Involuntary weight loss is a common AIDS-defining diagnosis, which is nearly universal in advanced AIDS [1,2]. Fat-free mass (FFM) or body cell mass has a close relationship with survival in AIDS [3-7]. Treatment therapies using parenteral nutrition  and appetite stimulants [9-11] for patients with AIDS wasting syndrome have resulted mostly in repletion of body fat rather than FFM. A number of factors may contribute to the loss of the metabolically active FFM, which may include nutritional, metabolic/hormonal abnormalities including HIV itself, low protein and energy intake, malabsorption, and the catabolic effects of repeated infections [12-20].
Approximately 50% of HIV-infected men who demonstrate AIDS wasting syndrome also have borderline- low serum testosterone levels (<500ng/dl). All the physiological consequences of borderline-low testosterone levels, such as acquired hypogonadism, in men with chronic wasting disorders are unknown. However, the low levels of testosterone may attenuate the effectiveness of any nutritional intervention therapy. Forbes  has shown that the effect of anabolic steroids on FFM follows a dose-response curve. At low doses the observed change in FFM was 1.5-3% of the initial value; this small amount falls within the precision of the techniques for measuring body composition. Large doses of anabolic steroids result in a progressive increase in FFM such that a total steroid dose of 2535mg constitutes a dose that provides a significant increase in both nitrogen retention and FFM.
Kotler et al.  have demonstrated that a critical level of body cell mass must be maintained for survival; below this level death is imminent. Therefore, the ability to accurately monitor changes in body composition is important in the management of AIDS patients. Research by Sluys et al.  focused on the validity of bioimpedance analysis (BIA) for assessing total body water and FFM in AIDS patients, whereas Wang et al.  compared seven methods for measuring body fat in AIDS patients. The investigations by these two groups, however, did not attempt to monitor any changes in body composition during a course of treatment in AIDS patients receiving anabolic therapy. It was therefore the purpose of our study to determine the accuracy of three different body composition methodologies, each varying in expense and technical requirements, for assessing changes in FFM during gonadal hormonal replacement therapy in a group of HIV-positive men with AIDS wasting syndrome.
Design and methods
This clinical study consisted of two phases: phase A was a 21-day, double-blind, randomized placebo-controlled inpatient intervention, followed by phase B, which was a 12-week open-label intervention. Other aspects of this trial are reported in detail elsewhere .
Men were confined to the metabolic research unit of the Western Human Nutrition Research Center. Seven days of weight stabilization and baseline measurements of body composition were followed by 14 days of nandrolone decanoate at either 65 or 195mg per week, or placebo (sterilized sesame oil) administered by intramuscular injections, then repeat body composition testing. Staff and patients were blinded to the randomization.
To rapidly achieve steady-state plasma levels of nandrolone decanoate, a loading dose (240mg for the high-dose group, 80mg for the low-dose group, and sesame oil in the placebo group) was administered intramuscularly on the first treatment day. Injections of 19 or 56mg nandrolone decanoate were administered every other day in the low and high dose groups, respectively.
Patients received a constant protein diet. Energy requirements were estimated using the Harris-Benedict equation with a physical activity factor of 1.5 . Protein intake was 1.46±0.02g/kg daily. Energy from protein was 16.1±0.4%, from carbohydrate 53.3±0.5%, and from fat was 30.6±0.2%. After achieving weight stability on a constant diet during the 7-day baseline period the treatment phase was started.
Weight was measured each morning after voiding and while wearing standardized clothing. Adverse clinical events were assessed by a physician. Prestudy exercise levels were maintained through two chaperoned walks of 1km daily. No other exercise was permitted while in the metabolic research unit.
During the 12-week open-label intervention, the men returned home and continued with normal daily activities. All 18 men were given nandrolone decanoate. Each man was required to report to the Western Human Nutrition Research Center fortnightly for administration of the drug therapy. Upon return to the center for intramuscular injections, follow-up measurements of body composition were made. Out of the 18 men completing the inpatient intervention, eight men completed 12 weeks of open-label intervention and all body composition procedures. The dose of nandrolone administered during the open-label phase was about one-half that given to the high-dose group during the inpatient phase (100 versus 195mg per week) or 200mg fortnightly. Reasons for withdrawal from the study included cytomegalovirus retinitis, chronic sinusitis, worsened lung disease, Pneumocystis carinii pneumonia, general deterioration, bacterial infection, new antiviral regimen, and relocation out of the area.
