Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance ROSS C. CUNEO, FRANC0 SALOMON, C. MARK RICHARD HESP, AND PETER H. SijNKSEN
WILES,
Divisions of Medicine and Neurology, United Medical and Dental Schools of Guy’s and St. Thomas’ Hospitals, St. Thomas’ Hospital, London SE1 7EH; and Division of Radio-Isotopes, Medical Research Council, Northwick Park, Harrow, Middlesex HA1 3UJ, United Kingdom CUNEO, Ross C., FRANCO SALOMON, C. MARK WILES, RICHARD HESP, AND PETER H. MNKSEN. Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance. J. Appl. Physiol. 70(2): 695-700, 1991.Growth hormone (GH) treatment in adults with GH deficiency increases lean body mass and thigh muscle cross-sectional area. The functional significance of this was examined by incremental cycle ergometry in 24 GH-deficient adults treated in a double-blind placebo-controlled trial with recombinant DNA human GH (rhGH) for 6 mo (0.07 U/kg body wt daily). Compared with placebo, the rhGH group increased mean maximal 0, uptake (00, m,) (+406 t 71 vs. +133 t 84 ml/min; P = 0.016) and maximal power output (+24.6 t 4.3 vs. +9.7 t, 4.8 W; P = 0.047), without differences in maximal heart rate or ventilation. Forced expiratory volume in 1 s, vital capacity, and corrected CO gas transfer were within normal limits and did not change with treatment. Mean predicted Vozmax, based on height and age, increased from 78.9 to 96.0% in the rhGH group (compared with 78.5 and 85.0% for placebo; P = 0.036). The anaerobic ventilatory threshold increased in the rhGH group (+159 t 39 vs. +l t 51 ml/min; P = 0.02). The improvement in VO 2maxwas noted when expressed per kilogram body weight but not lean body mass or thigh muscle area. We conclude that rhGH treatment in adults with GH deficiency improves and normalizes maximal exercise performance and improves submaximal exercise performance and that these changes are related to increases in lean body mass and muscle mass. Improved cardiac output may also contribute to the effect of rhGH on exercise performance. somatotropin; maximal oxygen uptake; anaerobic threshold; lean body mass ADULT PATIENTS with hypopituitarism
often complain of lethargy and fatigability despite optimal conventional pituitary hormone replacement. Because of the absence of the potent anabolic actions of growth hormone (GH), adults with GH deficiency have an -9% reduction in lean body mass compared with that predicted from sex, age, and body size (17). Since exercise capacity is related to indexes of lean body mass (8,19,22), the complaints of such patients may reflect alterations in body composition and hence impaired exercise capacity. With the advent of recombinant DNA technology, sufficient supplies of human GH have become available, allowing the possibility of treatment of patients with GH deficiency other than those in childhood. We have previously described the increases in lean body mass, 0161-7567/91
$1.50 Copyright
thigh muscle mass (as cross-sectional area on computerized tomographic scans), and limb girdle strength following recombinant DNA human GH (rhGH) treatment in adults with GH deficiency (4,17). If functional improvements also result, the cost of such treatment may be offset by increased occupational productivity. We now report the results of exercise testing in response to rhGH treatment in adults with GH deficiency. METHODS
Patients were GH deficient and, if necessary, received stable and clinically appropriate pituitary hormone replacement for at least 12 mo before entry to the trial. Entry requirements have been described previously (4, 17). Treatment with rhGH (Genotropin, KabiVitrum, Sweden) was given in a double-blind placebo-controlled fashion for 6 mo at 0.07 U/kg body wt as a single self-administered dose at 2000 h each day. Studies were performed at baseline and after 3 and 6 mo of treatment. Venous blood samples were taken on the morning of the test after an overnight fast. Exercise tests were usually performed later that afternoon at least 3 h after food. Patients requiring glucocorticoid replacement were transferred to cortisone acetate for the study day, taking 12.5 mg 2 h before the morning blood sampling and 12.S 25 mg l-2 h before the exercise test. Women were studied in the first half of their menstrual cycle when appropriate. Measurements of muscle mass (0, 3, and 6 mo) and lean body mass (0 and 6 mo) were made within 24 h of the exercise test. Exercise testing. After measurement of height (to the nearest 0.1 cm, Harpenden Staediometer) and weight (to the nearest 0.1 kg) patients were positioned on a frictionbraked cycle ergometer (Tunturi model W, Piispanristi, Finland). Calibration of the braking force was performed to the manufacturer’s instructions. Toe clips were fitted, and the seat height was optimized. The same seat height was used at subsequent tests. Familiarity with the cadence (chosen by the patient at either 50 or 60 Hz) and work loads to be anticipated initially preceded a resting period, during which the patient adjusted to breathing with a mouthpiece. 0, consumption (iTo,), CO, production (VCOJ, and ventilatory volumes were measured with a metabolic measurement cart (MMC, Horizon, Beckman Instruments, Anaheim, CA). This machine uses infrared CO, and paramagnetic 0, analyzers and a turbine
0 1991 the American
Physiological
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696
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pneumotachograph recording data every 100 ms. Calibration against standard gases (16% 0, and 4% CO,), volume (900 ml), operating temperature, and barometric pressure was performed immediately before each test. Patients did not start exercising until the respiratory exchange ratio (RER) approached 0.8. Work rate was set at 50 W for the 1st min and increased by 25 W each minute until a symptom-limited maximum was reached. Patients were vocally encouraged to maintain the chosen cadence and to maximize effort. Heart rate was recorded by surface electrocardiography during the last 5 s of each minute. A 19-point Borg scale was used to assess subjective exertion at the 6-mo test (1). In view of the abnormal body composition of these patients, a number of different methods for predicting maximal 0, uptake (TO, max)were compared (11) males:
V02
females: males:
VO,
m8x= 5.41 X Ht - 0.025 X age - 5.66 = 3.01 X Ht - 0.017 X age - 2.56 max= 0.83 X Ht2a7 X (1 - 0.007 X age)
= 0.62 X Ht2a7 X (1 - 0.007 X age) males: V02max = 3.45 X It- 0.028 X age + 0.022 x Wt - 3.76 females:
females:
It - 0.018
X
age
(1) (2)
(3)
+ 0.010 x Wt - 2.26 where Ht is height and Wt i s body weight. Predicted maximums for heart rate, ventilatory volumes, and 0, pulse used standard equations (11). Maxima1 voluntary ventilation represented forced expiratory volume in 1 s (FE&) multiplied by 35. 0, pulse was defined as VO, divided by heart rate and provides an approximation of stroke volume if arteriovenous 0, content at maximal exercise is assumed to differ little between individuals (11). The ventilatory anaerobic threshold was calculated from a plot of vo2 vs. ko2 and minute ventilation (VE) (23). Manual curve fitting was performed by one observer blinded as to the origin of the graph being assessed. The first deviation from the initial straight-line relationship was considered to be the anaerobic threshold. Although similar results were obtained from the VCO, vs. VO, plots alone, results reported are an average of the thresholds obtained from the ho, and VE plots inasmuch as this improved reproducibility. The coefficient of variation for repeat blinded measurements on 22 paired traces was 15.5%. FEV, and forced vital capacity (FVC) were measured with a wedge spirometer (Vitalograph). CO gas transfer was measured by the single- #breath technique and corrected for lung volumes (Kco; Ref. 3). Respiratory values were compared with standard predictions based on we and height (3). Measurements of lean body mass were performed at the Northwick Park Hospital using the total body potassium counter, and computerized tomographic cross-sectional area of the dominant midthigh was performed as previously reported (4, 17). Activity was assessed before
