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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1542-1547
Copyright © 1998 by The Endocrine Society

Original Studies

Effects of Chronic Growth Hormone Treatment on Energy Intake and Resting Energy Metabolism in Patients with Human Immunodeficiency Virus-Associated Wasting—A Clinical Research Center Study1

Kathleen Mulligan, Viva W. Tai and Morris Schambelan

Division of Endocrinology, San Francisco General Hospital, and the Department of Medicine, University of California, San Francisco, California 94110

Address all correspondence and requests for reprints to: Kathleen Mulligan, Ph.D., Division of Endocrinology, San Francisco General Hospital, Building 100, Room 321, 1001 Potrero Avenue, San Francisco, California 94110.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In previous studies, treatment with recombinant human GH (rhGH) produced sustained increases in weight and lean body mass (LBM) and decreases in fat mass in patients with human immunodeficiency virus (HIV)-associated wasting. To evaluate the effects of chronic rhGH treatment on components of energy balance, we recruited separate subgroups of HIV-positive patients with an involuntary weight loss of 10% or more to undergo paired measurements of resting energy metabolism (n = 6) or food intake (n = 11) before and during the final week of a 3-month rhGH (0.1 mg/kg·day) treatment period. In the energy metabolism subset, resting energy expenditure (REE) and substrate oxidation rates were measured by indirect calorimetry during brief admissions to a metabolic ward. Patients in the energy intake subset prepared written 4-day food intake diaries. Body composition was measured in both groups by bioelectrical impedance analysis.

Changes in weight (+2.2 ± 0.9 and +2.2 ± 0.6 kg), LBM (+3.2 ± 0.6 and +3.8 ± 0.5 kg), and fat (-1.0 ± 0.5 and -1.6 ± 0.5 kg) in the energy metabolism and energy intake subsets, respectively, did not differ between groups and were comparable to changes seen in a larger group of patients who received rhGH in a randomized, double blind, placebo-controlled multicenter study. In the energy metabolism subset, REE (+232 ± 69 Cal/day; P = 0.020) and lipid oxidation (+3.1 ± 1.0 Cal/kg LBM·day; P = 0.016) increased, whereas protein oxidation decreased (-1.3 ± 1.0 Cal/kg LBM·day; P = 0.027) during rhGH therapy. These changes in REE and substrate oxidation are comparable to changes we noted previously in a study of the effects of short term rhGH treatment in patients with HIV-associated wasting. Moreover, the sustained increases in lipid oxidation are consistent with the decreases in body fat content that occur with rhGH treatment. In the energy intake subset, a trend for increased daily energy intake (+203 ± 262 Cal; P = 0.456) is obviated when adjustments for changes in weight or LBM are made (+1.3 ± 4.0 and -0.5 ± 5.0 Cal/kg BW and LBM, respectively).

Taken together, these results demonstrate that increases in weight and LBM that occur with chronic rhGH therapy are accompanied by sustained increases in REE and lipid oxidation and decreases in protein oxidation. These changes in body composition occur without a significant increase in energy intake and may, instead, represent a redistribution of body energy stores.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
WASTING is a frequent manifestation of infection with the human immunodeficiency virus (HIV) and a cofactor in disease progression (1, 2) and survival (1, 2, 3, 4, 5, 6, 7). In particular, decreased body cell mass or lean tissue have been associated with increased risk of mortality (3, 6, 7). Because therapies that simply increase energy intake do not consistently restore lean tissue (8, 9, 10), specific protein anabolic agents such as recombinant human GH (rhGH) have been investigated as potential therapies in patients with HIV- associated wasting (11, 12, 13, 14). When studied under metabolic ward conditions with fixed energy intake, treatment with a pharmacological dose of rhGH (0.1 mg/kg·day) for 7 days resulted in weight gain and nitrogen retention in six men with HIV-associated wasting (11). Resting energy expenditure (REE) and rates of lipid oxidation increased, whereas protein oxidation decreased during the treatment period.