Recruitment was through advertisements, by referral of health-care providers and from the AIDS wasting clinic at San Francisco General Hospital. Twenty-three men met the entrance criteria (HIV-seropositive, documented involuntary weight loss >5% body weight, serum testosterone concentration <25th percentile for age-group or <33rd percentile with hypogonadal symptoms) and were enrolled in the study. Exclusion criteria were opportunistic infection within 60 days, oropharyngeal pathology, severe diarrhea, Karnofsky score <50, use of medications with metabolic or nutritional effects (corticosteroids, marinol, theophylline, β-agonists, other anabolic agents), change in antiviral regimen within 30 days or use of experimental medications. All subjects were sedentary or light exercisers and none had received androgen treatment in the previous 6 months.
Amongst the 23 men enrolled in the study, the group mean (±SD) CD4 cell count was 90±24×106/l, documented weight loss was 13±1%, and serum total testosterone was 382±133ng/dl. Of the initial 23 volunteers, 18 completed the 21-day inpatient intervention (seven in placebo group, four on low-dose nandrolone, seven on high-dose nandrolone). Two patients were discharged for non-compliance with specimen collection procedures, two left voluntarily due to inability to tolerate confinement, and one patient was disqualified for receiving a testosterone injection just prior to commencing the inpatient phase.
The research protocol was approved by the Institutional Review Boards of the University of California at San Francisco and the US Department of Agriculture. Each man was informed of the study objectives and procedures prior to giving his written consent.
Twenty-four-hour urine and fecal collections were obtained from all men during the inpatient phase. Urine spills were quantified by using preweighed absorbent towels to wipe up the spilled urine (the difference between wet and dry towel weight was calculated as the amount of urine spilled). Total urinary nitrogen was analyzed by combustion (Nitrogen Determinator FP-428, LECO Corporation, St Joseph, Michigan, USA) . Fecal samples were blended, aliquots were homogenized, lyophilized, crushed to a fine powder, dried, and analyzed for nitrogen content using the LECO analyzer. Nitrogen balance was calculated as the difference between dietary intake and the sum of urinary and fecal nitrogen excretion. Because of the variability in intestinal transit time due to intermittent diarrhea with or without the use of antimotility agents, the average daily value for fecal nitrogen measured during the baseline (first 7 days of phase A) or intervention (last 14 days of phase A) periods for each volunteer was used when calculating daily nitrogen balance. The mean baseline value was subtracted from the values during intervention to calculate the cumulative nitrogen retention. For each gram of nitrogen a corresponding value for FFM was calculated based on the constant of 32.5g for the chemical composition of FFM .
FFM was assessed by multifrequency bioimpedance spectroscopy (BIS 4000, Xitron Technologies, San Diego, California, USA) with spectra collected at 18 logarithmically spaced frequencies from 5 to 548kHz. Impedance data were collected using standard procedures with impedance injection electrodes on the dorsal surfaces of the hand and foot at the distal metacarpals and metatarsals; sensing electrodes were positioned between the lateral and medial malleoli of the ankle and the distal prominence of the radius and ulna. The impedance and phase data from all frequencies were fitted to an equivalent Cole-Cole circuit model using non-linear curve-fitting procedures. The estimate of FFM was obtained using the Hanai equation, which is based on emulsion theory and is independent of any known reference value. This method has been previously used and validated in young adult men and women , in women during pregnancy , and under other clinical conditions [30,31].
Dual energy x-ray absorptiometry (DEXA, Lunar Corporation, Madison, Wisconsin, USA) was used to assess bone mineral content and bone-free lean tissue. The sum of these two compartments represented total FFM and has been found to be a valid estimation of FFM when compared with other methods .