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EXERCISE
each visit by daily recordings averaged over 1 wk using a mechanical pedometer (Aurora, Japan) and at the 6-mo visit with a detailed activity questionnaire [7-day physical activity recall (20, 24)]. Statistics. Results are reported as means t SE. Comparisons between treatment groups were performed using analysis of covariance on the 6-mo data, with baseline data as the covariate. Significance was recognized at the 5% level. Relationships between single variables before treatment were explored with simple linear regressions and changes in variables after treatment with multiple linear regressions, with treatment as a stratifying or binary variable. For changes with more than one significant association, multiple linear regressions were also used, with treatment code as a stratifying variable. Treatment-variable interaction was explored and excluded in each case. Coefficient of variation was calculated using the SD of the differences between paired observations divided by the mean of all the observations. RESULTS
The demographic data have been reported previously (4, 17). Exercise tests were completed uneventfully, except that one 24-yr-old female in the placebo group fainted at the end of the test at the 3-mo visit. She recovered spontaneously. On the basis of subjective assessment, tests were considered maximal or close to maximal by the attendant clinicians. No patient showed plateauing of 60,. One male in the placebo group produced submaximal tests on each occasion because of intolerance of the mouthpiece (RERs at entry and 3 and 6 mo were 0.95, 1.01, and 1.02, respectively). Results are reported including all data, since exclusion of this patient did not alter the conclusions. Compared with results from the placebo group, 60, max increased 17% from 1.88 t 0.17 to 2.34 t 0.20 l/min in the rhGH group (placebo 1.84 t 0.17 to 1.98 t 0.13 l/min at 0 and 6 mo, respectively; P = 0.016; Fig. 1). The increase in vo 2maxwas associated with a significant increase in maximal power output (rhGH 148.6 t 13.2 to 177.5 t 16.4 W and placebo 138.7 t 9.3 to 148.4 t 9.2 W at entry and 6 mo, respectively; P = 0.047, Fig. 1). Compared with predicted values, VO, maxfor the whole study group before treatment was significantly below normal (Table 1). By use . of predictions based on height, weight, and age, vo 2max for the rhGH group increased into the normal range by 6 mo. This increase in Vo2max was not associated with changes in maximal heart rate, ventilatory volume, or maximal RER between the two groups (Table 2). Similarly, subjective assessment of the severity of effort did not differ between the two groups at the final test, with a mean Borg rating of 17 of 19 for both groups. As an index of stroke volume, maximal 0, pulse increased in the rhGH group (P = 0.025, Table 2). Even though the percentage of maximal predicted 0, pulse in the rhGH group increased from 91.0 t 5.0 at entry to 103.3 t 6.5 at 6 mo (placebo 90.9 t 5.6 to 94.0 t 3.2, respectively), the difference between the groups failed to reach statistical significance (P = 0.084). The anaerobic threshold increased in the rhGH group
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HORMONE
2.0
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697
EXERCISE
7.8
38.3 t 1.7 kcal/kg for the rhGH and placebo groups, respectively; P = 0.33). Correlation analysis showed significant associations between change in VO, maxand change in maximal power output (P = 0.018) but not with changes in lean body mass, thigh muscle area, or insulin-like growth factor I nor with sex, age, or past history of Cushing’s disease. The increase in anaerobic threshold correlated with the increase in 60~~~ (P = 0.027).
1.6
DISCUSSION
2.6 2.4 2.2 2.0
Or
d
i
i
180 160 -
0 3I
I
I
1
0
3
6
Months FIG. 1. Changes in maximal
O2 uptake (top) and power output (bottom) after growth hormone treatment (closed symbols) or placebo (open symbols). No significant differences existed between groups at baseline.
(Table 2). There was no change in the anaerobic threshold as a percentage of vo2 m8X(57 t 3 to 53 t 3 and 62 t 3 to 57 t 2% in the rhGH and placebo groups, respectively). The heart rate at the anaerobic threshold was not different between the groups (rhGH 119 t 5,126 t 5, and 123 t 5 beats/min and placebo 133 t 6,128 t 5, and 132 t 6 beats/min at 0, 3, and 6 mo, respectively). Changes in 60~~~~ expressed in terms of body weight, lean body mass, and thigh muscle cross-sectional area are shown in Table 3. When expressed per kilogram of body weight, VO, m8x increased significantly after rhGH treatment (P = 0.046). The anaerobic threshold expressed in terms of body weight (P = O.lO), lean body mass (P = 0.99), or thigh muscle cross-sectional area (P = 0.99) did not increase. Results of respiratory function tests are shown in Table 4. For the whole group before treatment, FEV, and FVC were not significantly different from normal. Reductions in gas transfer disappeared when corrected for lung volume. After treatment, no change was noted in any of these variables. Pedometer recordings did not change significantly between the groups (rhGH 7.0 t 0.6,5.9 t 0.8,7.5 t 1.3, and 9.5 + 1.3 km andplacebo 6.1 t 1.2,9.1+ 1.9,5.3 t 0.7, and 6.1 z 0.4 km at entry and 1,3, and 6 mo, respectively; P = 0.3). Daily activity at 6 mo, assessed by questionnaire, was not different between the groups (41.1 t 2.5 and
We have shown that adults with long-standing severe GH deficiency exhibit reduced maximal exercise performance that can be improved after 6 mo of treatment with rhGH. The 17% increase in VO, maxafter rhGH treatment was paralleled by an increase in maximal power output. Our conclusion that power output did increase is supported by two observations. Jorgensen et al. (12) reported an increase in maximal power output using an electromechanically braked ergometer in GH-de@cient adults treated with rhGH for 4 mo. Second, for VO, to increase without a concomitant increase in power output, either a hypermetabolic state or a major reduction in mechanical efficiency must be proposed. We have excluded the former by showing that basal metabolic rate per kilogram of lean body mass was not different after 6 mo (17) and saw no evidence for the latter. During maximal exercise no differences were noted between treatment groups with respect to objective signs of effort (heart rate, ventilatory volumes, and RER) or the subjective perception of exertion. The increases in objective signs of effort seen in both groups over the 6 mo, although greater in magnitude than expected for normal individuals (11), are consistent with familiarity gained with the testing procedure and equipment for novices and underscore the importance of a placebo-treated control group. Our data are in conflict with a reported increase in maximal and resting heart rates after rhGH treatment (l2), for which no obvious explanation exists. The increase in VO 2maxwas paralleled by an increase in the ventilatory anaerobic threshold. This observation is supported by the improvement in exercise performance without an increase in the subjective sensation of effort. These changes are important for daily activity. For example, the anaerobic threshold occurred at VO, near 1.0 l/ TABLE
1. Percentage
Method
Treatment
1
rhGH Placebo rhGH’ Placebo rhGH Placebo
2 3
of predicted Baseline
maximal
O2 uptake
6 mo
78.9t4.5*
96.Ok6.3
78.5+5.1t
84.9t2.6*
80.0t4.6” 79.8k5.4” 72.2t3.7” 73.1t4.3*
98.7k6.4 86.0+,2.9* 87.3+_4.7$ 78.9t2.8*
P
0.036 0.018 0.048
Values are means t SE. Methods of calculating predicted VO, - are detailed in text, but method 1 includes height and age, method 2 includes height2e7 and age, and method 3 includes height, weight, and age. Comparisons of differences from baseline to 6-mo values between the 2 groups (P) were performed with analysis of covariance. No significant differences existed between groups at baseline. Other comparisons performed with a single-sample t test against a predicted 100% are indicated: * P < 0.001; 3-P < 0.002; 5 P < 0.001.
