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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 5124-5131
Copyright © 2004 by The Endocrine Society

Growth Hormone Treatment Improves Peripheral Muscle Oxygen Extraction-Utilization during Exercise in Patients with Human Immunodeficiency Virus-Associated Wasting: A Randomized Controlled Trial

John G. Esposito, Scott G. Thomas, Lori Kingdon and Shereen Ezzat

Graduate Department of Rehabilitation Science, Faculty of Medicine (J.G.E., S.G.T.); Graduate Department of Exercise Sciences, Faculty of Physical Education and Health (S.G.T.); and Department of Medicine, Faculty of Medicine (S.E.), University of Toronto; and Freeman Center of Endocrine Oncology, Mount Sinai Hospital (L.K., S.E.), Toronto, Ontario, Canada M5G 1X5

Address all correspondence and requests for reprints to: Dr. Shereen Ezzat, Mount Sinai Hospital, 600 University Avenue, #437 Toronto, Ontario, Canada M5G 1X5. E-mail: sezzat{at}mtsinai.on.ca.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The arteriovenous oxygen difference (a-vO2 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-VO2) relationship. We investigated the impact of recombinant human GH (rhGH) treatment on a-vO2 difference and the Q-VO2 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/m2; maximum oxygen consumption, 33.6 ± 1.5 ml/kg·min), with documented unintentional weight loss (≥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 CO2 rebreathing), and subsequently a-vO2 difference, from Q-VO2 relationships. At study entry, the mean slope (8.1 ± 1.0 liters/min·1-liter increase in VO2) and intercept (3.1 ± 1.3 liters/min), generated from each patient’s Q-VO2 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-vO2 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-vO2 difference (at a VO2 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-VO2 relationship during exercise in patients with HIV-associated wasting despite antiretroviral therapy.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
DIMINISHED AEROBIC CAPACITY in patients infected with human immunodeficiency virus (HIV) is well demonstrated by clinical exercise testing (1, 2, 3, 4, 5, 6, 7). The decreased exercise capacity is a notable accompaniment of muscle wasting among such patients (8). Yet inadequate cardiorespiratory fitness and functional capacity in these patients may relate not only to sarcopenia, but also to cardiovascular dysfunction and peripheral muscle tissue pathology (9). The presence of cardiac abnormalities throughout the course of HIV infection has been extensively reported (10, 11, 12, 13, 14, 15), and although highly active antiretroviral therapy (HAART) has prolonged survival and decreased the incidence of cardiac involvement (16), many cardiovascular sequelae continue to develop (17). Moreover, the deficit in aerobic capacity in HIV-infected patients partly results from attenuated muscle oxygen extraction and utilization (18), possibly attributable to the use of HAART (19). Indeed, diminished peripheral muscle oxidative function has been observed in HIV-infected patients (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30).

The beneficial anabolic effects of recombinant human GH (rhGH) in a variety of age-related and non-age-related catabolic conditions (31, 32, 33, 34) has prompted interest in the use of this treatment in the area of HIV-associated wasting. Improvements in physiological and functional performance are particularly well substantiated in patients with adult GH deficiency treated with rhGH (35, 36, 37, 38, 39). Similarly, rhGH administration in patients with HIV improves exercise capacity (40, 41), in part from an increase in lean body mass (LBM) (41). However, it remains uncertain whether other GH-mediated physiological mechanisms are responsible for the improvement in exercise performance.

We present a randomized, double-blinded, placebocontrolled study of the effect of rhGH treatment on the physiological determinants of cardiorespiratory capacity in patients with HIV-associated wasting. We evaluated the cardiac output-oxygen consumption (Q-VO2) relationship and its response to rhGH treatment as well as the impact of this treatment on the arteriovenous oxygen difference (a-vO2 difference) response to submaximal exercise testing in these patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Fourteen patients (20–70 yr old) with documented HIV-associated wasting, defined as unintentional weight loss of at least 10% over the preceding 12 months, were selected for inclusion in the study. Patients had to have been receiving a stable regimen of antiretroviral therapy for at least 1 month before study entry and were to continue with the same treatment for the duration of the study. Patients must not have had rhGH treatment for at least 2 yr or received systemic glucocorticoids for at least 6 months before study entry. Those already receiving androgenic agents had to be receiving them for at least 6 continuous months before entry and were to continue for the duration of the study.

Patients were excluded from the study if any of the following criteria applied: 1) presence of chronic severe kidney disease (serum creatinine, ≥2.25x the upper limit of the normal range and/or repeated positive tests for hematuria and/or proteinuria); 2) presence of chronic severe liver disease (serum glutymal aminotransferase and/or aspartate aminotransferase and/or alanine aminotransferase ≥2.5x the upper limit of the normal range); 3) presence of impaired glucose tolerance (fasting glucose, ≥110 mg/dl); 4) presence or history of malignancy; 5) unstable hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg); 6) acute or severe illness during the 6 months before study entry; 7) presence of any concomitant disease, intercurrent illness, or resultant therapy that could interfere with the patient’s compliance with the study; or 8) known active drug addiction, including alcoholism or use of drugs for nontherapeutic purposes.

