Measures of submaximal aerobic performance evaluate and predict functional response to growth hormone (GH) treatment in GH-deficient adults

The impact of GH on functional performance in GH-deficient adults is not well understood. To investigate the effects of GH on skeletal muscle, physical, and functional capacity, we randomized 28 GH-deficient adults to receive 3 months of recombinant human GH [rhGH: somatotropin, 6.25 microg/kg lean body mass (LBM) for 1 month, 12.5 microg/kg LBM thereafter] in a double-blind placebo-controlled crossover trial. We measured muscle fiber type, size, and insulin-like growth factor I messenger RNA, aerobic capacity [maximal oxygen uptake (VO2max), ventilation threshold (VeT)], isokinetic strength, oxygen-cost-of-walking at normal and fast speeds, and fatigue determined by the profile of mood states questionnaire. As expected, GH treatment decreased body fat, increased LBM, increased muscle fiber size, and increased muscle insulin-like growth factor-I messenger RNA 5-fold; however, muscle strength remained unchanged. At baseline, VeT occurred at a high percentage of maximal VO2max (73.3% +/-2.6) because of low VO2max (1.74+/-0.1 L/min or 20.7+/-1.3 mL/ kg x min). Walking required high oxygen consumptions representing from 83+/-4% of VeT at normal speeds to 120+/-5% of VeT at fast speeds. After rhGH, there was a significant (P = 0.03) increase in VeT (18%), compared with placebo. This was paralleled by a nonsignificant rise in VO2max. Functionally, rhGH treatment decreased the oxygen cost of walking, relative to VeT, at normal (14% decrease, P = 0.019) and fast (21% decrease, P = 0.004) SPW speeds. A 3-variable model (baseline fast SPW speed, VeT/VO2max, and VeT) accounted for 39% of the variance of change in self-reported fatigue. These data indicate that GH-deficient adults require a high fraction of VeT for daily activities, explaining the perception of increased fatigue and impaired physical performance. The actions ofrhGH on muscle fiber size translate into physiological improvement in submaximal aerobic capacity and result in functional improvement in walking ability but do not necessarily alter strength. Thus, measures of effort-independent submaximal aerobic performance provide novel objective determinants of functional impairment and fatigue and can be used to evaluate and predict response to GH treatment.     

Growth hormone replacement therapy in adults with growth hormone deficiency improves maximal oxygen consumption independently of dosing regimen or physical activity

CONTEXT: Several studies have demonstrated an improvement in aerobic exercise capacity with 6 months of GH replacement in adults with GH deficiency (GHD). OBJECTIVE: The objective of the study was to determine whether improvements in aerobic exercise capacity with GH treatment in adults with GHD are related to changes in physical activity or affected by the GH dosing regimen. DESIGN: This was a randomized, two-arm, parallel, open-label study. SETTING: The study was conducted at five academic medical centers with exercise physiology laboratories. SUBJECTS: Study subjects were adults (n = 29) with GHD due to hypothalamic-pituitary disease. INTERVENTIONS: The intervention was GH replacement therapy, administered either as a fixed body weight-based dosing regimen as an individualized dose titration regimen for 32 wk. MAIN OUTCOME MEASURES: Maximal oxygen consumption (VO2 max) and oxygen consumption (VO2) at the lactate threshold, ventilatory threshold using a cycle ergometry protocol, and weekly energy expenditure (physical activity questionnaire), assessed at baseline and end point, were measured. RESULTS: In the group as a whole, VO2 max increased significantly (by 9%) from baseline (19.1+/- 0.89 ml/kg.min) to end point (21.6 +/- 1.23 ml/kg.min, P = 0.010). Compared with baseline, VO2 max also changed significantly within the individualized dose titration regimen group (+2.5 +/- 0.98 ml/kg.min, P =0.034) but not within the fixed body weight-based dosing regimen group (+1.2 +/- 0.78 ml/kg.min, P = 0.15), although these changes from baseline were not significantly different between the two groups. VO2 at lactate threshold, VO2 at ventilatory threshold, and weekly energy expenditure also did not change. CONCLUSIONS: GH replacement therapy in GH-deficient adults improved VO2 max similarly with both dosing regimens, without any influence of physical activity. There was no effect on submaximal exercise performance.     

Effect of timolol on cardiopulmonary exercise performance in men after myocardial infarction.