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698 TABLE
GROWTH
2. Maximal
heart rate, ventilation,
HORMONE
respiratory
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EXERCISE
exchange ratio, 0, pulse, and vent&tory
Treatment
Baseline
rhGH Placebo rhGH
156t6 1611r5 84.2tl.8 86.4tl.8 58.6S.O 56.5k5.4 52.4t2.5 48.lt3.9 1.10*0.02 l.llt0.02 12.ltl.l 11.6tl.2 1.05+0.08 l.lOt0.07
3 mo
anaerobic
threshold
6mo
P
168t6 168t5 90.3t2.6 90.5t2.0 78.4k7.6 70.4t3.9 67.5t5.4 58.9t4.0 1.2lt0.03 1.2lt0.03 13.9tl.O 12.0tl.O 1.22kO.09 l.lOt0.05
0.82
Values are means & SE. Comparisons of differences from baseline to 6-mo values between 2 groups (P) were performed covariance. No significant differences existed between groups at baseline.
with analysis of
Maximal heart rate beats/min %pred
Placebo Maximal
ventilation,
l/min
rhGH Placebo rhGH Placebo rhGH Placebo rhGH
Maximal voluntary ventilation, %pred Maximal respiratory exchange ratio Maximal O2 pulse, ml/beat Anaerobic
threshold,
Placebo rhGH Placebo
l/min
168t4 167-+4 90.7tl.9 89.9H.9 72.lk6.5 68.2k6.0 62.8k4.1 59.4t5.4 1.14t0.03 1.18t0.04 13.7kl.l 11.8tl.O 1.25t0.09 1.08t0.08
0.89 0.41 0.31 0.96 0.03 0.02
min, equivalent to -60 W or similar to walking on a flat production during exercise would have been reduced, surface at 6 km/h. Thus, if a given task can be done with leading to reduced gluconeogenesis and hepatic glucose production during prolonged exercise (14). Thus the duless physiological stress, these patients may be inclined to increase their work productivity. Indeed, many of the ration of exercise and small number of such patients are patients spontaneously described an increase in the ease unlikely to influence the conclusions regarding the effect of completing daily tasks. of rhGH treatment. We have. been careful to control for factors other than Cyclic variations in ovarian steroids affect glucose hoGH treatment that may have spuriously altered the con- meostasis during exercise (13), but all our female subclusions. Patients were receiving optimal conventional jects were studied during the follicular phase or first half pituitary hormone replacement for 12 mo before entering of an artificial menstrual cycle. Testosterone replacethe trial, minimizing the detrimental effects of abnormal ment in hypogonadal males is likely to increase lean body glucocorticoid or thyroid hormone status on muscle physiology (see Ref. 10 for review). We attempted to mimic TABLE 4. Respiratory function in adults with growth the acute exercise-induced increase in glucocorticoids with a dose of a short-acting steroid, cortisone acetate, to hormone deficiency before and after rhGH produce a peak of absorption that coincided with maxi- or placebo treatment mal exercise. Variations in corticosteroid absorption Treatment Baseline 6mo were unlikely to have major influences on our results, since the effects of endogenous glucocorticoids seem to FEV, liters rhGH 3.08kO.30 3.45kO.27 be most prominent in exercise tests of longer duration Placebo 3.29t0.22 3.52t0.20 than ours (9,18). Small increases in free triiodothyronine %pred rhGH 92.lk6.1 101.4k4.8 were noted after 1 mo of rhGH treatment (17). Because Placebo 99.0t5.3 106.4k4.9 FVC these changes occurred within the normal reference liters rhGH 3.97kO.32 4.37t0.32 range (or just above in three cases) and had resolved by 3 Placebo 3.9420.26 4.12t0.24 mo, adverse influences on the rhGH group’s exercise per%pred rhGH 94.8t5.6 102.lt5.2 formance at 6 mo are unlikely. In the three patients with Placebo 92.5t4.2 97.323.9 bilateral adrenalectomy, increased adrenal epinephrine FEVJFVC, % rhGH 76.9t2.4 79.2k2.4 PEFR ml/s
TABLE 3. Maximal 0, uptake expressed per body weight, lean body mass, and cross-sectional area of thigh muscle
%pred
ml/kg VO, -/lean body mass, ml/kg VO, -/thigh muscle area, ml/cm2
Treatment
Baseline
3 mo
rhGH Placebo rhGH Placebo rhGH Placebo
22.7kl.5 24.222.3 35.9tl.7 38.923.0 14.5t0.6 15.4tl.l
27.5kl.8 26.41k2.2 16.4kO.9 17.8tl.5
6 mo
27.8tl.6 25.8tl.7 40.571.6 41.7U.8 16.6t0.9 17.ktl.O
P
0.05
Transfer mmol
0.88
%pred
0.96
Values are means k SE. Lean body mass was measured by total body potassium content (&K) and cross-sectional area of thigh muscle by computerized tomography of dominant midthigh. Comparisons of differences from baseline to 6-mo values of 2 groups (P) performed with analysis of covariance. No significant differences existed between groups at baseline.
K co mmol %pred
l
l
factor min-’ . kPa-’
min-’
l
kPa-’
l
1-l
Placebo
83.8kl.4
85.7kl.l
rhGH Placebo rhGH Placebo
46Ok38 482+30 89.3+4.5* 93.6t4.1
459k27 468,+25 88.9t4.4 90.U3.6
rhGH Placebo rhGH Placebo
8.55kO.56 8.46kO.73 91.2+6.0* 89.4t5.9
8.5lkO.58 8.06kO.60 91.927.4 85.2t4.4
rhGH Placebo rhGH Placebo
1.71&0.09 1.7lt0.09 99.1t4.0 98.9k5.0
1.64t0.08 1.74t0.09 95.2t5.7 101.4t5.6
Values are means t SE. PEFR, peak expiratory flow rate. No significant differences existed between groups at baseline. * Differences between means of both groups before treatment compared with 100% with a single-sample t test (P c 0.02).