Study design

The study was reviewed and approved by the local ethics review committees. After written and informed consent was obtained, the referred patients underwent a prestudy evaluation for eligibility, which was completed within 1 month of proposed study entry and included a physical examination (i.e. weight, height, electrocardiogram, chest x-ray, routine hematology, blood biochemistry and urinalysis, and routine ophthalmology) and medical history assessment. Eligible patients were then studied for 9 months in a randomized, double-blinded, placebo-controlled, two-period, cross-over trial (Fig. 1Go) from November 2001 to June 2003. Treatment consisted of rhGH or placebo, which was self-administered as a nightly sc injection, at a dose of 6 mg/d. The rhGH (Serostim) was provided by Serono, Inc. (Rockland, MA) and was identical to placebo in preparation and packaging. The two-period x two-group trial was an A/B B/A design. Participants were randomized to receive either drug A (rhGH) or drug B (placebo) for 3 months (period 1). After a 3-month washout period, participants crossed over to receive the alternative treatment for 3 months (period 2). Participants randomized to group 1 received drug A (rhGH) in period 1 and drug B in period 2 (A/B); the treatment order for group 2 was B/A. Compliance was assessed from returned vials, self-reporting cards, and measurements of circulating IGF-I levels. Dose reduction was permitted if side-effects were alleged to be consequent of rhGH treatment. All measurements were made during six major study visits (months 0, 1, 3, 6, 7, and 9). Patients attended the Exercise Physiology Laboratory at 0900 h after an overnight fast. Baseline measurements (months 0 and 6) preceded each treatment period, and identical procedures were undertaken for both periods. In addition, 2 wk after the start of each period, patients were clinically examined for safety (i.e. routine hematology, blood biochemistry and urinalysis, and monitoring of adverse events). Participants were asked not to alter their physical activity throughout the study; this was monitored by the use of patient diaries. The randomization code was computer-generated at month 0, after baseline measurements were completed. Unblinding occurred after full completion of the study.



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  		FIG. 1. Study design and randomization.

 
Outcome measures

Circulating IGF-I. Serum levels of GH (Quest Diagnostics, Inc., San Juan Capistrano, CA) and IGF-I (Diagnostics Systems Laboratories, Inc., Webster, TX) were measured using immunoassays according to the manufacturers’ protocols.

Body composition assessment. Body mass and stature were measured to the nearest 0.1 kg and 0.5 cm, respectively, with light clothing and without shoes. Body mass index was calculated as body mass divided by the square of stature. Body composition (whole body) estimates of LBM and total body fat (TBF) were derived by dual energy x-ray absorptiometry using a DPX-L Plus bone densitometer (model 2288; Lunar Corp., Madison, WI).

Cardiorespiratory performance. All exercise tests were performed on a Trackmaster treadmill (model TMX425; Full Vision, Inc., Newton, KS) and assessed by the same trained researcher. Cardiorespiratory performance was determined using a continuous, progressive, pseudo-ramp (small step increases) protocol to a symptom-limited maximum. This was a walking protocol for all patients, and the initial treadmill work rate was based on the level of physical activity and fitness of each patient. Expired gas was analyzed by open-circuit spirometry using a MOXUS Modular VO2 System (AEI Technologies, Naperville, IL). Mixed expired gas was sampled downstream from a 4.2-liter mixing chamber and analyzed breath by breath. Data were processed and expressed in 20-sec averages for heart rate (HR), VO2, carbon dioxide production (VCO2), respiratory exchange ratio (RER: VCO2/VO2), ventilation (VE), respiratory frequency, and tidal volume (VT). HR was determined using a Polar monitor (Polar Electro Oy, Kempele, Finland), and blood pressure was measured every 2 min by automated auscultation (Tango Exercise Stress BP Monitor; SunTech Medical Instruments, Inc., Morrisville, NC). Measures included maximum oxygen uptake (VO2peak), ventilatory threshold (VeT), and maximum HR (HRpeak). VO2peak was simply the highest VO2 achieved for a presumed maximal exercise effort. A noninvasive method was used to estimate VeT from ventilatory equivalents for oxygen (VE/VO2) and carbon dioxide (VE/VCO2) as previously described (42). VeT was identified as VO2 at the point of inflection where VE/VO2 was lowest and then increased progressively with additional increases in treadmill work rate while VE/VCO2 reached a plateau or declined. The modified V-slope method (43), in which VCO2 is plotted as a function of VO2 and noting where VCO2 begins to increase out of proportion to VO2, was used to support the estimate of VeT by ventilatory equivalents. Two trained researchers, blinded to treatment, independently and randomly evaluated the graphs and were able to clearly identify VeT. The discrepancy in VeT between the two researchers was less than or equal to 10% in all cases, and the mean value was taken as the VeT. The HRpeak was compared with the maximal predicted HR, which was calculated as 220 minus age in years.