The effect of the nonselective beta blocker timolol on maximal cardiopulmonary exercise performance was evaluated in 28 men with previous myocardial infarction without effort angina (mean age 63 +/- 8 years). Patients were randomized to placebo or timolol (10 mg twice daily) for 4 weeks and then crossed over to the alternative therapy in a double-blind manner. At the completion of each treatment period, patients underwent symptom-limited maximal cardiopulmonary exercise on a cycle ergometer. Exercise time, heart rate, oxygen consumption (VO2), oxygen (O2) pulse and respiratory exchange ratio were measured at peak exercise and at a submaximal exercise level defined at a respiratory exchange ratio of 1.00. Timolol treatment reduced peak heart rate from 153 +/- 11 to 102 +/- 14 beats/min (-33%, p less than 0.001). Exercise time decreased from 680 +/- 91 to 633 +/- 78 seconds (-7%, p less than 0.001). Peak VO2 decreased from 25.3 +/- 4.7 to 21.4 +/- 3.5 ml/min/kg (-15%, p less than 0.001). O2 pulse increased from 12.9 +/- 1.9 to 16.7 +/- 2.3 ml/beat (+29%, p less than 0.001). Peak respiratory exchange ratio did not change significantly, indicating comparable effort. At submaximal exercise, defined at a respiratory exchange ratio of 1.00, there was no difference in exercise time between placebo and timolol. Heart rate decreased with timolol compared with placebo, from 126 +/- 16 beats/min by 31% (p less than 0.001), VO2 decreased from 18.5 +/- 4.3 ml/min/kg by 10% (p less than 0.001), O2 pulse increased from 11.5 +/- 2.0 ml/beat by 30% (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Growth hormone treatment improves peripheral muscle oxygen extraction-utilization during exercise in patients with human immunodeficiency virus-associated wasting: a randomized controlled trial

The arteriovenous oxygen difference (a-vO(2) difference), a measure of peripheral muscle oxygen extraction-utilization during exercise, is reduced in antiretroviral-treated patients with human immunodeficiency virus (HIV), thus causing a shift in the cardiac output-oxygen consumption (Q-VO(2)) relationship. We investigated the impact of recombinant human GH (rhGH) treatment on a-vO(2) difference and the Q-VO(2) relationship during submaximal exercise by randomizing 12 HIV-infected patients (mean +/- sem: age, 43.3 +/- 1.5 yr; body mass, 69.5 +/- 2.9 kg; body mass index, 22.4 +/- 0.9 kg/m(2); maximum oxygen consumption, 33.6 +/- 1.5 ml/kg x min), with documented unintentional weight loss (>or=10% within the preceding 12 months) despite antiretroviral therapy, to receive 3 months of rhGH (6 mg/d) in a double-blind, placebo-controlled, cross-over trial. We assessed Q (determined noninvasively using CO(2) rebreathing), and subsequently a-vO(2) difference, from Q-VO(2) relationships. At study entry, the mean slope (8.1 +/- 1.0 liters/min x 1-liter increase in VO(2)) and intercept (3.1 +/- 1.3 liters/min), generated from each patient's Q-VO(2) relationship, were greater and lower, respectively, than those reported for healthy individuals (6.0 and 4.0, respectively), thereby indicating a deficit in the a-vO(2) difference. After 3 months of rhGH treatment, the slope decreased to 7.0, and the intercept increased to 3.5. After 1 month of rhGH treatment, the a-vO(2) difference (at a VO(2) of 1250 ml/min) significantly (P < 0.05) increased (17.1 +/- 8.9%) from baseline (9.92 +/- 0.51 ml/dl) and remained elevated (10.39 +/- 0.48 ml/dl) after 3 months of treatment. No significant changes were seen with placebo. Therefore, treatment with rhGH leads to an improvement in peripheral muscle oxygen extraction-utilization and the Q-VO(2) relationship during exercise in patients with HIV-associated wasting despite antiretroviral therapy.     

Ventilation threshold as a measure of impaired physical performance in adults with growth hormone excess

OBJECTIVE: Fatigue is a prominent symptom among patients with GH excess and acromegaly. Identifying the physiological basis of such complaints and obtaining objective measures to quantify their severity remains an ongoing challenge. We investigated whether submaximal measures of aerobic performance can be used to assess GH excess-associated fatigue objectively. DESIGN AND PATIENTS: To investigate this possibility we examined the relation between physical function and physical capacity in 12 patients with active acromegaly and persistent fatigue before and after 3 and 6 months of treatment with the long-acting somatostatin analogue octreotide (LAR(R)). MEASUREMENTS: Heart rate (HR) and rating of perceived exertion (RPE using Borg's 10-point scale) were measured during a 160-metre self-paced walk test (SPW). Maximum oxygen uptake (VO2max) and ventilation threshold (VeT: a measure of work rate when breathlessness develops) were measured during a progressive treadmill test to fatigue or symptom-limited maximum. The Profile Of Mood States questionnaire (POMS) was used to quantify subjective feelings of fatigue and vigour. Morning fasting levels of GH and IGF-I were measured using immunoassay of serum samples. RESULTS: SPW speed at a fast pace of 1.69 +/- 0.18 m/s was achieved with higher than normal HR (112 +/- 15/min; normal = 102) and RPE (2.4 +/- 1.2). Similar to GH-deficient adults, VO2max (22.6 +/- 6.4 ml.kg-1.min-1; normal approximately 30 ml.kg-1.min-1) and VeT (13.1 +/- 2.9 ml.kg-1.min-1; predicted normal approximately 16 ml.kg-1(min-1) were low. However, VeT occurred at a normal fraction of VO2max (VeT/VO2max = 0.58). VeT was significantly increased and plasma IGF-I levels reduced following 3 and 6 months of octreotide LAR(R) treatment. Reduction in circulating IGF-I levels was correlated with improvement in reported vigour (r = 0.85) and VeT (r = 0.65) (P < 0.05). CONCLUSIONS: Our findings demonstrate impairment in physical function and physical capacity consistent with the perception of increased fatigue among acromegalic patients. These objective measures of compromised physical function are similar to the changes that we have reported previously in adults with GH deficiency. Taken together, these data suggest that a narrow window for GH/IGF-I levels is required to maintain optimal physical function.     