Total body water (TBW) was measured using deuterium oxide (D2 O) dilution techniques. Each subject consumed a constant 20g D2 O cocktail (99.8% enriched). Respiratory water-vapor samples were collected before and after the ingestion of the cocktail (0, 3 and 4h). Water vapor samples were analyzed using a Miran fixed filter (Foxboro Company, Foxboro, Massachusetts, USA) infrared spectrophotometer at a wavelength of 392nm. TBW results were corrected for isotopic fractionation using the constant of Wong et al.  and adjusted for D2 O dilution with non-aqueous hydrogen by 4%. Liters were converted to kilograms by multiplying by 0.9934 and to FFM using the constant of 0.73 for the TBW to FFM ratio.
Fig. 1 shows the experimental design of the inpatient and open-label phases of the study.
Descriptive statistics were used to characterize the subjects at the time of admission into the study. One-way analysis of variance (ANOVA) was used for comparing cumulative effects between groups. Repeated measures ANOVA was used for comparing changes in body composition over time. A significance level of P<0.05 was used for all tests.
Physical characteristics of the 18 men completing the inpatient phase are shown in Table 1. At baseline there were no statistically significant differences in age, CD4 cell count, percentage of usual body weight, FFM, fat mass, Karnofsky score, or total testosterone amongst the three groups (Table 1).
Nitrogen balance was not significantly different from zero in any group during the 7-day baseline period. However, during the 14-day intervention cumulative nitrogen balance for the three groups was significantly different (Table 2). During the first week of treatment the placebo group experienced an average nitrogen loss of 5.1g, whereas the low and high-dose treatment groups experienced positive nitrogen balances of 15.6 and 24.4g, respectively (Table 2). Overall, during the 14-day intervention, the placebo group experienced a loss of nitrogen (-11.0±10.7g), whereas low and high-dose nandrolone decanoate treatment groups demonstrated increases in nitrogen balance of 33.4±11.2 and 52.3±10.7g, respectively (Table 3). Assuming that each gram of nitrogen retained corresponds to an accretion of 32.5g FFM, the high-dose treatment group experienced a gain of 0.85±0.18kg FFM per week, the low-dose treatment group averaged 0.55±0.18kg FFM week, and the placebo group had a loss of 0.18±0.10kg FFM per week (Table 3).
Body weight and body composition measurements for the eight men completing all 12 weeks of the open-label phase are shown in Table 4. The initial value corresponded to the end of the inpatient intervention. Statistically significant differences (P<0.05) were observed in the assessment of FFM and fat mass among methods. Results from DEXA and the D2 O dilution methods were similar at the start of the open-label intervention with values of 61.2 and 60.6kg, respectively. The group mean for FFM estimated by the BIS method was 56.5kg, which was significantly lower (P<0.05) than either DEXA or D2 O dilution methods. The difference in the estimate of FFM by DEXA versus BIS persisted during the first 6 weeks of the open-label intervention, although the estimate of FFM by BIS and D2 O dilution were in agreement by 6 weeks of open-label intervention. By 12 weeks, no statistically significant differences were observed amongst the methods.
The accuracy of these three methods can be evaluated by comparison with the accretion of lean tissue based on nitrogen balance. Estimates of lean tissue accretion during the open-label phase were made based on nitrogen retention and accretion during the inpatient phase. The open-label dose was about one-half that on the inpatient intervention; therefore, the expected nitrogen retention would be one-half that observed during the inpatient intervention (0.42kg per week FFM). Table 5 shows the change in body weight, the estimated increase in lean tissue accretion, and the change in FFM assessed by the three different methods during 12 weeks of open-label intervention. The lean tissue accretion corresponded to the change in body weight, suggesting that the constant used was appropriate. At 6 weeks of open-label intervention, weight increased by a further 3.7kg. DEXA and BIS demonstrated increases of 1.8 and 2.8kg, respectively (Table 4). D2 O dilution showed no change in FFM after 6 weeks of open-label intervention. By 12 weeks of open-label intervention, the increase in body weight was slower and greater increases were observed in FFM (Table 5). However, the changes in body composition were not the same among methods. DEXA results showed an intermediate increase in FFM at 6 weeks (1.8kg) compared with BIS and D2 O dilution, with only an additional 1kg increase in FFM from 6 to 12 weeks. BIS results demonstrated a continual increase in FFM throughout the 12-week open-label period. The increases in FFM estimated by BIS most closely matched the projected lean tissue accretion from the nitrogen retention data. Although the 12-week estimate of FFM by BIS was slightly greater than the change in body weight, this can be explained by a loss 1.3kg in body fat from 6 to 12 weeks, resulting in a smaller increase in body weight. D2 O dilution showed a loss of FFM at 6 weeks of open-label intervention. Accordingly, the gain in body weight was attributed completely to a gain in fat mass. This pattern was reversed, however, by the 12-week open-label timepoint, with a 4.8kg increase in FFM and a 3.6kg loss in fat mass.