On the basis of the salutary effects of short term rhGH treatment on weight and nitrogen retention, a randomized, double blind, placebo-controlled trial was conducted to determine whether rhGH could produce sustained increases in weight and lean body mass (LBM) when studied in a large number of patients under their usual living conditions (12). Patients randomized to treatment with the same pharmacological dose of rhGH used in the metabolic ward study (n = 90) for 3 months experienced sustained increases in both weight (+1.6 ± 0.2 kg) and LBM (+3.0 ± 0.4 kg), and a decrease in fat mass (-1.7 ± 0.2 kg). In contrast, patients who received placebo (n = 88) experienced no net changes in weight or body composition during this period (12).

Thus, treatment with rhGH produced sustained protein anabolic effects in patients with HIV-associated wasting. In view of the fact that decreased energy intake coupled with inappropriately elevated REE are considered to be important factors in wasting in HIV infection (15, 16), we undertook the studies described herein to evaluate the effects of chronic rhGH treatment on these components of energy balance.


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

Two groups of HIV-infected patients with involuntary weight loss of 10% or more of preillness weight were recruited to participate in separate substudies of energy metabolism and dietary intake that were performed before and during the final week of a 3-month period of treatment with rhGH (0.1 mg/kg·day). Patients in both studies lived at home and consumed self-selected diets during the treatment period. They used no other protein anabolic or medicinal appetite-stimulating therapies, but were allowed to use oral nutritional supplements if they chose. The patients had no diagnosed acute infections within 30 days of baseline or at the time of the follow-up assessment. The studies were approved by the institutional review board for the University of California-San Francisco, and signed informed consent was obtained from each volunteer before enrollment in the study.

Effects of rhGH on energy metabolism

Six patients underwent brief (3- to 5-day) metabolic ward studies of REE and substrate utilization before and during the final week of a 3-month rhGH treatment period. For these evaluations, patients were hospitalized at the General Clinical Research Center at San Francisco General Hospital, where they consumed a constant metabolic diet at a level of energy intake that maintained current weight. The energy content of the diet during the follow-up admission was adjusted as necessary to reflect changes in weight that occurred during the treatment period. Protein, carbohydrate, and fat content were adjusted proportionally.

Patients were weighed on a calibrated scales each morning after arising and voiding. Patients wore only a hospital gown for this measurement. They immediately returned to bed and rested in preparation for measurement of REE. After an equilibration period of 30 min, resting O2 consumption and CO2 production were measured continuously for 30 min by indirect calorimetry, using a ventilated canopy system (DeltaTrac metabolic monitor, Sensormedics, Yorba Linda, CA). Urine was collected in 24-h pools for determination of urinary urea nitrogen excretion. Urinary creatinine levels were measured as an index of the completeness of collection. Rates of REE and substrate oxidation were calculated from the measured resting O2 consumption, CO2 production, and daily urinary urea nitrogen excretion (17). In our hands, day to day variability in REE in patients studied under metabolic ward conditions ranges from 2.5–3.0%. Biological variation in REE has been estimated to range from 2.2–2.5% (18, 19). The heat equivalents used for protein, fat, and carbohydrate oxidation were 4.32, 9.46, and 4.18 Cal/g, respectively (20).

Body composition was measured on the final day of each admission by bioelectrical impedance analysis (BIA). Values for resistance and reactance measured on a Valhalla model 1990B (San Diego, CA) single frequency impedance analyzer were used to calculate fat and LBM using published equations that have been validated in a broad spectrum of HIV-negative and HIV-positive individuals (21). In patients maintained on a constant diet, we found the coefficients of variation for LBM and fat measured by this technique to be 0.8% and 5.5%, respectively.

Effects of rhGH on dietary intake

A separate cohort of 11 patients prepared written food intake diaries before and during the final week of 3 months of treatment with rhGH. Patients were instructed to record all items consumed, including dietary supplements, using common household measures. Weight and body composition were measured on an out-patient basis after patients had fasted overnight, following the procedures described above. Body composition in this group was also measured by dual-energy x-ray absorptiometry (DEXA; Lunar model DPX, Madison, WI) (22), using software version 3.6. The coefficients of variation for these measurements in our hands are 0.2% and 3.4% for LBM and fat, respectively. The energy and macronutrient composition of the diets was calculated using Nutritionist IV software (N-squared Computing, San Bruno, CA). At each time point, records from 4 consecutive days were analyzed. The data reported are the average values for those 4 days.