Q-VO2 relationship. A stage 2 exercise test (44) with two submaximal exercise levels, corresponding to 40% and 60% of baseline VO2peak, was used to determine the Q-VO2 relationship and other associated variables for each patient. Each submaximal exercise level was sustained for 6 min, with a 6-min rest interval in between. At each level, Q was determined noninvasively by the indirect Fick CO2 equilibration method. The rebreathing apparatus consisted of an inflatable balloon-type, three-way valve assembly actuated by an automated controller (Hans Rudolph, Kansas City, MO) and attached to a 5-liter latex rubber rebreathing bag. A Nafion sample line, originating from the sampling port of the valve, was connected to the MOXUS Modular VO2 System. Attached to a three-way stopcock were the rebreathing bag, a 3-liter syringe (for the purpose of controlling the volume of gas injected into the bag), and a vacuum (for the purpose of emptying the bag). The syringe was also connected to tanks containing the rebreathing gases. Before rebreathing, VCO2 (as well as VO2 and VT) was measured in a steady state while patients inspired room air, and the arterial partial pressure of CO2 (PaCO2) was estimated from the partial pressure of end-tidal CO2 (PETCO2). The rebreathing bag was then filled with concentrated gas (1.5–2.0 times the patient’s VT), ranging from 10.5–12.0% CO2 in oxygen (44), and the valve assembly was activated to commence rebreathing. During rebreathing, patients breathed in and out of the bag until the partial pressure of CO2 (PCO2) reached an equilibrium plateau. Mixed venous PCO2 (PvCO2) was then estimated from this equilibrium PCO2 (PEqCO2). An arterial oxygen saturation of 95% was assumed. Mixed venous and arterial CO2 concentrations (CvCO2 and CaCO2, respectively) were estimated by the following equations (44): CvCO2 = 10.38(PvCO20.396)[PvCO2 = 0.76(PEqCO2) + 11] and CaCO2 = 10.38(PaCO20.396)[PaCO2 = 5.5 + 0.90(PETCO2) – 0.0021(VT). Cardiac output was then solved using the Fick equation: Q = VCO2/(CvCO2 – CaCO2).

Each patient’s Q-VO2 relationship was compared with the established relationship for healthy subjects (44): Q = 4.0 + 6.0 VO2 (liters/min), where 4.0 and 6.0 represent the intercept and slope, respectively. Q corresponding to a VO2 of 1250 ml/min(Q1250), was interpolated from each patient’s Q-VO2 relationship. The a-vO2 difference at this VO2 was calculated as the ratio of VO2/Q, and expressed as milliliters per deciliter. HR corresponding to the same VO2 of 1250 ml/min (HR1250) was interpolated from each patient’s HR-VO2 relationship, and stroke volume (SV) was calculated as the ratio of Q/HR and expressed in milliliters.

Statistical analyses

All statistical analyses were performed using SigmaStat for Windows (version 2.03; SPSS, Inc., Chicago, IL). Data are expressed as the mean ± SEM unless otherwise stated. All measures were examined for equality of carryover effects, using a two-sample t test of patient totals for period 1 plus period 2 values at P < 0.10 (45). When there was no evidence of a carryover effect, the two patient groups were combined, and repeated measures ANOVA was used to examine within- and between-treatment differences from baseline to 1 and 3 months of placebo and rhGH treatment. Diagnostic tests of normality and equal variance preceded repeated measures ANOVA. Post hoc comparisons were made using Student-Newman-Keuls tests. The level of significance was P < 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics

Fourteen patients met the inclusion criteria and gave informed consent to participate in this study. One patient, from group 1, withdrew before completion of the study because of arthralgias and headaches, and another patient, also from group 1, died from a cerebrovascular accident during the washout period. Therefore, 12 patients completed the 9-month trial. One patient, from group 1, did not complete measures at the 1 month visit and neither did another patient, from group 2, at the 7-month visit. Blinded dose reduction to 3 mg/d was required in four patients because of side-effects (arthralgias) during the rhGH treatment period. Eight patients were cigarette smokers. There were no significant differences among baseline characteristics (Table 1Go) between groups 1 (treatment order A/B) and 2 (treatment order B/A). There was also no significant carryover effect for each of the outcome measures. All patients had been receiving a stable regimen of antiretroviral therapy for at least 1 month before study entry and continued it throughout the course of the study (Table 2Go).


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  		TABLE 1. Demographic and baseline patient characteristics by group

 

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  		TABLE 2. Medication regimen

 
Biochemical changes

Circulating IGF-I concentrations at baseline were within the age-matched normative range in 92% (11 of 12) of the patients. One patient had an IGF-I concentration (277 µg/liter) above the upper limit of normal (256 µg/liter). IGF-I concentrations significantly increased (P < 0.05) from 177.0 ± 16.1 µg/liter (rhGH period baseline) to 717.0 ± 122.5 µg/liter after 1 month of rhGH treatment. Due to the dose reduction necessitated by side-effects (arthralgias), IGF-I levels declined after 3 months of active treatment to 430.5 ± 45.9 µg/liter (P < 0.05), but remained elevated above baseline (P < 0.05). IGF-I levels remained stable during placebo treatment (213.6 ± 27.8 and 189.8 ± 21.7 µg/liter, after 1 and 3 months respectively; Fig. 2AGo). At baseline, red blood cell counts were slightly low in 58% (seven of 12) of the patients, yet hematocrits and hemoglobin concentrations were in normal range in 92% (11 of 12) of the patients. There were no significant changes in any hematological measures with either treatment.



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  		FIG. 2. Mean (±SEM) changes in IGF-I concentration, VO2peak, HRpeak, and VeT during treatment with rhGH (•) and placebo ({circ}). P values denote differences between treatments.

 
Body composition

Body mass significantly increased from the rhGH period baseline (70.0 ± 2.6 kg) after 1 month (72.2 ± 3.2 kg; P < 0.001) and remained elevated after 3 months (71.5 ± 2.7 kg; P = 0.039) of rhGH treatment. The decrease in body mass from 1 to 3 months was also significant (P = 0.011). Body mass remained unchanged after 1 and 3 months of placebo treatment (69.6 ± 3.0 and 69.0 ± 3.0 kg, respectively).