Enhancement of the peripheral sensitivity to growth hormone in adults with GH deficiency

OBJECTIVE: Adults with severe GH deficiency (GHD) need recombinant human growth hormone (rhGH) replacement to restore body composition, structure functions and metabolic abnormalities. The optimal rhGH dose for replacement has been progressively reduced to avoid side effects. The aim of the present study was to define the minimal rhGH dose able to increase both IGF-I and IGF binding protein (BP)-3 levels in GHD and to verify the possible change in GH sensitivity. DESIGN AND PATIENTS: To this goal, we studied the effect of 4-day treatment with 3 rhGH doses (1.25, 2.5 and 5.0 microg/kg/day) on IGF-I and IGFBP-3 levels in 25 panhypopituitary adults with severe GHD (12 males and 13 females, age: 44.5+/-3.0 years, body mass index (BMI): 27.0+/-0.9 kg/m(2)) and 21 normal young adult volunteers (NV, 12 males and 9 females, age: 30.5+/-2.0 years, BMI: 20.8+/-0.5 kg/m(2)). RESULTS: Basal IGF-I and IGFBP-3 levels in GHD were lower (P<0.001) than in NV. In NV the 1.25 microg/kg dose of rhGH did not modify IGF-I levels. The dose of 2.5 microg/kg rhGH significantly increased IGF-I levels in men (P<0.001) but not in women, while the 5.0 microg/kg dose increased IGF-I levels in both sexes (P<0.001). IGFBP-3 levels were not modified by any of the administered rhGH doses. In GHD patients, all rhGH doses increased IGF-I levels 12 h after both the first (P<0.01) and the fourth rhGH dose (P<0.001). At the end of treatment percentage increases in IGF-I were higher (P<0.001) in GHD patients than in NV. In contrast with NV, in GHD patients the IGF-I response to short-term stimulation with rhGH was independent of gender. Moreover, GHD patients showed increases in IGFBP-3 after the fourth administration of both 2.5 and 5.0 microg/kg rhGH. CONCLUSION: The results of the present study demonstrate that the minimal rhGH dose able to increase IGF-I and IGFBP-3 levels in GHD patients is lower than in normal subjects, at least after a very short treatment. This evidence suggests an enhanced peripheral GH sensitivity in GH deprivation.     

Long-term effects of cardiac rehabilitation on end-exercise heart rate recovery after myocardial infarction.

BACKGROUND: Heart rate recovery (HRR) is a marker of vagal tone that is a powerful predictor of mortality in patients with coronary artery disease. DESIGN: This study aims at evaluating the effects of long-term exercise training on HRR after acute myocardial infarction (AMI), in order to clarify whether prolonged exercise training could maintain a long-term improvement of HRR. METHODS: Forty-four patients after AMI were enrolled in a 3-month hospital-based exercise training programme. At the end, patients were subdivided into two groups: group A (n=22), patients discharged with a specific home-based exercise training programme and instructions for improving leisure-time physical activity; group B (n=22), patients discharged with generic instructions to maintain physical activity. All patients underwent a cardiopulmonary exercise test before, at the end of 3 months exercise training and at 6 months follow-up. RESULTS: At the end of the hospital-based exercise training programme we observed an increase in peak oxygen consumption [VO2peak; from 13.9+/-3.6 to 18+/-2.7 ml/kg per min (A) and from 14.1+/-3.9 to 17.9+/-2.1 ml/kg per min (B), P<0.001] and in HRR [from 17.1+/-1.8 to 23.4+/-1.4 beats/min (A), and from 18.8+/-2.1 to 24.3+/-1.9 beats/min (B), P<0.001]. At 6 months' follow-up we observed a further improvement in VO2peak (from 18.0+/-2.7 to 20.3+/-2.7 ml/kg per min, P<0.001) and in HRR (from 23.4+/-1.4 to 27.8+/-2.1 beats/min, P<0.001) in group A, but a significant decrease in VO2peak and in HRR in group B (P<0.001). CONCLUSION: Long-term exercise training is useful for maintaining or improving the beneficial results of the standard 3-month exercise training programme on cardiovascular capacity and HRR. This observation may bear beneficial prognostic effects on patients after AMI.     

Effect of 6 months of GH treatment on myosin heavy chain composition in GH-deficient patients.

