous gift of rhGH (Humatrope) from Eli Lilly Canada (Toronto, Canada) is acknowledged.

	Footnotes

 
This work was supported by a grant from the Heart and Stroke Foundation of Ontario.

The authors have no financial and personal relationships with other people or organizations that could bias this work.

Abbreviations: GHD, GH deficiency; HR, heart rate; POMS, profile of mood states; rhGH, recombinant human GH; VeT, ventilation threshold; V_E/VO₂, ventilatory equivalents for O₂; VO₂peak, peak O₂ uptake.

Received April 11, 2003.

Accepted August 24, 2003.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thomas, S. G. Articles by Ezzat, S. Search for Related Content PubMed PubMed Citation Articles by Thomas, S. G. Articles by Ezzat, S.