Treatment with rhGH resulted in a significant increase from baseline in LBM (P < 0.001) after 1 month (8.6 ± 1.4%) and 3 months (6.1 ± 1.0%). This was paralleled by significant decreases (P < 0.05) in TBF (21.7 ± 5.8% and 22.6 ± 5.8% at 1 and 3 months, respectively). No significant changes were noted in LBM or TBF after treatment with placebo. Differences between the effects of placebo and rhGH on body mass and LBM were also significant (P < 0.01).

Cardiorespiratory performance

At baseline, the VO2peak (33.6 ± 1.5 ml/kg·min) was significantly lower (P = 0.015) than age-specific normative values (38.6 ± 0.5 ml/kg·min) (46), and the HRpeak (159.3 ± 2.9 beats/min) was 9.8 ± 2.3% lower (P = 0.002) than the age-predicted maximum. After 3 months of treatment with rhGH, nonsignificant increases in the VO2peak (34.9 ± 2.0 ml/kg·min) and the HRpeak (160.6 ± 4.6 beats/min) were observed. In contrast, there was a nonsignificant decrease in the VO2peak (31.3 ± 2.1 ml/kg·min) and the HRpeak (151.6 ± 5.1 beats/min) after 3 months of placebo. However, the differences between the effects of placebo and rhGH on the VO2peak and HRpeak were significant after 3 months (P < 0.05; Fig. 2Go, B and C). The HRpeak exceeded 90% of the age-predicted maximal HR only during active treatment. The VeT at baseline (17.9 ± 0.9 ml/kg·min) was approximately 24% lower (P < 0.001) than that predicted for healthy sedentary males of similar age, body mass, and stature (47). The VeT significantly improved after 1 month (18.9 ± 1.1 ml/kg·min; P < 0.05) and 3 months (19.8 ± 1.3 ml/kg·min; P < 0.05) of rhGH treatment. No statistically significant changes were noted after treatment with placebo. Differences between the effects of placebo and rhGH on VeT were statistically significant (P < 0.05) as well (Fig. 2DGo). The RER at VO2peak did not change significantly after either treatment and did not exceed 1.15 at any of the time points.

Q-VO2 relationship and a-vO2 difference

Data for VO2 and Q at the 40% and 60% of VO2peak exercise levels during placebo and rhGH treatment periods are presented in Table 3Go. The significant increase in VO2 at both exercise levels after 1 month of rhGH treatment reflects increased oxygen consumption on account of the rhGH-induced increase in body mass. At baseline, the mean slope and intercept, generated from each patient’s Q-VO2 relationship, were 8.1 ± 1.0 liters/min/1-liter increase in VO2 and 3.1 ± 1.3 liters/min, respectively. After 3 months of rhGH treatment, the slope and intercept decreased and increased, respectively, albeit the changes were not statistically significant. Conversely, the slope and intercept tended to increase and decrease, respectively, after treatment with placebo (Table 4Go).


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  		TABLE 3. VO2 and Q at the 40% and 60% of VO2peak exercise levels during placebo and rhGH periods

 

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  		TABLE 4. Q-VO2 relationship during placebo and rhGH periods

 
At baseline, the Q1250 was 13.2 ± 0.7 liters/min, 15.1 ± 5.7% higher than expected for healthy individuals (44), and the avO2 difference was 9.7 ± 0.5 ml/dl. Nonsignificant decreases in Q1250 from baseline were observed after 1 month (10.7 ± 5.7%) and 3 months (6.0 ± 3.7%) of rhGH treatment. There was a smaller decline in Q1250 after 1 and 3 months of placebo (Fig. 3AGo). The a-vO2 difference, calculated from the same VO2, significantly increased from 9.9 ± 0.5 to 11.5 ± 0.6 ml/dl (P = 0.039) after 1 month of rhGH treatment (Fig. 3BGo). After 3 months of rhGH treatment, the a-vO2 difference decreased to 10.4 ± 0.5 ml/dl; however, the change from 1 month was not significant. There were no significant changes in a-vO2 differences after placebo treatment. In addition, the greatest increase in HR1250 from baseline (~6 beats/min; P = 0.051) was observed after 1 month of active treatment and was significantly greater than that observed with placebo (P = 0.012; Fig. 3CGo). The SV, at the same VO2, significantly decreased from baseline after 1 month of rhGH treatment (P = 0.011) and was significantly lower than that observed after 1 month of placebo (P = 0.028). However, changes were not significant after 3 months of treatment with rhGH (Fig. 3DGo).



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  		FIG. 3. Mean (±SEM) changes in cardiac output (Q), a-vO2, HR, and SV at a VO2 of 1250 ml/min during treatment with rhGH (•) and placebo ({circ}). P values denote differences between treatments. *, Significant difference (P = 0.039) within treatment compared with baseline.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our results are consistent with those from previous studies demonstrating impairment in aerobic capacity among HIV-infected patients (1, 2, 3, 4, 5, 6, 7). At baseline, we found elevated cardiac output during exercise despite normal hemoglobin concentrations. This was probably in compensation for an insufficient a-vO2 difference, an accepted indicator of muscle oxygen extraction-utilization. This is in agreement with previous findings of diminished a-vO2 difference accompanied by decreased VO2peak during maximal treadmill exercise testing in HAART-treated HIV patients (18, 19). In contrast to these earlier studies, however, we used submaximal exercise testing to obtain Q-VO2 relationships. By measuring Q at submaximal intensities below the lactate threshold, we avoided potential errors in the measurement of Q. Estimating CvCO2 from PvCO2 without knowledge of mixed venous pH may lead to errors in Q above the lactate threshold (48).

