Belton A. Burrows

Effects of Androgen Administration in Men with the AIDS Wasting Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

The AIDS wasting syndrome is characterized by loss of lean body mass out of proportion to weight [1, 2]. The few effective treatments that have been identified are short-term pharmacologic agonists. Because loss of lean body mass is associated with decreased survival in men with the AIDS wasting syndrome [3], development of therapeutic strategies to increase lean body mass is of critical importance. Half of all men with AIDS are hypogonadal [4], and serum androgen levels correlate with lean body mass among hypogonadal men with the AIDS wasting syndrome [5]. Previous studies in non-HIV-infected hypogonadal men show that androgen administration has a significant anabolic effect on body composition [6-10]. We hypothesized that loss of the potent anabolic hormone testosterone in men with the AIDS wasting syndrome may contribute to the critical loss of lean body mass. Therefore, we investigated the effects of physiologic testosterone administration in men with the AIDS wasting syndrome. Methods Patients In 1995 and 1996, 51 HIV-positive men (42 8 years of age) were recruited from the multidisciplinary HIV practice at the Massachusetts General Hospital and from newspaper, television, and radio advertisements. Weight, testosterone levels, and medication history were determined at a screening assessment. To be included in the study, patients had to have decreased free testosterone levels, defined as less than 42 pmol/L at screening (normal range for men 18 to 49 years of age, 42 to 121 pmol/L [12.0 to 35.0 pg/mL]), and wasting, defined as weight less than 90% of ideal body weight or involuntary weight loss greater than 10% of baseline weight [11]. The CD4 count was not an inclusion criterion. We excluded patients with severe diarrhea (>6 stools/d); hemoglobin value less than 5.0 mmol/L (<8 g/dL); platelet count less than 50 000 cells/mm3; creatinine concentration greater than 177 mol/L (>2 mg/dL); new opportunistic infection within 6 weeks of screening; use of testosterone, anabolic steroids, growth hormone, ketoconazole, or systemic steroid therapy within 3 months before screening; or history of prostate cancer. In addition, patients receiving antiretroviral agents, including protease inhibitors, were required to be receiving a stable regimen for at least 6 weeks before study entry. Ten patients were receiving long-term, stable therapy with megestrol acetate for at least 8 weeks before study entry and were equally distributed between the two treatment groups (5 in the testosterone group and 5 in the placebo group). All patients gave written consent, and the study was approved by the Human Studies Committee of the Massachusetts General Hospital. Protocol Patients were randomly assigned to receive testosterone enanthate, 300 mg (Bio-Technology General Corp., Iselin, New Jersey), or placebo intramuscularly every 3 weeks by self-injection. Participants were stratified for weight less than or greater than 90% of ideal body weight and megestrol acetate use before randomization. Randomization was performed by the Massachusetts General Hospital Pharmacy by using a permuted block algorithm. The correspondence between patient code number and drug was generated by the study statistician; this list was available to the hospital pharmacist but not to the investigators or patients. The placebo contained sesame oil with chlorobutanol as a preservative and matched testosterone enanthate in color and consistency. The study drug was bottled by the Massachusetts General Hospital Pharmacy in containers labeled with the study name, expiration date, and patient code. Before the first injection, participants returned within approximately 2 weeks of the screening visit for a 3-day baseline inpatient visit to the General Clinical Research Center at the Massachusetts General Hospital for hormonal, nutritional, immune function, and body composition analysis, which included assessment by dual-energy x-ray absorptiometry, bioimpedance analysis, potassium-4040 K) isotope analysis, and measurement of urinary creatinine excretion. No patient experienced the onset of a new opportunistic infection, other complication, or substantial weight change between the screening and baseline visits. Patients were instructed on the proper technique for intramuscular injection; those who were unable to self-administer the study drug received injections every 3 weeks from the nursing staff of the General Clinical Research Center. Patients returned for an outpatient visit at 3 months for assessment of weight and determination of total-body potassium content and for a 3-day inpatient visit at 6 months; this visit was identical to the baseline evaluation. Patients also reported on response to therapy at the 6-month visit. Baseline data from 26 patients have been reported elsewhere [5]. Subsequent study visits were timed to correspond to the midpoint between study drug injections. Study drug compliance was confirmed by history, medication diaries, outpatient injection records, empty vial counts, and serum testosterone levels. History of medication use was assessed at each visit. The change in fat-free mass assessed by dual-energy x-ray absorptiometry was the primary clinical end point; changes in weight, muscle mass, total body potassium content, and quality of life were secondary end points. Body Composition Analysis Body composition was determined by four methods: 1) dual-energy x-ray absorptiometry to assess fat and fat-free mass (Hologic-2000 densitometer, Hologic, Inc., Waltham, Massachusetts; precision error, 3% for fat and 1.5% for fat-free mass [12], 2) 40K isotope analysis to assess total-body potassium content in a whole-body counter with sodium iodide detectors fixed above and below