OBJECTIVE: To investigate the effect of GH on myosin heavy chain (MHC) isoform composition, physical fitness and body composition in GH-deficient (GHD) patients. DESIGN: Twenty-two GHD patients were randomized in a double blind manner and half were treated with recombinant human GH (rhGH) and half were treated with placebo for 6 months. Twelve age-matched controls were also included in the study. METHODS: MHC isoform composition in biopsies obtained from the vastus lateralis muscle was determined using SDS-PAGE. Physical fitness was determined on a bicycle ergometer and body composition was determined using bioelectrical impedance analysis. RESULTS: More MHC IIX (28.9 +/- 4.1% and 10.0 +/- 3.1% in GHD and controls respectively (means +/- S.E.M.)) and less MHC I (36.2 +/- 2.4% and 51.7 +/- 3.9% in GHD and controls respectively (means +/- S.E.M.)) were present in the GHD patients compared with the controls. No significant difference in the amount of MHC IIA was detected. Linear regression was used to determine the relationship between variables. There were no significant relationships between the concentration of insulin-like growth factor-I (IGF-I) or the body composition and the MHC composition. Maximal oxygen uptake (VO(2)max) per kg body weight (BW) (litres/min per kg) correlated significantly with the amount of MHC I (r=0.60) and MHC IIX (r=-0.72) but not with the amount of MHC IIA (r=0.35). Treatment of GHD patients with rhGH for 6 months increased the concentration of IGF-I, lean body mass and decreased fat mass but had no effect on MHC composition and physical fitness. CONCLUSIONS: We conclude that a major part of the differences in MHC composition between GHD patients and age-matched controls can be explained by variation in physical fitness. The severity of the GHD and the body composition does not seem to be important for the MHC composition. Furthermore, treatment with GH for 6 months does not affect MHC composition in GHD patients.     

The negative GH auto-feedback in childhood: effects of rhGH and/or GHRH on the somatotroph response to GHRH or hexarelin, a peptidyl GH secretagogue, in children

Aim of the present study was to further clarify the negative GH auto-feedback mechanisms in childhood. To this goal we studied the effects of rhGH and/or GHRH administration on the GH response to GHRH or hexarelin (HEX), a peptidyl GH secretagogue, in normal short children. In 34 prepubertal children (12 girls and 22 boys, age 8.2- 14.2 yr) with normal short stature (normal height velocity and IGF-I levels) the following tests were performed: group A (no.=11): GHRH (GHRH 1 - 29, Geref, Serono; 1 microg/kg iv at 150 min) preceded by saline or GHRH at 0 min; group B (no.=6): GHRH preceded by saline or rhGH (0.005 IU/kg iv at 0 min); group C (no.=6): GHRH preceded by rhGH alone or combined with GHRH; group D (no.=6): HEX (2 microg/kg iv at 150 min) alone or preceded by rhGH. In group A, the GH response to GHRH was not modified by pre-treatment with GHRH (GH peak, mean+/-SEM: 16.7+/-2.9 vs 15.1+/-2.3 microg/l, respectively). In group B, the GH response to GHRH was clearly inhibited by rhGH (8.7+/-2.3 vs 38.8+/-4.5 microg/l, p<0.001); the GH rise after rhGH in group B overlapped with that after GHRH in group A. In group C, the GH response to GHRH after pre-treatment with rhGH (13.2+/-4.0 microg/l) was similar to that in group B and was not significantly modified by pre-treatment with rhGH+ GHRH (6.9+/-2.7 microg/l); the GH rise after rhGH+GHRH was higher (p<0.05) than that after rhGH alone. In group D, the GH response to HEX was significantly blunted by pre-treatment with rhGH (34.1+/-11.7 vs 51.2+/-17.9 microg/l, p<0.05). Our results demonstrate that in childhood the somatotroph response to GHRH is preserved after GHRH while it is inhibited after rhGH administration, which is also able to blunt the GH response to HEX. Thus, the somatostatin-mediated negative GH auto-feedback is already operative in childhood; the reason why the GHRH- induced GH rise is not inhibited by GHRH pre-treatment is unexplained.     

Oxygen-uptake (VO2) kinetics and functional mobility performance in impaired older adults

BACKGROUND: Measures of maximal oxygen uptake (VO(2max)) are limited in disabled older adults, and measures of submaximal oxygen uptake (VO(2)) may better predict functional mobility limitations. These measures may include oxygen-uptake kinetics at the onset of submaximal exercise or during recovery. We sought to determine whether the lag in oxygen uptake at the beginning of exercise (oxygen deficit) and excess oxygen uptake above rest following exercise (excess postexercise oxygen consumption) (a) predict physical performance in impaired older adults with decreased aerobic function, and (b) predict physical performance better than peak VO(2). METHODS: Two groups of community-dwelling volunteers aged 65 or older were recruited according to their performance on a maximal graded exercise test. Using the Social Security Administration criterion of disability of a peak VO(2) 18 (Unimpaired, n = 21, mean +/- SEM age 76 +/- 1 years). RESULTS: The mean +/- SEM peak VO(2) was 58% lower in the Impaired (14 +/- 1 ml/kg/min) than the Unimpaired (24 +/- 1 ml/kg/min) adults. The time constant for oxygen deficit, tc(deficit), was more than twice as high in the Impaired than the Unimpaired (p <.05), and the time constant for excess postexercise oxygen consumption, tc(EPOC), tended to be higher in the Impaired than the Unimpaired (by 43%, p =.09). Measures of submaximal oxygen-uptake kinetics were as strong or more strongly predictive of functional mobility performance than peak VO(2) in both Unimpaired and Impaired older adults. The major predictor of functional performance for the Unimpaired was a measure of oxygen deficit accruing during exercise (tc(deficit)), and for the Impaired, it was a measure of oxygen debt during recovery, tc(EPOC). CONCLUSIONS: Measurement of submaximal oxygen-uptake kinetics may provide a more practical and relevant assessment of deconditioning in frail older adults, and may eventually supplant maximal (peak) oxygen uptake as a predictor of functional disability in older adults.     