The a-vO2 difference depends on the extent of oxygen extraction from blood by muscle and its subsequent utilization. This, in turn, is influenced by the metabolic rate, regional distribution of peripheral flow, local muscle capillary density and perfusion, changes in the oxyhemoglobin dissociation curve, and activity of muscle respiratory enzymes (44). Deficits among any of these factors give rise to impaired exercise performance.

Nucleoside reverse transcriptase inhibitors (NRTI), a cornerstone of antiretroviral therapy, have been shown to induce mitochondrial dysfunction and decrease mitochondrial enzyme function (49). Toxic mitochondrial myopathy caused by long-term therapy with zidovudine has been documented in vivo (20, 23, 24, 26, 29). The a-vO2 difference is significantly lower in patients taking NRTI compared with those using other antiretroviral agents (i.e. protease inhibitors and non-NRTI) (19). In our study approximately 92% of the patients were taking NRTI; 58% were receiving zidovudine in particular. Because the rate of oxygen utilization is dependent on normal mitochondrial enzyme function (50), the decreased a-vO2 difference and aerobic capacity in our patients may have been due to a nucleoside analog-induced diminution of oxidative enzyme function.

Impairment in the redistribution of central circulation to active tissue resulting from autonomic dysfunction is another potential mechanism for the reduced muscle oxygen extraction-utilization observed in this patient population. Autonomic dysfunction has been reported in HIV-infected patients (51, 52, 53, 54); however, it could not be specifically elucidated using the approaches adopted in our current study.

We chose a dose (6 mg/d) that has been previously shown to be efficacious in improving body composition and exercise capacity among patients with HIV-associated wasting (40, 41). A major finding in our study was the significant increase in a-vO2 difference at a specified submaximal VO2, accompanied by an improvement in the Q-VO2 relationship, in response to GH treatment. Arthralgias, necessitating a halving of dose in nearly a third of our patients, were associated with a nearly 4-fold increase in IGF-I levels after 1 month of rhGH treatment. There was a significant reduction in IGF-I levels from 1 to 3 months of rhGH treatment, probably as a consequence of the rhGH dose reduction, paralleled by a reduction in a-vO2. It is plausible that treatment with rhGH at a dose of 6 mg/d is required to effect a significant response in a-vO2 difference during submaximal exercise in patients with HIV-associated wasting.

GH treatment stimulates erythropoiesis in adult GH deficiency (55) and may thus contribute to the increased exercise performance seen in these patients (36, 39). However, GH treatment did not alter red blood cell count, hemoglobin, and/or hematocrit in our patients. It remains unclear whether GH per se stimulates oxidative enzyme activity in skeletal muscle. In normal rats, the pharmacological use of GH does not improve either mitochondrial mass or the muscle oxidative properties of isolated mitochondria (56). Yet when combined with physical endurance training, GH administration increases skeletal muscle oxidative enzyme activity more than training alone in healthy elderly women (57). IGF-I stimulates differentiation of myoblasts by induction of myogenin gene expression (58). Moreover, myogenin induces a shift from glycolytic to oxidative metabolism in muscle (59). Thus, by stimulating IGF-I production, GH treatment may indirectly enhance myogenin expression and subsequent muscle oxidative activity in patients with HIV-associated wasting. Nevertheless, additional investigations examining muscle oxygen extraction-utilization and mitochondrial oxidative enzyme activity in GH-treated sarcopenic patients are warranted.

The observed increase in VO2peak during GH treatment should be interpreted with caution. Attainment of an RER greater than 1.15 and/or a plateau in oxygen uptake despite increasing workload confirms that maximal effort has been elicited during graded exercise testing (46). In our study RER did not exceed 1.15 at any of the time points, and a plateau was not consistently seen; therefore, the improvement in VO2peak should not be readily accepted as a valid marker of improved aerobic capacity in our patients. In the majority of our patients, exercise cessation resulted from local muscle fatigue before an RER of 1.15 or a plateau in oxygen uptake could be attained.

VeT, which is observed at a submaximal work rate, may be a more useful indicator of aerobic capacity in HIV-infected patients. VeT is an effort-independent physiological measure of ability to perform submaximal, prolonged activity. It corresponds to the point at which pulmonary ventilation disproportionately increases during graded exercise in its relation to oxygen consumption at about the same time blood lactate begins to accumulate (50). Exercise at intensities above VeT results in metabolic acidosis, hyperventilation, impaired muscle contraction, and, inevitably, an inability to sustain performance (60). Muscle fiber type, blood flow, capillary density, mitochondrial size and number, and oxidative enzyme concentrations play integral roles in determining VeT (50). The increase in a-vO2 difference in our patients, which was consistently measured at a VO2 corresponding to baseline VeT (1250 ml/min), paralleled the increase in VeT after 1 month of rhGH treatment. However, after 3 months of active treatment, the a-vO2 difference remained elevated above baseline, but not as significantly as VeT. Recent results from our laboratory have shown that GH-induced increases in LBM are associated with improvements in VeT (61). Therefore, the GH-induced improvement in a-vO2 difference during exercise may be reliant on a much greater IGF-I response to GH than that required for improvements in VeT and LBM.