Statistical analyses

Data are reported as the mean ± SEM. Values for LBM measured by BIA were used when expressing energy intake, REE, and substrate oxidation rates per kg LBM, as data evaluated by this technique were available in all patients studied. Results in each group were analyzed by paired t test, using patients as their own controls. Unpaired t tests were used to evaluate differences between groups. P < 0.05 was considered statistically significant.


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

Height, age, body mass index, and weight loss at baseline were comparable in the two groups of subjects (Table 1Go). During 3 months of rhGH therapy, weight and LBM increased significantly in both groups, whereas fat mass declined (Table 1Go). These changes are similar in direction and magnitude to those obtained in the aforementioned randomized, double blind, placebo-controlled, multicenter study of rhGH (12). In the energy intake subset, average LBM and fat measured by DEXA and BIA were similar at baseline. Moreover, DEXA and BIA detected very similar changes in LBM and fat over 12 weeks of rhGH therapy (Table 1Go).


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  		Table 1. Patient characteristics

 
REE and substrate oxidation rates

In patients who participated in the substudy of energy metabolism, baseline REE averaged 32.1 ± 0.6 Cal/kg LBM·day. In all six patients, measured REE exceeded that predicted by the Harris-Benedict equation (range, 105–119%; average, 111 ± 0.2%). After 3 months of therapy with rhGH, REE was significantly increased relative to the baseline (change, +232 ± 69 Cal/day; P = 0.02; Fig. 1aGo). Values for REE increased in all six patients, and in five of six, the differences between baseline and 3 month values were greater than could be explained by increased maintenance needs resulting from increases in LBM (Fig. 1bGo). After adjusting for changes in LBM, the difference in REE approached statistical significance (+2.1 ± 1.0 Cal/kg LBM·day; P = 0.083).



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  		Figure 1. Changes in REE during 3 months of rhGH therapy. Individual data, expressed as kilocalories per day (a) and kilocalories per kg LBM/day (b), depict the results of paired measurements of REE before and during the final week of a 3-month rhGH treatment period. Individual data are indicated by small black squares, and the group mean ± SEM are shown by larger unshaded squares. The mean differences between baseline and rhGH values were +232 ± 69 Cal/day (P = 0.020) and +2.08 ± 0.96 Cal/kg LBM· day (P = 0.083).

 
Lipid oxidation was significantly increased after 3 months of rhGH therapy (+3.1 ± 1.0 Cal/kg LBM·day; P = 0.027; Fig. 2aGo). A more modest, but statistically significant, decrease in protein oxidation also occurred (-1.3 ± 0.4 Cal/kg LBM·day; P = 0.016; Fig. 2bGo). Carbohydrate oxidation rates were unchanged (+0.3 ± 1.1 Cal/kg LBM·day).



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  		Figure 2. Changes in lipid and protein oxidation rates during 3 months of rhGH therapy. Individual data depict the results of paired measurements of resting substrate oxidation rates by indirect calorimetry before and during the final week of a 3-month rhGH treatment period. Individual data for both lipid (a) and protein (b) oxidation are indicated by small black squares, and the group mean ± SEM are shown by larger unshaded squares. Lipid oxidation increased, whereas protein oxidation decreased significantly during rhGH treatment (+3.1 ± 1.0 vs. -1.3 ± 1.0 Cal/kg LBM· day; P = 0.016 and 0.027, respectively). Carbohydrate oxidation was not significantly affected during chronic rhGH therapy (data not shown).

 
Dietary intake

In the subset of patients who prepared food intake diaries, baseline energy intake averaged 42.1 ± 3.6 Cal/kg BW/day (Table 2Go). Fat, protein, and carbohydrate accounted for 31.0 ± 0.3%, 15.8 ± 0.5%, and 53.2 ± 3.2% of daily energy intake, respectively. There were no significant changes in the intake of energy or macronutrients at the end of 3 months of treatment with rhGH (Table 2Go). A modest and nonsignificant trend for an increase in energy intake, expressed as kilocalories per day, was obviated when adjusted for increases in weight or LBM (Table 2Go).