Selective low-level leg muscle training alleviates dyspnea in patients with heart failure

OBJECTIVES: The purpose of this study was to demonstrate in patients with moderate to severe heart failure that exertional dyspnea can be alleviated by improving muscle function. BACKGROUND: Dyspnea is a frequent limiting symptom in patients with chronic heart failure (CHF). This sensation may originate from activation of receptors in the musculature rather than the lung. METHODS: To investigate whether dyspnea could be alleviated by selective changes in leg muscle function, we performed isolated lower-limb training in 17 patients with severe CHF. Eight patients learned guided imagery relaxation techniques and served as an active control group. Exercise training consisted of three months of low-level bicycle and treadmill exercise such that minute ventilation was <25 l/min. Leg calisthenics were also performed. Maximal and submaximal exercise performance, respiratory and quadriceps muscle strength and endurance and quality-of-life and dyspnea scales were measured before and after each intervention. Metabolic stress testing (VO(2)), pulmonary function tests and isokinetic strength testing were also performed. RESULTS: In the active control group, no changes in leg muscle function, pulmonary function, maximal and submaximal exercise performance or quality-of-life questionnaires were observed. In the training group, peak torque of leg flexors (pre: 39 +/- 15 ft-lb; post: 50 +/- 13 ft-lb; p < 0.002) increased and the fatigue ratio decreased, indicating improved strength and endurance of the leg muscles. Maximal inspiratory and expiratory mouth pressures and maximum voluntary ventilation were unchanged. Peak VO(2) was increased (pre:12 +/- 2.2 ml/kg/min; post: 14 +/- 2.6 ml/kg/min) as well as the duration of exercise at 70% peak VO(2) increased (pre: 11.5 +/- 3.1 min; post: 21.5 +/- 5.4 min; p < 0.003). Perceived dyspnea during the submaximal testing was decreased. Minnesota Living with Heart Failure Score, Guyatt Dyspnea Scale, and the Transitional Dyspnea Index were all improved with training (all p < 0.05). CONCLUSIONS: We concluded that improvement of limb muscle function alleviates dyspnea and improves exercise performance in patients with CHF.     

Growth hormone isoforms release in response to physiological and pharmacological stimuli

Ten healthy subjects used to performing regular physical activity and eight subjects affected by idiopathic isolated GH deficiency (GHD) were enrolled; 22- and 20-kDa GH secretion and its biological activity were evaluated in response to pharmacological stimuli such as arginine, L-dopa or glucagon in GHD children, while the hormonal response to exercise was studied according to Bruce protocol in healthy subjects. We found a significant increase in 22- and 20-kDa GH level in healthy subjects after monitored physical exercise (MPE; basal 0.28+/-0.12 vs 7.37+/-2.08 ng/ml and basal 0.076+/-0.04 vs 0.18+/-0.05 ng/ml, respectively). Furthermore, the 22-kDa/20-kDa ratio significantly increased in children who had undergone MPE and the GH bioactivity basal mean value also increased significantly after exercise (basal 2.86+/-0.76 vs 7.64+/-1.9 ng/ml). The mean value of 22-kDa GH in GHD patients increased significantly following GH pharmacological stimulation (2.78+/-0.63 ng/ml) when compared with mean basal (0.20+/-0.11 ng/ml) value. In the GHD group the basal concentration of 20-kDa GH significantly increased following GH pharmacological stimulation (0.34+/-0.11 vs 0.72+/-0.2 ng/ml); the 22-kDa/20-kDa ratio significantly increased too. Likewise, GH bioactivity in children with GHD increased significantly after pharmacological stimulation test (basal 2.53+/-0.56 vs 7.33+/-1.26 ng/ml). Both GH isoform concentrations and their biological activity are significantly increased in healthy subjects after submaximal exercise protocol and in GHD children after pharmacological stimuli.     