The a-vO2 difference at a VO2 of 1250 ml/min significantly increased after 1 month of rhGH treatment; however, the change compared with that after placebo treatment was not statistically significant. The possibility exists that the sample size (n = 12) was inadequate, perhaps rendering the study not powerful or sensitive enough to show a difference. Therefore, the possibility of a false negative result or type II error with respect to a-vO2 difference cannot be ruled out. Retrospective power analysis revealed a statistical power less than 0.80.

In the present study cardiorespiratory exercise testing, and the expired gas analyses thereof, elucidated reduced extraction and utilization of oxygen by peripheral muscle tissue in patients with HIV-associated wasting. GH treatment transiently corrected this, subsequently improving the Q-VO2 relationship in our patients. Therefore, the beneficial effect of GH on physiological performance attests to its potential ergogenicity in patients with HIV-associated wasting despite the use of antiretroviral therapy.


   Footnotes
 
Abbreviations: a-vO2 difference, Arteriovenous oxygen difference; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; HR, heart rate; HRpeak, maximum heart rate; LBM, lean body mass; NRTI, nucleoside reverse transcriptase inhibitor; Q-VO2, cardiac output-oxygen consumption; RER, respiratory exchange ratio; rhGH, recombinant human GH; SV, stroke volume; TBF, total body fat; VCO2, carbon dioxide production; VE, ventilation; VeT, ventilatory threshold; VO2peak, maximum oxygen uptake; VT, tidal volume.

Received March 5, 2004.