the patient at the xiphoid level (Canberra Nuclear, Meriden, Connecticut; precision error < 2.5% on the basis of repeated calibration with a known potassium chloride source [Appendix]), 3) urinary creatinine excretion averaged over 3 days (during which the patient received a meat-free diet) multiplied by a constant of 18 kg of muscle per gram of urinary creatinine and indexed for height to determine the percentage of predicted muscle mass [13, 14], and 4) bioimpedance analysis to determine total-body water content (Bioelectrical Impedance Analyzer Model BIA-101, RJL Systems, Clinton Turnpike, Michigan; correlation with deuterium oxide equivalent to R = 0.99 [15]). Lean body mass was derived from total-body potassium content by using the Equation of Forbes and Lewis of 68.1 mEq of potassium per kg of lean body mass [16]. Nutritional Assessment Weight was measured on the first day of each visit after an overnight fast. The percentage of ideal body weight was calculated on the basis of standard height and weight tables [17]. Patients were instructed on completion of a 4-day food record, which was analyzed for total calorie, fat, protein, and carbohydrate content (Minnesota Nutrition Data Systems, version 8A/2.6, Minneapolis, Minnesota) by the Clinical Research Center dietitian. Patients received an isocaloric, meat-free, protein-substituted diet 3 days before and during the inpatient assessments at baseline and at 6 months, during which creatinine excretion and nitrogen balance were measured. Total urinary nitrogen excretion was measured by the Kjeldal technique from consecutive 24-hour collections averaged over 3 days. Nonurinary nitrogen losses were assumed to be constant at 4 g/d [13, 18, 19]. Nitrogen intake was derived from total protein intake divided by a constant of 6.25 g of protein per g of nitrogen [19]. Calorie and protein intake were monitored on a daily basis and were modified to match the reports in the outpatient food records immediately before these visits. Resting energy expenditure was measured by indirect calorimetry with a metabolic cart. Energy requirements were calculated by using the Harris-Benedict equation [20]. Patient Reports of Response to Therapy Each patients perceived well-being was assessed at the end of the study by using nine linear analogue-scale questions on the overall treatment effect, change in quality of life, personal appearance, weight, and appetite (Table 1) [21]. A Karnofsky score was also determined at each visit. Table 1. Assessment of Patient Response to Therapy* Exercise Functional Testing Exercise history was assessed by a standardized questionnaire adapted from the study by Kohl and coworkers [22]. Exercise functional status was determined at the baseline and final visits by the physical therapy department of the Massachusetts General Hospital by using the 6-minute walk test, the timed sit-to-stand test, and the timed get-up-and-go test [23-25]. The distance covered in 6 minutes, the number of times the patient was able to move from a sitting to standing position in 10 seconds, and the time to cover a distance of 3 meters after standing from a seated position was recorded for each patient. Biochemical and Immunologic Assays Hematocrit and serum levels of follicle-stimulating hormone, luteinizing hormone, sex hormone-binding globulin, and prolactin were measured at the baseline and final visits by using published methods [26]. Serum levels of total and free testosterone were measured by radioimmunoassay kit (Diagnostics Products Corp., Los Angeles, California) with intra-assay coefficients of variation of 5% to 12% for total testosterone and 3.2% to 4.3% for free testosterone. CD4 cell counts were measured by flow cytometry (Becton Dickinson Immunocytochemistry Systems, San Jose, California). Viral burden was determined by using the Amplicor HIV-1 monitor test (Roche Molecular Systems, Branchburg, New Jersey). Statistical Analysis Sample size was based on the change in lean body mass in response to testosterone administration among adult men with acquired hypogonadism [8]. A change of 3.2% 4.0% was expected over 6 months. With 20 patients in each group, the study had an 80% chance of seeing an effect of testosterone at a two-sided

Effects of Testosterone and Progressive Resistance Training in Eugonadal Men with AIDS Wasting: A Randomized, Controlled Trial

Substantial loss of lean body and muscle mass occur among HIV-infected patients with relatively preserved body weight (1); these changes are associated with reduced functional status and strength (2). Protease inhibitor therapy has not been shown to increase muscle mass in patients with AIDS wasting (3), suggesting the need for successful anabolic strategies in these patients. Testosterone therapy and progressive resistance training increase lean body mass in hypogonadal men with AIDS wasting (4-6). However, most men with AIDS wasting have normal testosterone levels (7). We assessed the independent effects of progressive resistance training and testosterone in eugonadal men with AIDS wasting. Baseline (2) and screening data (7) from a subset of participants were previously reported. Methods Patients From 1997 to 1999, 54 HIV-infected men with AIDS-related wasting (weight<90% ideal body weight or self-reported weight loss>10%) and a normal serum level of free testosterone (>42 pmol/L) were recruited through community advertisements and contact with physicians in the multidisciplinary HIV practice at the Massachusetts General Hospital, Boston, Massachusetts, and other community clinics. Exclusion criteria were new opportunistic infection diagnosed within 6 weeks of the study; other contraindication to exercise; use of a new antiretroviral agent within 8 weeks of the study; abnormal prostate-specific antigen level; symptomatic prostatism; prostate malignancy; bipolar disorder; use