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GROWTH
HORMONE
mass through effects on protein synthesis (see Refs. 15 and 25 for review). Testosterone replacement was stable before and unchanged during the trial. To minimize the effect of training, we encouraged our patients not to alter their habitual activity during the trial. This is reflected in the pedometer and activity questionnaire data. The normalization of VO 2mmwithout a training effect underlines the powerful influence of rhGH treatment. Before treatment, adults with GH deficiency had reduced exercise performance compared with normal populations. For a given body weight, adults with GH deficiency have reduced lean body mass and excess fat mass (17). Thus the greatest deficit in mean VO, maxbefore rhGH treatment of 27% was noted in comparison to VO 2 maxp where the prediction included weight in the equation, reflecting the abnormality of body composition. In the placebo group at 6 mo, significant reductions in percentage of predicted Tjo2 maxstill existed. Thus unfamiliarity with the test procedure cannot alter the conclusion that patients with GH deficiency have reduced exercise performance. The mechanisms for the increases in Vo2max and anaerobic threshold after rhGH treatment may include alterations in muscle mass or metabolism, 0, delivery, substrate flux, or a combination of these. The changes in vo 2max,when expressed per lean body mass and thigh muscle area, suggest that the improved exercise performance is in part due to increased lean body mass and muscle mass. Although not directly measured in our patients, erythrocyte mass is likely to have increased with rhGH treatment, since GH is known to stimulate erythropoiesis (2). Cardiac output may also have increased in these patients, as suggested by the increase in maximal 0, pulse. The assumption that arteriovenous 0, content is not altered after rhGH treatment requires confirmation before the conclusion that increased 0, pulse accurately reflects an increase in stroke volume in this group of patients. GH has, however, been reported to increase resting cardiac output modestly in normal adults (21) and markedly in a male with dilated cardiomyopathy (5). Static and maximal respiratory function appeared to be unaffected by GH status and did not limit exercise performance. We were unable to confirm the findings of De Troyer et al. (6), who described reduced lung volumes in adults with GH deficiency. In their study, corrections for differences in height were not applied and may flaw the conclusions, since several of their patients were of short stature. If predictions that include height are used, our patients had normal lung volumes, suggesting that any effect of GH deficiency on lung volumes occurs through alterations in body proportions. The relatively modest increases in muscle strength after rhGH treatment in our patients (4) combined with more dramatic improvements in exercise performance suggest that GH treatment enhances relative type I muscle fiber area or metabolism in preference to that of type II fibers. Stimulation of tyrosine kinase activity by insulin-like growth factor I, the mediator of many of GH’s actions, has been reported to be two to three times higher in red as opposed to white muscle fibers in the rat, despite similar insulin-like growth factor receptor populations (26). The effects of GH on carbohydrate and lipid metabo-
AND
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EXERCISE
lism may influence exercise performance. Growth hormone increases hepatic glycogen content (see Ref. 16 for discussion) and may also increase muscle glycogen stores. Even though GH is lipolytic, seen in our study by decreases in fat mass and skinfold thickness (l7), the brief duration of our exercise tests (7) and the minimal changes in fasting FFA levels (17) suggest that the contribution of free fatty acids as a fuel source to the increase in exercise performance is limited. In summary, we have shown that adults with longstanding GH deficiency have reduced maximal exercise performance. After 6 mo of treatment with rhGH, maximal and submaximal exercise performance improved, most likely because of increases in lean body or muscle mass. Contributions from increased cardiac output, erythrocyte mass, or substrate supply require further investigation. We thank Dr. C. Lowy and Prof. H. Jacobs for allowing us to study their patients and Richard Morris and Sue Chinn for statistical advice. We are also grateful to Jennifer Wallace and Geraldine O’Connell for performing the respiratory function tests. This study was supported in part by KabiVitrum, Sweden, which also provided the human growth hormone. F. Salomon was supported by a grant from the Swiss National Foundation for Scientific Research. Present addresses: R. C. Cuneo, Dept. of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane 4102, Australia; F. Salomon, Dept. of Medicine, University Hospital, 8091 Zurich, Switzerland; and C. M. Wiles, Dept. of Medicine, University of Wales College of Medicine, Cardiff CF4 4XN, Wales. Address for reprint requests: P. H. Sonksen, Div. of Medicine, St. Thomas’ Hospital, London SE1 7EH, UK. Received 13 March
1990; accepted in final form 21 September
1990.
REFERENCES 1. BORG, G. A. V. Psychophysical bases of perceived exertion. Med. Sci. Sports Exercise 14: 377-381, 1982. 2. CLAUSTRES, M., P. CHATELAIN, AND C. SULTAN. Insulin-like growth factor 1 stimulates human erythroid colony formation in vitro. J. Clin. Endocrinol. Metab. 65: 78-83, 1987. 3. COTES, J. E. Lung Function (3rd ed.). Oxford, UK: Blackwell, 1975, p. 238-259. 4. CIJNEO, R. C., F. SALOMON, C. M. WILES, R. HESP, AND P. H. S~NKSEN. Growth hormone treatment in growth hormone-deficient adults. I. Effects on skeletal muscle mass and strength. J. Appl. Physiol., 70: 688-694, 1991. 5. CUNEO, R. C., P. WILMSHURST, C. LOWY, G. MCGAULEY, AND P. H. S~NKSEN. Cardiac failure responding to growth hormone. Lancet 1: 838-839, 1989. 6. DE TROYER, A., D. DESIR, AND G. COPINSCHI. Regression of lung size in adults with growth hormone deficiency. Q. J. Med. New Ser. 49: 329-340,198O. 7. FELIG, P., AND J. WAHREN. Fuel homeostasis during prolonged exercise. N. Engl. J. Med. 293: 1078-1084, 1975. 8. FLEG, J. L., AND E. G. LAKATTA. Role of muscle loss in the age-associated reduction in VO, -. J. Appl. physiol. 65: 1147-1151,1988. 9. GOROSTIAGA, E. M., S. M. CZERWINSKI, AND R. C. HICKSON. Acute glucocorticoid effects of glycogen utilization, O2 uptake, and endurance. J. Appl. Physiol. 64: 1098-1106, 1988. 10. HUDGSON, P., AND R. HALL. Endocrine myopathies. In: Skeletal Muscle Pathology, edited by F. L. Mastaglia and J. Walton. Edinburgh: Churchill Livingstone, 1982, p. 393-408. 11. JONES, N. L. Clinical Exercise Testing. Philadelphia, PA: Saunders, 1988, p. 165-173. 12. JBRGENSEN, J. 0. L., S. A. PEDERSEN, L. THEUSEN, J. JBRGENSEN, N. E. SKAKKEBAEK, AND J. S. CHRISTIANSEN. Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1: 12211225,1989. 13. LAVOIE, J.-M., N. DIONNE, R. HELIE, AND G. R. BRISSON. Menstrual cycle phase dissociation of blood glucose homeostasis during exercise. J. Appt. Physiol. 62: 1084-1089, 1987. 14. MOATES, J. M., D. B. LACY, R. E. GOLDSTEIN, A. D. CHERRING-
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TON, AND D. H. WASSERMAN. Metabolic role of the exercise-induced increment in epinephrine in the dog. Am. J. Physiol. 255 (Endocrinol. Metab. 18): E428-E436, 1988. 15. MOORADIAN, A. D., J. E. MORLEY, AND S. G. KORENMAN. Biological actions of androgens. Endocr. Reu. 8: l-28, 1987. 16. PRESS, M. Growth hormone and metabolism. Diabetes Metab. Rev. 4: 391-414,1988. 17. SALOMON, F., R. C. CUNEO, R. HESP, AND P. H. S~NKSEN. The
effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N. Engl. J. Med. 321: 1797-1803,1989. 18. SELLERS, T. L., A. W. JAUSSI, H. T. YANG, R. W. HENINGER, AND W. W. WINDER. Effect of the exercise-induced increase in glucocorticoids on endurance-in the rat. J. Appl. Physiol. 65: 173-178, 1988. 19. SHEPARD, R. J., E. BOUHLEL,
Muscle mass as a factor limiting
H. VANDEWALLE, AND H. MONOD. physical work. J. Appl. Physiol. 64:
1472-1479,1988. 20. TAYLOR, C. B., T. COFFEY, K. BERRA, R. IAFFALDANO, AND W. L. HASKELL. Seven-day activity and self-report
AND
to direct measure of physical activity. Am. J. Epidemiol.