Accepted July 8, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Cade WT, Peralta L, Keyser RE 2002 Aerobic capacity in late adolescents infected with HIV and controls. Pediatr Rehab 5:161–169
  2. Johnson JE, Anders GT, Blanton HM, Hawkes CE, Bush BA, McAllister CK, Matthews JI 1990 Exercise dysfunction in patients seropositive for the human immunodeficiency virus. Am Rev Respir Dis 141:618–622[Medline]
  3. Keyser RE, Peralta L, Cade WT, Miller S, Anixt J 2000 Functional aerobic impairment in adolescents seropositive for HIV: a quasiexperimental analysis. Arch Phys Med Rehab 81:1479–1484[CrossRef][Medline]
  4. MacArthur RD, Levine SD, Birk TJ 1993 Supervised exercise training improves cardiopulmonary fitness in HIV-infected persons. Med Sci Sports Exerc 25:684–688[Medline]
  5. Perna FM, LaPerriere A, Klimas N, Ironson G, Perry A, Pavone J, Goldstein A, Majors P, Makemson D, Talutto C, Schneiderman N, Fletcher MA, Meijer OG, Koppes L 1999 Cardiopulmonary and CD4 cell changes in response to exercise training in early symptomatic HIV infection. Med Sci Sports Exerc 31:973–979[Medline]
  6. Pothoff G, Wassermann K, Ostmann H 1994 Impairment of exercise capacity in various groups of HIV-infected patients. Respiration 61:80–85[Medline]
  7. Stringer WW, Berezovskaya M, O’Brien WA, Beck CK, Casaburi R 1998 The effect of exercise training on aerobic fitness, immune indices, and quality of life in HIV+ patients. Med Sci Sports Exerc 30:11–16[Medline]
  8. Grinspoon S, Corcoran C, Rosenthal D, Stanley T, Parlman K, Costello M, Treat M, Davis S, Burrows B, Basgoz N, Klibanski A 1999 Quantitative assessment of cross-sectional muscle area, functional status, and muscle strength in men with the acquired immunodeficiency syndrome wasting syndrome. J Clin Endocrinol Metab 84:201–206[Abstract/Free Full Text]
  9. Stringer WW 2000 Mechanisms of exercise limitation in HIV+ individuals. Med Sci Sports Exerc 32(7 Suppl):S412–S421
  10. Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G 1998 Cardiac involvement in the acquired immunodeficiency syndrome: a multicenter clinical-pathological study. Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators. AIDS Res Hum Retroviruses 14:1071–1077[Medline]
  11. Cardoso JS, Moura B, Martins L, Mota-Miranda A, Rocha Goncalves F, Lecour H 1998 Left ventricular dysfunction in human immunodeficiency virus (HIV)-infected patients. Int J Cardiol 63:37–45[CrossRef][Medline]
  12. Coudray N, de Zuttere D, Force G, Champetier de Ribes D, Pourny JC, Antony I, Lecarpentier Y, Chemla D 1995 Left ventricular diastolic function in asymptomatic and symptomatic human immunodeficiency virus carriers: an echocardiographic study. Eur Heart J 16:61–67
  13. Fath-Ordoubadi F, van der Watt MJ, Noble MI 1997 Early presentation of dilated cardiomyopathy as a part of seroconversion illness in human immunodeficiency virus infection. Clin Cardiol 20:738–739[Medline]
  14. Milei J, Grana D, Fernandez Alonso G, Matturri L 1998 Cardiac involvement in acquired immunodeficiency syndrome–a review to push action. The Committee for the Study of Cardiac Involvement in AIDS. Clin Cardiol 21:465–472[Medline]
  15. Rerkpattanapipat P, Wongpraparut N, Jacobs LE, Kotler MN 2000 Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med 160:602–608[Abstract/Free Full Text]
  16. Pugliese A, Isnardi D, Saini A, Scarabelli T, Raddino R, Torre D 2000 Impact of highly active antiretroviral therapy in HIV-positive patients with cardiac involvement. J Infect 40:282–284[CrossRef][Medline]
  17. Barbaro G, Klatt EC 2002 HIV infection and the cardiovascular system. AIDS Rev 4:93–103[Medline]
  18. Cade WT, Fantry LE, Nabar SR, Keyser RE 2003 Decreased peak arteriovenous oxygen difference during treadmill exercise testing in individuals infected with the human immunodeficiency virus. Arch Phys Med Rehab 84:1595–1603[CrossRef][Medline]
  19. Cade WT, Fantry LE, Nabar SR, Shaw DK, Keyser RE 2003 A comparison of Qt and a-vO2 in individuals with HIV taking and not taking HAART. Med Sci Sports Exerc 35:1108–1117[CrossRef][Medline]
  20. Arnaudo E, Dalakas M, Shanske S, Moraes CT, DiMauro S, Schon EA 1991 Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 337:508–510[CrossRef][Medline]
  21. Benbrik E, Chariot P, Bonavaud S, Ammi-Said M, Frisdal E, Rey C, Gherardi R, Barlovatz-Meimon G 1997 Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells. J Neurol Sci 149:19–25[CrossRef][Medline]
  22. Cabello A, Martinez-Martin P, Gutierrez-Rivas E, Madero S 1990 Myopathy with nemaline structures associated with HIV infection. J Neurol 237:64–65[CrossRef][Medline]
  23. Chariot P, Benbrik E, Schaeffer A, Gherardi R 1993 Tubular aggregates and partial cytochrome c oxidase deficiency in skeletal muscle of patients with AIDS treated with zidovudine. Acta Neuropathol 85:431–436[CrossRef][Medline]
  24. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL 1990 Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 322:1098–1105[Abstract]
  25. Gherardi RK 1994 Skeletal muscle involvement in HIV-infected patients. Neuropathol Appl Neurobiol 20:232–237[Medline]
  26. Mhiri C, Baudrimont M, Bonne G, Geny C, Degoul F, Marsac C, Roullet E, Gherardi R 1991 Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol 29:606–614[CrossRef][Medline]
  27. Modica-Napolitano JS 1993 AZT causes tissue-specific inhibition of mitochondrial bioenergetic function. Biochem Biophys Res Commun 194:170–177[CrossRef][Medline]
  28. Morgello S, Wolfe D, Godfrey E, Feinstein R, Tagliati M, Simpson DM 1995 Mitochondrial abnormalities in human immunodeficiency virus-associated myopathy. Acta Neuropathol 90:366–374[Medline]
  29. Peters BS, Winer J, Landon DN, Stotter A, Pinching AJ 1993 Mitochondrial myopathy associated with chronic zidovudine therapy in AIDS. Q J Med 86:5–15
  30. Weissman JD, Constantinitis I, Hudgins P, Wallace DC 1992 31P magnetic resonance spectroscopy suggests impaired mitochondrial function in AZT-treated HIV-infected patients. Neurology 42:619–623[Abstract/Free Full Text]
  31. Baum HB, Biller BM, Finkelstein JS, Cannistraro KB, Oppenhein DS, Schoenfeld DA, Michel TH, Wittink H, Klibanski A 1996 Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebo-controlled trial. Ann Intern Med 125:883–890[Abstract/Free Full Text]