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  		Table 2. Energy and macronutrient intake before and at the end of 3 months of rhGH therapy

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present studies were undertaken to evaluate the effects of chronic treatment with a pharmacological dose of rhGH on energy intake and REE, two components of the energy balance equation that have been previously demonstrated to be altered in many patients with HIV infection. Decreased energy intake has been demonstrated to be the primary factor responsible for weight loss, particularly during episodes of rapid weight loss associated with secondary infection (15, 16). Increased rates of REE, which could be taken to represent a failure to adapt to decreased energy intake, have been observed in patients along all points in the spectrum of HIV infection (11, 15, 16, 23, 24, 25, 26), and we have previously reported a positive correlation between viral load and REE in HIV-infected men (27).

The present studies demonstrate that sustained increases in weight and LBM in patients treated with rhGH for 3 months are accompanied by sustained increases in REE and lipid oxidation and decreases in protein oxidation. The baseline values for REE in patients in the present study (32.1 ± 0.6 Cal/kg LBM·day) are comparable to those reported previously in a group of patients with HIV-associated wasting who were also studied under metabolic ward conditions (32.4 ± 0.5 Cal/kg LBM·day) and whose average REE was 10% greater than that seen in similarly studied HIV-negative controls (11). Likewise, the magnitude of the increase in REE after 3 months of rhGH therapy in the present study is strikingly similar to that reported previously in patients studied during short term rhGH treatment (11).

Increases in REE have also been observed in a broad spectrum of subjects studied during treatment with GH, including obese women consuming eucaloric (28) and hypocaloric diets (29), normal (30, 31) and GH-deficient adults (32, 33, 34), and children of short stature (35). Likewise, REE was reported to be increased in acromegalics, relative to that in normal controls, and declined to normal levels after pituitary adenomectomy (36). None of the individuals given rhGH in these other studies had increased rates of REE during the pretreatment period. In contrast, in the present study, the observed increase in REE was superimposed on already elevated rates of REE, thus, in a sense, exacerbating a metabolic abnormality that is frequently observed in patients with HIV infection. From the standpoint of energy balance, exacerbation of hypermetabolism cannot be regarded as a beneficial result in patients attempting to gain weight and LBM. However, these results demonstrate that reversal of hypermetabolism is not a prerequisite for realizing a protein anabolic effect of rhGH.

The observed sustained increases in lipid oxidation are consistent with the decreases in body fat content noted during 3 months of therapy. This increased ability to rely on fat as fuel might be viewed as particularly beneficial during states of negative energy balance, when increased lipid oxidation might spare body protein stores. However, the overall benefit of increased lipid oxidation and a loss of fat in HIV-infected individuals who are gaining weight is less apparent.

It is unlikely that the increase in lipid oxidation is a reflection of increased dietary fat intake. Patients were fed fixed diets during the brief in-patient admissions during which these measurements were performed. Although energy intake was increased during the second in-patient assessment according to changes in weight, the proportional contributions of all three macronutrients to energy intake were maintained. Moreover, increases in lipid oxidation were also noted in the previous metabolic ward study in patients whose energy and macronutrient intake were fixed before and during rhGH treatment (11).

The present studies suggest that increases in weight and LBM occurred during rhGH treatment in the absence of significant sustained increases in energy intake. We recognize that our method for estimating energy and macronutrient intake (written food diaries), although widely used, is associated with a number of potential sources of error and considerable inter-and intraindividual variability (37, 38, 39). Thus, we cannot exclude the possibility that the failure to note a significant increase in overall energy intake (+203 ± 262 Cal/day; P = 0.456) may have been the result of a type II error. However, it is notable that the average levels of energy intake at baseline and week 12 (42.1 ± 3.6 and 43.4 ± 2.8 Cal/kg·day) are comparable to pre- and posttreatment values in subjects who received both rhGH and insulin-like growth factor I in a study of this combination therapy for HIV-associated weight loss (44 and 43 Cal/kg at baseline and week 12, respectively) (40).