120: 8l8-
824, 1984. 21. THUESEN, L., J. S. CHRISTIANSEN, K. E. SORENSEN, J. 0. L. JORGENSEN, H. ORSKOV, AND P. HENINGSEN. Increased myocardial
22. 23.
24.
25. 26.
K. CASEY, compared
EXERCISE
contractility following growth hormone administration in normal man. Dan. Med. Bull. 35: 193-196, 1988. VON DOEBLN, W. Maximal oxygen intake, body size, and total haemoglobin in normal man. Acta Physiol. Scand. 38: 193-199, 1956. WASSERMAN, K., B. J. WHIPP, S. N. KOYAL, AND W. L. BEAVER. Anaerobic threshold and respiratory gas exchange during exercise. J. Appl. Physiol. 35: 236-243, 1973. WILSON, P. W. F., R. S. PAFFENBARGER, JR., J. N. MORRIS, AND R. J. HAVLIK. Assessment methods for physical activity and physical fitness in population studies: report of NHLBI workshop. Am. Heart J. 111: 1177-1191, 1986. WILSON, J. D., AND J. E. GRIFFIN. The uses and misuse of androgens. Metab. Clin. Exp. 29: 1278-1295, 1980. ZORZANO, A., D. E. JAMES, N. B. RUDERMAN, AND P. F. PILCH. Insulin-like growth factor 1 binding and receptor kinase in red and white muscle. FEBS Lett. 234: 257-262, 1988.
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WILES,
Divisions of Medicine and Neurology, United Medical and Dental Schools of Guy’s and St. Thomas’ Hospitals, St. Thomas’ Hospital, London SE1 7EH; and Division of Radio-Isotopes, Medical Research Council, Northwick Park, Harrow, Middlesex HA1 3UJ, United Kingdom CUNEO, Ross C., FRANCO SALOMON, C. MARK WILES, RICHARD HESP, AND PETER H. MNKSEN. Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance. J. Appl. Physiol. 70(2): 695-700, 1991.Growth hormone (GH) treatment in adults with GH deficiency increases lean body mass and thigh muscle cross-sectional area. The functional significance of this was examined by incremental cycle ergometry in 24 GH-deficient adults treated in a double-blind placebo-controlled trial with recombinant DNA human GH (rhGH) for 6 mo (0.07 U/kg body wt daily). Compared with placebo, the rhGH group increased mean maximal 0, uptake (00, m,) (+406 t 71 vs. +133 t 84 ml/min; P = 0.016) and maximal power output (+24.6 t 4.3 vs. +9.7 t, 4.8 W; P = 0.047), without differences in maximal heart rate or ventilation. Forced expiratory volume in 1 s, vital capacity, and corrected CO gas transfer were within normal limits and did not change with treatment. Mean predicted Vozmax, based on height and age, increased from 78.9 to 96.0% in the rhGH group (compared with 78.5 and 85.0% for placebo; P = 0.036). The anaerobic ventilatory threshold increased in the rhGH group (+159 t 39 vs. +l t 51 ml/min; P = 0.02). The improvement in VO 2maxwas noted when expressed per kilogram body weight but not lean body mass or thigh muscle area. We conclude that rhGH treatment in adults with GH deficiency improves and normalizes maximal exercise performance and improves submaximal exercise performance and that these changes are related to increases in lean body mass and muscle mass. Improved cardiac output may also contribute to the effect of rhGH on exercise performance. somatotropin; maximal oxygen uptake; anaerobic threshold; lean body mass ADULT PATIENTS with hypopituitarism
often complain of lethargy and fatigability despite optimal conventional pituitary hormone replacement. Because of the absence of the potent anabolic actions of growth hormone (GH), adults with GH deficiency have an -9% reduction in lean body mass compared with that predicted from sex, age, and body size (17). Since exercise capacity is related to indexes of lean body mass (8,19,22), the complaints of such patients may reflect alterations in body composition and hence impaired exercise capacity. With the advent of recombinant DNA technology, sufficient supplies of human GH have become available, allowing the possibility of treatment of patients with GH deficiency other than those in childhood. We have previously described the increases in lean body mass, 0161-7567/91
$1.50 Copyright
thigh muscle mass (as cross-sectional area on computerized tomographic scans), and limb girdle strength following recombinant DNA human GH (rhGH) treatment in adults with GH deficiency (4,17). If functional improvements also result, the cost of such treatment may be offset by increased occupational productivity. We now report the results of exercise testing in response to rhGH treatment in adults with GH deficiency. METHODS
Patients were GH deficient and, if necessary, received stable and clinically appropriate pituitary hormone replacement for at least 12 mo before entry to the trial. Entry requirements have been described previously (4, 17). Treatment with rhGH (Genotropin, KabiVitrum, Sweden) was given in a double-blind placebo-controlled fashion for 6 mo at 0.07 U/kg body wt as a single self-administered dose at 2000 h each day. Studies were performed at baseline and after 3 and 6 mo of treatment. Venous blood samples were taken on the morning of the test after an overnight fast. Exercise tests were usually performed later that afternoon at least 3 h after food. Patients requiring glucocorticoid replacement were transferred to cortisone acetate for the study day, taking 12.5 mg 2 h before the morning blood sampling and 12.S 25 mg l-2 h before the exercise test. Women were studied in the first half of their menstrual cycle when appropriate. Measurements of muscle mass (0, 3, and 6 mo) and lean body mass (0 and 6 mo) were made within 24 h of the exercise test. Exercise testing. After measurement of height (to the nearest 0.1 cm, Harpenden Staediometer) and weight (to the nearest 0.1 kg) patients were positioned on a frictionbraked cycle ergometer (Tunturi model W, Piispanristi, Finland). Calibration of the braking force was performed to the manufacturer’s instructions. Toe clips were fitted, and the seat height was optimized. The same seat height was used at subsequent tests. Familiarity with the cadence (chosen by the patient at either 50 or 60 Hz) and work loads to be anticipated initially preceded a resting period, during which the patient adjusted to breathing with a mouthpiece. 0, consumption (iTo,), CO, production (VCOJ, and ventilatory volumes were measured with a metabolic measurement cart (MMC, Horizon, Beckman Instruments, Anaheim, CA). This machine uses infrared CO, and paramagnetic 0, analyzers and a turbine
0 1991 the American
Physiological
Society
695
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696
GROWTH
HORMONE