Borderline hypogonadism occurs in a variety of clinical conditions and is characterized by weight loss, infection, or stress. Decreased reproductive function may be adaptive in many animal models during food scarcity, although the functional significance in humans and clinical reversibility observed in chronic wasting disorders is uncertain.
Previous investigators [1,7] have shown that body cell mass is depleted in HIV-positive patients with AIDS wasting syndrome. Depletion of body cell mass is characterized by a low body weight (<10%) and low total body potassium, independent of body fat levels. The average value for percentage of usual body weight was 86-87% for the present investigation and body fat ranged from 13 to 20%. Kotler et al.  have also demonstrated an increased extracellular fluid volume (ECF) in patients with AIDS wasting syndrome or a relative overhydration of the ECF compartment compared with TBW. These results would suggest that a technique that can distinguish ECF from TBW might be useful in monitoring patient progress.
As a follow-up to the studies by Kotler et al., Wang et al.  used a variety of body composition techniques to assess body composition (specifically body fat) in HIV-positive men. Using in vivo neutron activation (IVNA) as the reference method, Wang et al.  demonstrated that all methods were significantly correlated. However, in the computation of FFM by IVNA a measurement is needed for TBW, and tritium dilution was therefore used for this purpose. Consequently, the relationship between IVNA and tritium dilution as a separate independent measure of body composition was confounded. Another difficulty with the results of Wang et al.  was the use of single frequency BIA, which cannot separate ECF from TBW. Therefore, an increase in ECF would be interpreted as a general increase in TBW and thus FFM, the net result being a lower estimate of fat mass. The research of Kotler et al.  and Wang et al.  was useful in that they demonstrated a depletion in body cell mass and its association with time of death. They did not, however, use different methodologies to monitor changes in patients during the course of therapy.
Sluys et al.  used multiple isotope dilution techniques to estimate TBW, exchangeable sodium and potassium, and body cell mass. These measurement techniques were compared with results obtained from BIA. Again, a strong relationship was observed amongst the methods, but once again the measurements were made under static conditions and not longitudinally during a course of therapy.
The test of any method for body composition assessment in a clinical setting, however, must coincide with a treatment regimen, and it must be able to assess change in patient status. To this end, Katznelson et al.  monitored changes in body composition during an 18-month testosterone enanthate therapy study. Similar to our study, baseline measurements were made while the patients resided in the General Clinical Research Center at Massachusetts General Hospital, and longitudinal measurements were made at 6, 12 and 18 months during an open-label outpatient phase. Body fat was determined using a single frequency BIA instrument, and lean muscle mass (defined as muscle mass minus muscle fat) was determined from quantitative computed tomography images taken at the level of the umbilicus. Similar to the results of our study, Katznelson et al.  demonstrated a 7% increase in lean muscle mass and a decline in body fat. Their work supports the use of BIA as a useful measurement of body fat during the course of long-term anabolic therapy. Research with other methodologies for body composition assessment in this clinical population is lacking.