The observation that weight and LBM can increase with rhGH despite no significant increase in energy intake is consistent with the results of our previously reported metabolic ward study in which patients were fed a constant metabolic diet at a level of energy intake that maintained weight constant during a 7-day baseline period. During the 7-day rhGH treatment period that followed, HIV-positive patients with an average weight loss of 19% experienced increases in weight (2.0 ± 0.3 kg) and urinary nitrogen retention (288 ± 17 mmol/day) (11) during a period in which energy intake was fixed. Although the design of the present study does not allow us to determine in a quantitative manner whether there was some transient stimulation of appetite and consequent increase in energy intake that occurred early in the course of treatment with rhGH, we can report that there were very few subjective reports of increased appetite or food intake upon initiation of treatment.

Taken together, these results suggest that the increases in LBM achieved with rhGH could reflect a redistribution of the body’s energy stores, with endogenous fat stores providing the energy required to synthesize and support the metabolic demands of the additional LBM. Because fasting weights were not obtained in these patients in the weeks immediately following initiation of rhGH therapy, no conclusions can be drawn about the time course of body composition changes in the present studies. However, it should be noted that patients treated with rhGH in a placebo-controlled multicenter trial experienced significant increases in weight and LBM after 6 weeks of therapy that were sustained, but not further increased, in the 6 weeks that followed (12). A similar pattern was observed in a second trial, in which patients treated with rhGH experienced a weight gain (+1.6 kg) over 3 months that was identical in magnitude to that in the earlier trial but was not statistically significant because of a high degree of variability in the placebo group (41). This latter trial did not measure body composition, but in the former trial (12), LBM and fat were measured by DEXA, and total body and extracellular fluid volumes were determined by deuterium oxide and sodium bromide dilution, respectively. Intracellular fluid, calculated as the difference between total and extracellular fluid, increased, as did extracellular fluid in patients treated with rhGH. However, the hydration of LBM, calculated by dividing total body water by LBM measured by DEXA, was unaffected (12). Because the changes in weight, LBM, and fat in patients in the present studies were similar in magnitude and direction to those seen in the larger trial, we think it is reasonable to assume that the patients in the present studies experienced increases in intra- and extracellular fluid that were also comparable to those in the larger trial and that a portion of the observed increases in LBM represents an increase in the metabolically active intracellular compartment.

The present studies did not include measurement of total energy expenditure, so it cannot be determined whether overall energy requirements increased concurrent with the increase in REE or whether patients maintained a constant total energy expenditure by decreasing overall activity levels. It should be noted, however, that work capacity increased in patients who participated in the aforementioned multicenter trial, as evidenced by increased treadmill work output at volitional exhaustion (12). These results argue against a systematic decrease in overall activity level. Moreover, many patients in the present studies reported anecdotally that they were able to resume regular exercise regimens during rhGH therapy. Taken together, these observations certainly provide no evidence of decreased activity levels.

In summary, the results of the present studies demonstrate that the increases in weight and LBM that occur with chronic rhGH therapy are accompanied by sustained increases in REE and lipid oxidation and decreases in protein oxidation. Moreover, it appears that these changes in body composition occur without a significant increase in energy intake and instead represent a redistribution of body energy stores. These results suggest that in the absence of a significant increase in energy intake, body fat stores might ultimately limit the magnitude of the increases in LBM and weight that can be achieved with rhGH. Given the evidence that rhGH does not stimulate appetite, these results might also be taken to suggest that in clinically stable patients with a history of weight loss, this agent might best be used in the context of continuing, aggressive nutritional support or in combination with an appetite stimulant. However, prospective studies will be required to determine whether the protein anabolic effects of rhGH can be optimized in this manner.


   Acknowledgments
 
The authors gratefully acknowledge the assistance of Peter Bacchetti, Ph.D., statistician for the General Clinical Research Center, with data analysis; Jennifer Culp with dietary analysis; Wendy Pagett with data collection; and Serono Laboratories (Norwell, MA), who provided the rhGH used in these studies.


   Footnotes
 
1 This work was supported by grants from the NIH (DK-45833) and the University of California Universitywide AIDS Research Program (R90SF211). The studies were conducted at the General Clinical Research Center (RR-83) at San Francisco General Hospital with support by the Division of Research Resources. Back

Received May 29, 1997.

Revised January 12, 1998.

Accepted January 20, 1998.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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