pneumotachograph recording data every 100 ms. Calibration against standard gases (16% 0, and 4% CO,), volume (900 ml), operating temperature, and barometric pressure was performed immediately before each test. Patients did not start exercising until the respiratory exchange ratio (RER) approached 0.8. Work rate was set at 50 W for the 1st min and increased by 25 W each minute until a symptom-limited maximum was reached. Patients were vocally encouraged to maintain the chosen cadence and to maximize effort. Heart rate was recorded by surface electrocardiography during the last 5 s of each minute. A 19-point Borg scale was used to assess subjective exertion at the 6-mo test (1). In view of the abnormal body composition of these patients, a number of different methods for predicting maximal 0, uptake (TO, max)were compared (11) males:
V02
females: males:
VO,
m8x= 5.41 X Ht - 0.025 X age - 5.66 = 3.01 X Ht - 0.017 X age - 2.56 max= 0.83 X Ht2a7 X (1 - 0.007 X age)
= 0.62 X Ht2a7 X (1 - 0.007 X age) males: V02max = 3.45 X It- 0.028 X age + 0.022 x Wt - 3.76 females:
females:
It - 0.018
X
age
(1) (2)
(3)
+ 0.010 x Wt - 2.26 where Ht is height and Wt i s body weight. Predicted maximums for heart rate, ventilatory volumes, and 0, pulse used standard equations (11). Maxima1 voluntary ventilation represented forced expiratory volume in 1 s (FE&) multiplied by 35. 0, pulse was defined as VO, divided by heart rate and provides an approximation of stroke volume if arteriovenous 0, content at maximal exercise is assumed to differ little between individuals (11). The ventilatory anaerobic threshold was calculated from a plot of vo2 vs. ko2 and minute ventilation (VE) (23). Manual curve fitting was performed by one observer blinded as to the origin of the graph being assessed. The first deviation from the initial straight-line relationship was considered to be the anaerobic threshold. Although similar results were obtained from the VCO, vs. VO, plots alone, results reported are an average of the thresholds obtained from the ho, and VE plots inasmuch as this improved reproducibility. The coefficient of variation for repeat blinded measurements on 22 paired traces was 15.5%. FEV, and forced vital capacity (FVC) were measured with a wedge spirometer (Vitalograph). CO gas transfer was measured by the single- #breath technique and corrected for lung volumes (Kco; Ref. 3). Respiratory values were compared with standard predictions based on we and height (3). Measurements of lean body mass were performed at the Northwick Park Hospital using the total body potassium counter, and computerized tomographic cross-sectional area of the dominant midthigh was performed as previously reported (4, 17). Activity was assessed before
AND
EXERCISE
each visit by daily recordings averaged over 1 wk using a mechanical pedometer (Aurora, Japan) and at the 6-mo visit with a detailed activity questionnaire [7-day physical activity recall (20, 24)]. Statistics. Results are reported as means t SE. Comparisons between treatment groups were performed using analysis of covariance on the 6-mo data, with baseline data as the covariate. Significance was recognized at the 5% level. Relationships between single variables before treatment were explored with simple linear regressions and changes in variables after treatment with multiple linear regressions, with treatment as a stratifying or binary variable. For changes with more than one significant association, multiple linear regressions were also used, with treatment code as a stratifying variable. Treatment-variable interaction was explored and excluded in each case. Coefficient of variation was calculated using the SD of the differences between paired observations divided by the mean of all the observations. RESULTS
The demographic data have been reported previously (4, 17). Exercise tests were completed uneventfully, except that one 24-yr-old female in the placebo group fainted at the end of the test at the 3-mo visit. She recovered spontaneously. On the basis of subjective assessment, tests were considered maximal or close to maximal by the attendant clinicians. No patient showed plateauing of 60,. One male in the placebo group produced submaximal tests on each occasion because of intolerance of the mouthpiece (RERs at entry and 3 and 6 mo were 0.95, 1.01, and 1.02, respectively). Results are reported including all data, since exclusion of this patient did not alter the conclusions. Compared with results from the placebo group, 60, max increased 17% from 1.88 t 0.17 to 2.34 t 0.20 l/min in the rhGH group (placebo 1.84 t 0.17 to 1.98 t 0.13 l/min at 0 and 6 mo, respectively; P = 0.016; Fig. 1). The increase in vo 2maxwas associated with a significant increase in maximal power output (rhGH 148.6 t 13.2 to 177.5 t 16.4 W and placebo 138.7 t 9.3 to 148.4 t 9.2 W at entry and 6 mo, respectively; P = 0.047, Fig. 1). Compared with predicted values, VO, maxfor the whole study group before treatment was significantly below normal (Table 1). By use . of predictions based on height, weight, and age, vo 2max for the rhGH group increased into the normal range by 6 mo. This increase in Vo2max was not associated with changes in maximal heart rate, ventilatory volume, or maximal RER between the two groups (Table 2). Similarly, subjective assessment of the severity of effort did not differ between the two groups at the final test, with a mean Borg rating of 17 of 19 for both groups. As an index of stroke volume, maximal 0, pulse increased in the rhGH group (P = 0.025, Table 2). Even though the percentage of maximal predicted 0, pulse in the rhGH group increased from 91.0 t 5.0 at entry to 103.3 t 6.5 at 6 mo (placebo 90.9 t 5.6 to 94.0 t 3.2, respectively), the difference between the groups failed to reach statistical significance (P = 0.084). The anaerobic threshold increased in the rhGH group
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GROWTH
HORMONE
2.0
AND
697
EXERCISE
7.8
38.3 t 1.7 kcal/kg for the rhGH and placebo groups, respectively; P = 0.33). Correlation analysis showed significant associations between change in VO, maxand change in maximal power output (P = 0.018) but not with changes in lean body mass, thigh muscle area, or insulin-like growth factor I nor with sex, age, or past history of Cushing’s disease. The increase in anaerobic threshold correlated with the increase in 60~~~ (P = 0.027).
1.6
DISCUSSION
2.6 2.4 2.2 2.0
Or
d
i
i
180 160 -
0 3I
I
I
1
0
3
6
Months FIG. 1. Changes in maximal
O2 uptake (top) and power output (bottom) after growth hormone treatment (closed symbols) or placebo (open symbols). No significant differences existed between groups at baseline.