  32. Bengtsson BA, Eden S, Lonn L, Kvist H, Stokland A, Lindstedt G, Bosaeus I, Tolli J, Sjostrom L, Isaksson OG 1993 Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 76:309–317[Abstract]
  33. Gore DC, Honeycutt D, Jahoor F, Wolfe RR, Herndon DN 1991 Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients. Arch Surg 126:38–43[Abstract/Free Full Text]
  34. Vance ML, Mauras N 1999 Growth hormone therapy in adults and children. N Engl J Med 341:1206–1216[Free Full Text]
  35. Johannsson G, Bengtsson BA, Andersson B, Isgaard J, Caidahl K 1996 Long-term cardiovascular effects of growth hormone treatment in GH-deficient adults. Preliminary data in a small group of patients. Clin Endocrinol (Oxf) 45:305–314[CrossRef][Medline]
  36. Nass R, Huber RM, Klauss V, Muller OA, Schopohl J, Strasburger CJ 1995 Effect of growth hormone (hGH) replacement therapy on physical work capacity and cardiac and pulmonary function in patients with hGH deficiency acquired in adulthood. J Clin Endocrinol Metab 80:552–557[Abstract]
  37. Orme SM, Sebastian JP, Oldroyd B, Stewart SP, Grant PJ, Stickland MH, Smith MA, Belchetz PE 1992 Comparison of measures of body composition in a trial of low dose growth hormone replacement therapy. Clin Endocrinol (Oxf) 37:453–459[Medline]
  38. Rodriguez-Arnao J, Jabbar A, Fulcher K, Besser GM, Ross RJ 1999 Effects of growth hormone replacement on physical performance and body composition in GH deficient adults. Clin Endocrinol (Oxf) 51:53–60[CrossRef][Medline]
  39. Woodhouse LJ, Asa SL, Thomas SG, Ezzat S 1999 Measures of submaximal aerobic performance evaluate and predict functional response to growth hormone (GH) treatment in GH-deficient adults. J Clin Endocrinol Metab 84:4570–4577[Abstract/Free Full Text]
  40. Moyle GJ, Daar ES, Gertner JM, Kotler DP, Melchior JC, O’Brien F, Svanberg E 2004 Growth hormone improves lean body mass, physical performance, and quality of life in subjects with HIV-associated weight loss or wasting on highly active antiretroviral therapy. J Acquir Immune Defic Syndr 35:367–375
  41. Schambelan M, Mulligan K, Grunfeld C, Daar ES, LaMarca A, Kotler DP, Wang J, Bozzette SA, Breitmeyer JB 1996 Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group. Ann Intern Med 125:873–882[Abstract/Free Full Text]
  42. Caiozzo VJ, Davis JA, Ellis JF, Azus JL, Vandagriff R, Prietto CA, McMaster WC 1982 A comparison of gas exchange indices used to detect the anaerobic threshold. J Appl Physiol 53:1184–1189[Abstract/Free Full Text]
  43. Beaver WL, Wasserman K, Whipp BJ 1986 A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 60:2020–2027[Abstract/Free Full Text]
  44. Jones NL 1997 Clinical exercise testing. 4th ed. Philadelphia: Saunders
  45. Grizzle JE 1965 The two-period change-over design and its use in clinical trials. Biometrics 21:467–480[CrossRef][Medline]
  46. American College of Sports Medicine 2000 ACSM’s guidelines for exercise testing and prescription. 6th ed. Philadelphia: Lippincott Williams & Wilkins
  47. Davis JA, Storer TW, Caiozzo VJ 1997 Prediction of normal values for lactate threshold estimated by gas exchange in men and women. Eur J Appl Physiol Occup Physiol 76:157–164[CrossRef][Medline]
  48. Sun XG, Hansen JE, Stringer WW, Ting H, Wasserman K 2001 Carbon dioxide pressure-concentration relationship in arterial and mixed venous blood during exercise. J Appl Physiol 90:1798–1810[Abstract/Free Full Text]
  49. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP 1998 Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 12:1735–1744[Medline]
  50. McArdle WD, Katch FI, Katch VL 2001 Exercise physiology: energy, nutrition, and human performance. 5th ed. Philadelphia: Lippincott Williams & Wilkins
  51. Becker K, Gorlach I, Frieling T, Haussinger D 1997 Characterization and natural course of cardiac autonomic nervous dysfunction in HIV-infected patients. AIDS 11:751–757[CrossRef][Medline]
  52. Freeman R, Roberts MS, Friedman LS, Broadbridge C 1990 Autonomic function and human immunodeficiency virus infection. Neurology 40:575–580[Abstract/Free Full Text]
  53. Rogstad KE, Shah R, Tesfaladet G, Abdullah M, Ahmed-Jushuf I 1999 Cardiovascular autonomic neuropathy in HIV infected patients. Sex Transm Infect 75:264–267[Abstract]
  54. Gluck T, Degenhardt E, Scholmerich J, Lang B, Grossmann J, Straub RH 2000 Autonomic neuropathy in patients with HIV: course, impact of disease stage, and medication. Clin Auton Res 10:17–22[CrossRef][Medline]
  55. Christ ER, Cummings MH, Westwood NB, Sawyer BM, Pearson TC, Sonksen PH, Russell-Jones DL 1997 The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency. J Clin Endocrinol Metab 82:2985–2990[Abstract/Free Full Text]
  56. Peyreigne C, Raynaud E, Fedou C, Prefaut C, Brun JF, Mercier J 2002 Does growth hormone treatment alter skeletal muscle mitochondrial respiration in rats? Horm Res 58:287–291[CrossRef][Medline]
  57. Lange KH, Isaksson F, Juul A, Rasmussen MH, Bulow J, Kjaer M 2000 Growth hormone enhances effects of endurance training on oxidative muscle metabolism in elderly women. Am J Physiol 279:E989–E996
  58. Florini JR, Ewton DZ, Coolican SA 1996 Growth hormone and the insulin-like growth factor system in myogenesis. Endocr Rev 17:481–517[Abstract/Free Full Text]
  59. Hughes SM, Chi MM, Lowry OH, Gundersen K 1999 Myogenin induces a shift of enzyme activity from glycolytic to oxidative metabolism in muscles of transgenic mice. J Cell Biol 145:633–642[Abstract/Free Full Text]
  60. Wasserman K, Hansen JE, Sue DY, Casaburi R, Whipp BJ 1999 Principles of exercise testing and interpretation: including pathophysiology and clinical applications. 3rd ed. Philadelphia: Lippincott Williams & Wilkins
  61. Esposito JG, Thomas SG, Kingdon L, Gertner JM, Ezzat S, Growth hormone-induced anabolism enhances aerobic capacity in patients with human immunodeficiency virus (HIV)-associated wasting. Program of the 86th Annual Meeting of The Endocrine Society, New Orleans, LA, 2004 (Abstract OR9-3)



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J. G. Esposito, S. G. Thomas, L. Kingdon, and S. Ezzat
Anabolic growth hormone action improves submaximal measures of physical performance in patients with HIV-associated wasting
Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E494 - E503.
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