Aerobic exercise attenuates an exaggerated exercise blood pressure response in normotensive young adult African-American men

An exaggerated exercise blood pressure response (EEBPR) may be associated with an increased risk of hypertension. We hypothesized that aerobic exercise training can decrease EEBPR and the risk for hypertension by decreasing arterial resistance. We studied the effects of aerobic training on the submaximal exercise blood pressure (BP) of eight normotensive young adult African-American men with an EEBPR. Subjects were trained on a stationary bicycle at an intensity of 70% peak oxygen uptake (VO2peak), for 30 min, three times per week, for 8 weeks. BP, heart rate, cardiac output (CO), stroke volume (SV) and total peripheral vascular resistance (TPR) were measured at rest and during submaximal exercise at a work intensity of 50% VO2peak. Significance of the training effects were evaluated by comparing the pre- and post-training measures (t-test, p < 0.05). A 15% post-training increase in VO2peak (34.6 +/- 1.4 to 40 +/- 1.4 ml/kg/min) and a 9.5 ml post-training increase in mean resting stroke volume were found. A 16.2 mmHg decrement in mean systolic BP, an 11.5 mmHg decrement in mean diastolic BP, a 120 dyne/s/cm5 decrement in TPR and a 1.2 l/min increase in CO were detected during the post-training submaximal exercise tests. These results suggest that reductions in TPR may attenuate the EEBPR of normotensive African-American males following an 8-week training regimen of stationary bicycling at 70% VO2peak. Aerobic exercise training may, therefore, reduce the risk of hypertension in normotensive African-American males by the mechanism of a reduction in TPR. Because of the limited number of subjects, the results of this study should be interpreted cautiously pending confirmation by a larger controlled trial.     

Effects of long-term enalapril therapy on cardiopulmonary exercise performance after myocardial infarction

BACKGROUND. The Enalapril Postinfarction Exercise (EPIE) trial was designed to study the effect of enalapril treatment on peak and submaximal cardiopulmonary exercise performance over the course of 1 year in men after myocardial infarction with mild exercise intolerance. METHODS AND RESULTS. One hundred sixty men with a peak VO2 less than 25 ml/kg/min and without effort angina were randomized to receive enalapril 20 mg qd or placebo on a double-blind basis. The mean age was 60.3 +/- 7.6 years. All patients received concurrent beta-blocker therapy for secondary prophylaxis. Treatment began at 21 days (group 1, n = 100) or more than 6 months after infarction (group 2, n = 60). Patients underwent exercise with real-time gas-exchange analysis nine times over the course of 48 weeks. In group 1, improvement in exercise performance occurred during the course of the trial in both groups of patients receiving placebo or enalapril. The mean peak VO2 for the placebo-treated patients in group 1 increased from 18.3 +/- 3.4 ml/kg/min by 4.9% at 48 weeks (p less than 0.05). The corresponding values for enalapril-treated patients were 18.9 +/- 3.8 ml/kg/min with a 3.7% increase (p = 0.07). Total exercise time increased in the placebo-treated patients from 645 +/- 96 seconds by 7.3% (p less than 0.01). Corresponding values for enalapril-treated patients were 674 +/- 103 seconds with a 5.4% increase (p less than 0.01). In group 2, the mean peak VO2 at baseline for the placebo-treated patients of 20.3 +/- 3.8 ml/kg/min increased by 4.4% at 48 weeks (p = NS). The corresponding values for enalapril-treated patients were 19.2 +/- 3.6 ml/kg/min with a 2.6% increase (p = NS). Total exercise time increased in the placebo-treated patients from 677 +/- 114 seconds by 0.7% (p = NS). Corresponding values for enalapril-treated patients were 659 +/- 99 seconds with a 1.1% increase (p = NS). There were no significant differences between the placebo and enalapril subgroups at any time with regard to peak VO2, exercise duration, or the VO2 at the anaerobic threshold. CONCLUSIONS. This trial demonstrates that long-term converting enzyme inhibition with enalapril had no significant effect on the peak or submaximal cardiopulmonary exercise performance over the course of 1 year in men after myocardial infarction with only mildly reduced exercise capacity.     

TNF-alpha levels in children with growth hormone deficiency and the effect of long-term growth hormone replacement therapy.

OBJECTIVE: Growth hormone (GH) has been suggested to modulate the release of some cytokines including TNF-alpha. To investigate TNF-alpha levels in children with GH deficiency (GHD), to evaluate alteration in TNF-alpha levels during recombinant human GH (rhGH) treatment, and to analyze possible correlations between TNF-alpha and GH, IGF-1 and IGFBP-3. DESIGN: Twenty-four children, aged 12.60+/-2.27 years, with isolated GHD and given rhGH therapy, as subcutaneous ingestion of 0.03-0.04mg/kg once-daily dose, were evaluated. Eleven had complete and 13 had partial GHD. Thirty-three healthy children were studied as controls. Age and sex distribution, body mass indexes of two groups were similar. In children with GHD, blood samples were drawn before (TNF-alpha0), and at 6 (TNF-alpha6) and 12 (TNF-alpha12) months of the treatment with rhGH. TNF-alpha was determined using a human TNF-alpha ELISA assay (Biosource International). RESULTS: TNF-alpha0 levels were significantly higher in children with GHD than in controls (41.79+/-25.04 and 8.63+/-4.48pg/ml, respectively, p<0.001) and decreased significantly during rhGH treatment (TNF-alpha0=41.79+/-25.04, TNF-alpha6=13.67+/-9.95, TNF-alpha12=10.86+/-6.61pg/ml, p<0.05). There was no correlation between TNF-alpha levels and BMI, IGF-1/logIGF1, IGFBP-3 levels and growth velocity of the patients with GHD. Although no correlation between TNF-alpha and peak GH levels after stimulation was present; a moderate reverse correlation between TNF-alpha and basal serum concentrations of GH (r=-0.512, p=0.046) was demonstrated. CONCLUSIONS: TNF-alpha levels are significantly higher in children with GHD than the controls, and long-term therapy with rhGH effectively reduces its level. Our data suggest that GH plays an inhibitory role on TNF-alpha release in humans. However, due to inconsistent results up to now, further prospective, controlled and long term studies are needed to elucidate the issue.     