(Table 2). There was no change in the anaerobic threshold as a percentage of vo2 m8X(57 t 3 to 53 t 3 and 62 t 3 to 57 t 2% in the rhGH and placebo groups, respectively). The heart rate at the anaerobic threshold was not different between the groups (rhGH 119 t 5,126 t 5, and 123 t 5 beats/min and placebo 133 t 6,128 t 5, and 132 t 6 beats/min at 0, 3, and 6 mo, respectively). Changes in 60~~~~ expressed in terms of body weight, lean body mass, and thigh muscle cross-sectional area are shown in Table 3. When expressed per kilogram of body weight, VO, m8x increased significantly after rhGH treatment (P = 0.046). The anaerobic threshold expressed in terms of body weight (P = O.lO), lean body mass (P = 0.99), or thigh muscle cross-sectional area (P = 0.99) did not increase. Results of respiratory function tests are shown in Table 4. For the whole group before treatment, FEV, and FVC were not significantly different from normal. Reductions in gas transfer disappeared when corrected for lung volume. After treatment, no change was noted in any of these variables. Pedometer recordings did not change significantly between the groups (rhGH 7.0 t 0.6,5.9 t 0.8,7.5 t 1.3, and 9.5 + 1.3 km andplacebo 6.1 t 1.2,9.1+ 1.9,5.3 t 0.7, and 6.1 z 0.4 km at entry and 1,3, and 6 mo, respectively; P = 0.3). Daily activity at 6 mo, assessed by questionnaire, was not different between the groups (41.1 t 2.5 and
We have shown that adults with long-standing severe GH deficiency exhibit reduced maximal exercise performance that can be improved after 6 mo of treatment with rhGH. The 17% increase in VO, maxafter rhGH treatment was paralleled by an increase in maximal power output. Our conclusion that power output did increase is supported by two observations. Jorgensen et al. (12) reported an increase in maximal power output using an electromechanically braked ergometer in GH-de@cient adults treated with rhGH for 4 mo. Second, for VO, to increase without a concomitant increase in power output, either a hypermetabolic state or a major reduction in mechanical efficiency must be proposed. We have excluded the former by showing that basal metabolic rate per kilogram of lean body mass was not different after 6 mo (17) and saw no evidence for the latter. During maximal exercise no differences were noted between treatment groups with respect to objective signs of effort (heart rate, ventilatory volumes, and RER) or the subjective perception of exertion. The increases in objective signs of effort seen in both groups over the 6 mo, although greater in magnitude than expected for normal individuals (11), are consistent with familiarity gained with the testing procedure and equipment for novices and underscore the importance of a placebo-treated control group. Our data are in conflict with a reported increase in maximal and resting heart rates after rhGH treatment (l2), for which no obvious explanation exists. The increase in VO 2maxwas paralleled by an increase in the ventilatory anaerobic threshold. This observation is supported by the improvement in exercise performance without an increase in the subjective sensation of effort. These changes are important for daily activity. For example, the anaerobic threshold occurred at VO, near 1.0 l/ TABLE
1. Percentage
Method
Treatment
1
rhGH Placebo rhGH’ Placebo rhGH Placebo
2 3
of predicted Baseline
maximal
O2 uptake
6 mo
78.9t4.5*
96.Ok6.3
78.5+5.1t
84.9t2.6*
80.0t4.6” 79.8k5.4” 72.2t3.7” 73.1t4.3*
98.7k6.4 86.0+,2.9* 87.3+_4.7$ 78.9t2.8*
P
0.036 0.018 0.048
Values are means t SE. Methods of calculating predicted VO, - are detailed in text, but method 1 includes height and age, method 2 includes height2e7 and age, and method 3 includes height, weight, and age. Comparisons of differences from baseline to 6-mo values between the 2 groups (P) were performed with analysis of covariance. No significant differences existed between groups at baseline. Other comparisons performed with a single-sample t test against a predicted 100% are indicated: * P < 0.001; 3-P < 0.002; 5 P < 0.001.
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698 TABLE
GROWTH
2. Maximal
heart rate, ventilation,
HORMONE
respiratory
AND
EXERCISE
exchange ratio, 0, pulse, and vent&tory
Treatment
Baseline
rhGH Placebo rhGH
156t6 1611r5 84.2tl.8 86.4tl.8 58.6S.O 56.5k5.4 52.4t2.5 48.lt3.9 1.10*0.02 l.llt0.02 12.ltl.l 11.6tl.2 1.05+0.08 l.lOt0.07
3 mo
anaerobic
threshold
6mo
P
168t6 168t5 90.3t2.6 90.5t2.0 78.4k7.6 70.4t3.9 67.5t5.4 58.9t4.0 1.2lt0.03 1.2lt0.03 13.9tl.O 12.0tl.O 1.22kO.09 l.lOt0.05
0.82
Values are means & SE. Comparisons of differences from baseline to 6-mo values between 2 groups (P) were performed covariance. No significant differences existed between groups at baseline.
with analysis of
Maximal heart rate beats/min %pred
Placebo Maximal
ventilation,
l/min
rhGH Placebo rhGH Placebo rhGH Placebo rhGH
Maximal voluntary ventilation, %pred Maximal respiratory exchange ratio Maximal O2 pulse, ml/beat Anaerobic
threshold,
Placebo rhGH Placebo
l/min
168t4 167-+4 90.7tl.9 89.9H.9 72.lk6.5 68.2k6.0 62.8k4.1 59.4t5.4 1.14t0.03 1.18t0.04 13.7kl.l 11.8tl.O 1.25t0.09 1.08t0.08
0.89 0.41 0.31 0.96 0.03 0.02
min, equivalent to -60 W or similar to walking on a flat production during exercise would have been reduced, surface at 6 km/h. Thus, if a given task can be done with leading to reduced gluconeogenesis and hepatic glucose production during prolonged exercise (14). Thus the duless physiological stress, these patients may be inclined to increase their work productivity. Indeed, many of the ration of exercise and small number of such patients are patients spontaneously described an increase in the ease unlikely to influence the conclusions regarding the effect of completing daily tasks. of rhGH treatment. We have. been careful to control for factors other than Cyclic variations in ovarian steroids affect glucose hoGH treatment that may have spuriously altered the con- meostasis during exercise (13), but all our female subclusions. Patients were receiving optimal conventional jects were studied during the follicular phase or first half pituitary hormone replacement for 12 mo before entering of an artificial menstrual cycle. Testosterone replacethe trial, minimizing the detrimental effects of abnormal ment in hypogonadal males is likely to increase lean body glucocorticoid or thyroid hormone status on muscle physiology (see Ref. 10 for review). We attempted to mimic TABLE 4. Respiratory function in adults with growth the acute exercise-induced increase in glucocorticoids with a dose of a short-acting steroid, cortisone acetate, to hormone deficiency before and after rhGH produce a peak of absorption that coincided with maxi- or placebo treatment mal exercise. Variations in corticosteroid absorption Treatment Baseline 6mo were unlikely to have major influences on our results, since the effects of endogenous glucocorticoids seem to FEV, liters rhGH 3.08kO.30 3.45kO.27 be most prominent in exercise tests of longer duration Placebo 3.29t0.22 3.52t0.20 than ours (9,18). Small increases in free triiodothyronine %pred rhGH 92.lk6.1 101.4k4.8 were noted after 1 mo of rhGH treatment (17). Because Placebo 99.0t5.3 106.4k4.9 FVC these changes occurred within the normal reference liters rhGH 3.97kO.32 4.37t0.32 range (or just above in three cases) and had resolved by 3 Placebo 3.9420.26 4.12t0.24 mo, adverse influences on the rhGH group’s exercise per%pred rhGH 94.8t5.6 102.lt5.2 formance at 6 mo are unlikely. In the three patients with Placebo 92.5t4.2 97.323.9 bilateral adrenalectomy, increased adrenal epinephrine FEVJFVC, % rhGH 76.9t2.4 79.2k2.4 PEFR ml/s
TABLE 3. Maximal 0, uptake expressed per body weight, lean body mass, and cross-sectional area of thigh muscle
%pred
ml/kg VO, -/lean body mass, ml/kg VO, -/thigh muscle area, ml/cm2
Treatment
Baseline
3 mo
rhGH Placebo rhGH Placebo rhGH Placebo
22.7kl.5 24.222.3 35.9tl.7 38.923.0 14.5t0.6 15.4tl.l
27.5kl.8 26.41k2.2 16.4kO.9 17.8tl.5
6 mo
27.8tl.6 25.8tl.7 40.571.6 41.7U.8 16.6t0.9 17.ktl.O
P
0.05
Transfer mmol
0.88
%pred
0.96
Values are means k SE. Lean body mass was measured by total body potassium content (&K) and cross-sectional area of thigh muscle by computerized tomography of dominant midthigh. Comparisons of differences from baseline to 6-mo values of 2 groups (P) performed with analysis of covariance. No significant differences existed between groups at baseline.