Validation studies of methodologies such as DEXA and BIS are numerous but rarely include their use in clinical studies other than for weight loss. DEXA has been viewed as an acceptable methodology for the assessment of bone mineral parameters as well as body fat and the soft tissue lean compartment. Van Loan and Mayclin  demonstrated that body fat values from DEXA were equivalent to those obtained by hydrodensitometry in adult women, although the DEXA estimate of body fat was significantly lower than that of hydrodensitometry for adult men. The underestimation of body fat for men resulted in an equivalent overestimation of lean tissue. Other research has shown that the DEXA technique is influenced by tissue depth and composition [35,36]. Laskey et al.  measured controlled standards of varying amounts of lard (to represent fat) and water (to represent fat-free tissue), and found that the assessment of total tissue mass, which is equivalent to body weight, was very accurate and precise. However, fat tissue mass was slightly overestimated (103% of actual value) and lean tissue mass slightly underestimated (98% of actual value). Similarly, Jebb et al.  found differences in body composition assessment of porcine meat when tissue depth changed. Specifically, all data indicated a trend in the measurement of fat mass with depth, such that more fat was measured at extreme depths than at intermediate depths. In meat samples weighing approximately 55kg, DEXA significantly underestimated the absolute fat mass compared with direct chemical analysis. These results have direct relevance to both research and clinical work when using this technique. A confounding issue with the DEXA technique is the observed differences amongst instruments. Modlesky et al.  examined body composition of adult men using both Lunar and Hologic DEXA instruments. Both instruments gave the same result for total body mass; however, Lunar DEXA gave lower values for body fat and higher values for FFM compared with Hologic DEXA. The lower fat mass by Lunar DEXA was about 2kg, whereas FFM was higher by about 2kg. The differences in these body composition parameters were due to differences in the trunk region. The findings of Modlesky et al.  were similar to those in our investigation, namely that DEXA consistently gave lower body fat values and higher FFM values than either BIS or D2 O dilution methods.
Of the methods used in our study, BIS has been evaluated using healthy men and women  and under clinical conditions such as pregnancy , in growth hormone-deficient adults , and in progressive cellular dehydration . In the case of pregnancy , BIS estimates of TBW and ECF were not significantly different from those obtained by D2 O and bromide dilution methods at any time throughout pregnancy. Van Marken Lichtenbelt et al.  used D2 O and bromide dilution methods as the standard techniques for assessment of ECF and TBW in growth hormone-deficient adults. Results from the dilution techniques were confirmed by BIS measurements. Thus, BIS provided an accurate estimate of both ECF and TBW compared with standard dilution methods. In a study of progressive cellular dehydration and proteolysis in critically ill patients, Finn et al.  also used standard dilution techniques to monitor ECF and TBW. BIS was used as well as whole-body neutron activation analysis and whole-body potassium counting. Over the course of the study, intracellular fluid decreased by 15-20%, total body protein by 15%, and total body potassium by about 20%. Intracellular fluid was calculated as TBW minus ECF. There was a substantial decline in ECF (5.9l by bromide dilution); similarly, BIS demonstrated a decline of 5.87l. In all these studies, the investigators demonstrated that BIS was able to distinguish extracellular fluid from TBW. It is the distinction of these fluid compartments that is critical in the accurate assessment of changes in body composition. Based on the nitrogen balance and retention data, our study demonstrated that the BIS method most closely matched the changes in lean tissue accretion in men with AIDS wasting syndrome undergoing anabolic therapy and is therefore a valid method for monitoring changes in body composition.
In conclusion, body composition assessment was performed using nitrogen balance and retention as well as DEXA, BIS, and D2 O dilution in a group of HIV- positive men treated for AIDS wasting syndrome. All of the methods demonstrated an improvement of FFM with nandrolone decanoate intervention. However, changes in FFM, based on nitrogen balance and retention data, during the course of nandrolone decanoate therapy were most closely matched by BIS. Based on previous research, the ability of BIS to distinguish ECF from TBW may be the underlying reason for the greater accuracy in monitoring changes in body composition.
The authors wish to express their appreciation to Mr Patrick Mayclin and Ms Barbara Gale for their assistance in the collection of the DEXA and BIS body composition data as well as the collection of respiratory water vapor for the assessment of TBW. We also wish to thank Mr Manual Tengonciang for his analysis of the D2 O samples. Thanks are due to the staff members of the Bionetics Company that provide nursing and dietary support for the metabolic research unit; without their daily work this study would not have been possible. Finally, acknowledgment and appreciation is extended to the individuals who served as research volunteers for this study.
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