Sustained effects of recombinant GH replacement after 7 years of treatment in adults with GH deficiency

CONTEXT: The goal of GH replacement with recombinant human GH (rhGH) is to ameliorate symptoms, signs, and complications of adult GH deficiency (GHD) in the long term. To determine whether the observed short-term beneficial effects of rhGH treatment are sustained in the long term, we evaluated biochemical and anthropometric parameters after 7 years of rhGH replacement. PATIENTS AND METHODS: After 2, 5, and 7 years of rhGH replacement, 63 adult GHD patients (30 men, 52 adult-onset GHD) were assessed. IGF-I increased during rhGH replacement, and a stable dose of rhGH was reached within 1 year of rhGH substitution. Thereafter, this individualized dose was continued. RESULTS: Plasma levels of total cholesterol and low-density lipoprotein cholesterol decreased even after 5 years of rhGH replacement (11% decrease, P < 0.001; 22% decrease, P < 0.001 respectively). High-density lipoprotein cholesterol levels increased during 7 years of rhGH replacement (1.4 +/- 0.5 mmol/l at baseline vs 1.7 +/- 0.5 mmol/l after 7 years, P < 0.001), whereas triglyceride concentrations remained unchanged. Fasting glucose levels increased during follow-up, mainly during the first 2 years of rhGH replacement (4.4 +/- 0.7 mmol/l to 5.0 +/- 1.0 mmol/l, P < 0.001). Body mass index increased during follow-up, whereas waist circumference and waist-to-hip ratio remained unchanged. Diastolic blood pressure decreased (P = 0.002), but when patients using antihypertensive medication were excluded this decrease did not reach significance (P = 0.064). Systolic blood pressure remained unchanged. CONCLUSION: The beneficial effects of rhGH replacement, described after short-term rhGH replacement, are sustained in the long term up to 7 years.     

Comparison of ramp versus step protocols for exercise testing in patients > or = 60 years of age

To evaluate whether individualized ramp protocols may be better than step protocols in patients > or = 60 years of age referred for exercise testing, peak cardiopulmonary responses and accuracy in prediction of oxygen uptake (VO2) for individualized ramp and step protocols (Bruce or modified Bruce) were compared. Twenty-four subjects (67+/-3 years) with known or suspected coronary artery disease performed both tests in random order. Protocols were selected based on estimated exercise capacity using a pretest activity questionnaire. No differences were observed between peak VO2 (19.3+/-6.3 and 19.1+/-6.4 ml/kg/min), heart rate (127+/-15 and 126+/-16 beats/min), rate-pressure product (24.0+/-4.8 and 23.4+/-4.9 beats/min x mm Hg x 10(3)) and anaerobic threshold (16.6+/-3.7 and 16.0+/-4.7 ml/kg/min) for the ramp and step protocols, respectively. The relation between measured submaximal VO2 and American College of Sports Medicine (ACSM)-predicted VO2 during the ramp protocol is demonstrated by the regression coefficient (beta), where beta = 0.92 (95% confidence intervals [CI] 0.85 to 0.99) and for the step protocols where beta = 1.02 (95% CI 0.84 to 1.20). Peak cardiopulmonary responses in the elderly are similar during individualized ramp and step protocols when appropriately selected based on a pretest activity questionnaire. Both protocols appear to provide clinically reasonable estimates of VO2 when gas exchange analysis is not used.     

Treatment of GH-deficient children with two different GH doses: effect on final height and cost-benefit implications

OBJECTIVE: Treatment of GH-deficient (GHD) children with higher doses of recombinant human GH (rhGH) than conventional ones has been reported to result in higher growth velocity and increased final height. These findings, however, were observed by comparing large but heterogeneous groups of children. We wanted to verify whether the same results could be obtained in two groups of appropriately well-matched children with isolated GHD treated with high vs conventional doses of rhGH. METHODS: Out of two cohorts of GHD children, cohort A (on a weekly rhGH dose of 0.3 mg/kg body weight) and cohort B (on a weekly rhGH dose of 0.15 mg/kg body weight), we selected two groups, each including 13 patients, who before treatment were matched for age, sex and height standard deviation score (SDS). They were followed up until final height. RESULTS: Final height SDS was significantly higher in group A (-0.45+/-0.36 (s.d.) vs -1.07+/-0.7; P=0.008), as well as height gain SDS (1.81+/-0.58 vs 1.23+/-0.62; P=0.002). The difference between final height SDS and target height SDS was positive only in group A and significantly higher in group A than in group B (0.33+/-0.51 vs -0.46+/-0.7; P=0.01). Glucose tolerance was always normal in the group treated with higher doses. CONCLUSION: The final height of children treated with higher doses of rhGH is increased, also in relation to their genetic target. The economical burden of this choice of treatment, however, has to be taken into account when evaluating the results.     