K co mmol %pred
l
l
factor min-’ . kPa-’
min-’
l
kPa-’
l
1-l
Placebo
83.8kl.4
85.7kl.l
rhGH Placebo rhGH Placebo
46Ok38 482+30 89.3+4.5* 93.6t4.1
459k27 468,+25 88.9t4.4 90.U3.6
rhGH Placebo rhGH Placebo
8.55kO.56 8.46kO.73 91.2+6.0* 89.4t5.9
8.5lkO.58 8.06kO.60 91.927.4 85.2t4.4
rhGH Placebo rhGH Placebo
1.71&0.09 1.7lt0.09 99.1t4.0 98.9k5.0
1.64t0.08 1.74t0.09 95.2t5.7 101.4t5.6
Values are means t SE. PEFR, peak expiratory flow rate. No significant differences existed between groups at baseline. * Differences between means of both groups before treatment compared with 100% with a single-sample t test (P c 0.02).
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GROWTH
HORMONE
mass through effects on protein synthesis (see Refs. 15 and 25 for review). Testosterone replacement was stable before and unchanged during the trial. To minimize the effect of training, we encouraged our patients not to alter their habitual activity during the trial. This is reflected in the pedometer and activity questionnaire data. The normalization of VO 2mmwithout a training effect underlines the powerful influence of rhGH treatment. Before treatment, adults with GH deficiency had reduced exercise performance compared with normal populations. For a given body weight, adults with GH deficiency have reduced lean body mass and excess fat mass (17). Thus the greatest deficit in mean VO, maxbefore rhGH treatment of 27% was noted in comparison to VO 2 maxp where the prediction included weight in the equation, reflecting the abnormality of body composition. In the placebo group at 6 mo, significant reductions in percentage of predicted Tjo2 maxstill existed. Thus unfamiliarity with the test procedure cannot alter the conclusion that patients with GH deficiency have reduced exercise performance. The mechanisms for the increases in Vo2max and anaerobic threshold after rhGH treatment may include alterations in muscle mass or metabolism, 0, delivery, substrate flux, or a combination of these. The changes in vo 2max,when expressed per lean body mass and thigh muscle area, suggest that the improved exercise performance is in part due to increased lean body mass and muscle mass. Although not directly measured in our patients, erythrocyte mass is likely to have increased with rhGH treatment, since GH is known to stimulate erythropoiesis (2). Cardiac output may also have increased in these patients, as suggested by the increase in maximal 0, pulse. The assumption that arteriovenous 0, content is not altered after rhGH treatment requires confirmation before the conclusion that increased 0, pulse accurately reflects an increase in stroke volume in this group of patients. GH has, however, been reported to increase resting cardiac output modestly in normal adults (21) and markedly in a male with dilated cardiomyopathy (5). Static and maximal respiratory function appeared to be unaffected by GH status and did not limit exercise performance. We were unable to confirm the findings of De Troyer et al. (6), who described reduced lung volumes in adults with GH deficiency. In their study, corrections for differences in height were not applied and may flaw the conclusions, since several of their patients were of short stature. If predictions that include height are used, our patients had normal lung volumes, suggesting that any effect of GH deficiency on lung volumes occurs through alterations in body proportions. The relatively modest increases in muscle strength after rhGH treatment in our patients (4) combined with more dramatic improvements in exercise performance suggest that GH treatment enhances relative type I muscle fiber area or metabolism in preference to that of type II fibers. Stimulation of tyrosine kinase activity by insulin-like growth factor I, the mediator of many of GH’s actions, has been reported to be two to three times higher in red as opposed to white muscle fibers in the rat, despite similar insulin-like growth factor receptor populations (26). The effects of GH on carbohydrate and lipid metabo-
AND
699
EXERCISE
lism may influence exercise performance. Growth hormone increases hepatic glycogen content (see Ref. 16 for discussion) and may also increase muscle glycogen stores. Even though GH is lipolytic, seen in our study by decreases in fat mass and skinfold thickness (l7), the brief duration of our exercise tests (7) and the minimal changes in fasting FFA levels (17) suggest that the contribution of free fatty acids as a fuel source to the increase in exercise performance is limited. In summary, we have shown that adults with longstanding GH deficiency have reduced maximal exercise performance. After 6 mo of treatment with rhGH, maximal and submaximal exercise performance improved, most likely because of increases in lean body or muscle mass. Contributions from increased cardiac output, erythrocyte mass, or substrate supply require further investigation. We thank Dr. C. Lowy and Prof. H. Jacobs for allowing us to study their patients and Richard Morris and Sue Chinn for statistical advice. We are also grateful to Jennifer Wallace and Geraldine O’Connell for performing the respiratory function tests. This study was supported in part by KabiVitrum, Sweden, which also provided the human growth hormone. F. Salomon was supported by a grant from the Swiss National Foundation for Scientific Research. Present addresses: R. C. Cuneo, Dept. of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane 4102, Australia; F. Salomon, Dept. of Medicine, University Hospital, 8091 Zurich, Switzerland; and C. M. Wiles, Dept. of Medicine, University of Wales College of Medicine, Cardiff CF4 4XN, Wales. Address for reprint requests: P. H. Sonksen, Div. of Medicine, St. Thomas’ Hospital, London SE1 7EH, UK. Received 13 March
1990; accepted in final form 21 September
1990.
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