Plasma ghrelin levels during exercise in healthy subjects and in growth hormone-deficient patients

OBJECTIVE: To characterise plasma levels of the recently identified endogenous ligand for the GH secretagogue receptor (ghrelin) during submaximal aerobic exercise in healthy adults and in GH-deficient adults. DESIGN: Eight healthy males (mean+/-s.e. age, 40.8+/-2.9 years) and eight hypopituitary males with verified GH deficiency (mean+/-s.e. age, 40.8+/-4.7 years) underwent a baseline test of their peak aerobic capacity (VO(2) peak) and lactate threshold (LT) on a cycle ergometer, as well as an evaluation of body composition. The patients were then studied on two occasions in random order when they exercised for 45 min at their LT. On one occasion, GH replacement had been discontinued from the evening before, whereas on the other occasion they received their evening GH in addition to an intravenous infusion of GH (0.4 IU) during exercise the following day. The healthy subjects exercised at their LT on one occasion without GH. RESULTS: The patients were significantly more obese and had lower VO(2) max (corrected for body weight) and LT as compared with the control subjects. Exercise induced a peak in serum GH concentrations after 45 min in the control group (11.43+/-3.61 microg/l). Infusion of GH in the patients resulted in a peak level after 45 min, whereas no increase was detected when exercising without GH (9.77+/-2.40 (GH) vs 0.11+/-0.07 microg/l (no GH)). Plasma ghrelin levels did not change significantly with time in either study, and no correlations were detected between ghrelin levels and parameters such as GH and IGF-I levels, age or body composition. Plasma ghrelin levels were significantly lower during the study period with GH as compared with the study with no GH. CONCLUSIONS: Submaximal aerobic exercise of an intensity sufficient to stimulate GH release was not associated with significant alterations in plasma ghrelin concentrations, which indicated that systemic ghrelin is not involved in the exercise-induced stimulation of GH secretion. The observation that ghrelin levels were lower during GH replacement suggests that GH may feedback-inhibit systemic ghrelin release.     

Idiopathic growth hormone (GH) deficiency, and GH deficiency secondary to hypothalamic germinoma: effect of single and repeated administration of human GH-releasing factor (hGRF) on plasma GH level and endogenous hGRF-like immunoreactivity level in cerebrospinal fluid

Plasma GH responses to iv administered synthetic human GH-releasing factor-(1-44)-NH2 (hGRF) and the concentration of endogenous hGRF-like immunoreactivity (hGRF-LI) in the cerebrospinal fluid (CSF) were examined in 16 children with GH deficiency (GHD). Ten patients had idiopathic GHD, and six had GHD secondary to germinoma. An iv bolus hGRF (1 microgram/kg BW) injection test was performed the day before and the day after treatment, with a daily 1-h iv infusion of hGRF (2 micrograms/kg BW) for 3 days. Plasma GH increases (greater than 5 ng/ml) after the first iv bolus injection of hGRF occurred in 2 of the 10 idiopathic GHD children and in 4 of the 6 GHD patients with germinoma whereas the first bolus hGRF injection failed to elicit GH release in the remaining 10 patients. The mean +/- SEM peak plasma GH level after the first bolus hGRF dose in the patients with germinoma (8.2 +/- 2.2 ng/ml) was significantly higher than that in the idiopathic GHD patients (2.9 +/- 0.9 ng/ml; P less than 0.05), but significantly lower than that in normal children with short stature (18.5 +/- 2.5 ng/ml; P less than 0.05). In the 2 patients with germinoma and in 5 of the 8 idiopathic GHD children who did not respond to the first hGRF bolus dose, a significant plasma GH response to hGRF occurred during a daily iv infusion of hGRF for 3 consecutive days, whereas the remaining 3 idiopathic GHD children failed to respond to the daily hGRF infusions. The plasma GH response after the second hGRF bolus dose given after treatment with daily hGRF infusions for 3 days was not different from that after the first hGRF bolus in patients with germinoma or that in the idiopathic GHD children. hGRF-LI was not detected (less than 5.8 pg/ml) in the CSF in any of 5 patients with germinoma, whereas it was present in 5 idiopathic GHD patients (mean, 17.5 +/- 0.9 pg/ml), 3 of whom were nonresponders to daily hGRF infusions. From these results, GHD secondary to destruction of hypothalamic GRF neurons might be defined by the following findings: 1) lack of a GH response to the standard provocative tests acting through the hypothalamus; 2) significant increase in plasma GH after a single bolus and/or repetitive iv administration of hGRF; and 3) undetectable or extremely low levels of endogenous hGRF-LI in the CSF. Most of the idiopathic GHD patients responded to the repetitive hGRF infusion, suggesting insufficient secretion of hypothalamic hGRF as the primary defect. However, since hGRF-LI was detectable in the CSF in some of the idiopathic GHD patients, its pathogenesis must be multifactorial.