of parenteral nutrition, megestrol acetate, glucocorticoids, androgen, estrogen, growth hormone or other anabolic agent within 3 months of the study; hemoglobin value less than 90 g/L or greater than 170 g/L; platelet count less than 50 000 cells/mm3; or serum creatinine concentration greater than 177 mol/L (2.0 mg/dL). All patients gave written consent, and the study was approved by the Human Studies Committee of the Massachusetts General Hospital. Protocol Eligible patients were stratified for weight less than 90% of ideal body weight or 90% or greater than ideal body weight. Using a 2 2 factorial design, we randomly assigned patients to receive intramuscular injections of testosterone enanthate (200 mg/wk; Bio-Technology General Corp., Iselin, New Jersey) or placebo and to progressive resistance training (three times per week) or no training for 12 weeks. The study statistician used a permuted-block algorithm with blocks of 8 to perform randomization; the code was available only to the hospital pharmacy that bottled the study drug. Placebo contained sesame oil with chlorobutanol as a preservative and matched testosterone enanthate in color and consistency. Compliance with drug therapy was confirmed by history, outpatient injection records, and vial counts. Patients assigned to training participated in supervised progressive strength training and aerobic conditioning three times per week for 12 weeks. During each session, patients began by performing 20 minutes of aerobic exercise on a stationary bicycle at a target heart rate of 60% to 70% of their age-predicted maximum, in accordance with American College of Sports Medicine recommendations (8). A cool-down period of 15 minutes and normalization of heart rate preceded resistance training. Training was performed isotonically on the following computerized equipment (Life Fitness, Franklin Park, Illinois): leg extension, leg curl, leg press, latissimus dorsi pull-down, arm curl, and triceps extension. A one-repetition maximum weight was established at baseline for each patient on each machine in the best of three efforts. Patients increased resistance as follows: weeks 1 and 2, 2 sets, 8 repetitions/set, 60% one-repetition maximum; weeks 3 through 6, 2 sets, 8 repetitions/set, 70% one-repetition maximum; weeks 7 through 12, 3 sets, 8 repetitions/set, 80% one-repetition maximum. Patients were asked to refrain from exercise for 2 weeks before the baseline visit and to refrain from any exercise or activity beyond normal daily activity during the study. Food intake was ad libitum; caloric intake was determined by using a 4-day food record (Nutrition Data System for Research, version 12A/2.91, Nutrition Coordinating Center, University of Minnesota, Minneapolis, Minnesota). Resting and predicted energy expenditure were calculated (VMAX 29N, SensorMedics, Inc., Loma Linda, California). Clinical End Points Clinical end points were assessed at baseline and 12 weeks. Lean body mass and fat mass were measured by using dual-energy x-ray absorptiometry (QDR-4500 Densitometer, Hologic, Inc., Waltham, Massachusetts) with a precision error of 1.5% for fat-free mass (9). Cross-sectional muscle areas of the leg and arm were assessed by performing computed tomography of the midfemur and humerus (General Electric High Speed Helical CAT Scanner, Milwaukee, Wisconsin; SE 3% for arm muscle area and 1% for leg muscle area). The location of the midfemur and humerus were determined from the scout image. Upper- and lower-extremity muscle strength were measured by using the quantitative muscle function test (10, 11). Peak isometric force of shoulder flexion, shoulder extension, elbow flexion, elbow extension, knee flexion, knee extension, dorsiflexion, and grip were measured on the best of two repetitions (10, 12). Z scores were calculated for upper- and lower-extremity strength (MVCT Computer Analysis Software, Boston, Massachusetts) by standardizing to a group of healthy male controls (11, 12). Serum levels of total and free testosterone were measured by using a radioimmunoassay kit (Diagnostics Products Corp., Los Angeles, California) (4). CD4 cell counts were measured by using flow cytometry (Becton-Dickinson Immunocytochemistry Systems, San Jose, California); viral load was measured by using the Amplicor HIV-1 Monitor (Roche Molecular Systems, Branchburg, New Jersey). Other tests were done according to published methods (13). A digital prostate examination was performed at each visit. Statistical Analysis The effects of training and testosterone were simultaneously assessed in the same factorial model. In the primary analysis, we used analysis of covariance to assess change from baseline at 3 months simultaneously in the testosterone arm (testosterone recipients vs. placebo recipients) and the training arm (trained patients vs. nontrained patients), controlling for baseline values. To test for an interaction between testosterone and training, we used analysis of covariance with an interaction term. Change in lean body mass was the primary clinical end point for the effect of testosterone, and change in cross-sectional muscle area was the primary end point for the effect of resistance training. Change from baseline was also determined within each individual treatment group and was compared with zero change by using analysis of covariance. The t- test was used to compare treatment groups at baseline. All available data are included in the analysis. Results are reported as the mean SD. Results No patient withdrew from the study because of an adverse event or side effect; dropout rates did not differ by group (Appendix Figure). Patients had lost significant weight but were not severely ill or low weight at study entry (Table 1). Seventy-six percent of patients were receiving antiretroviral therapy and 72% were receiving highly active antiretroviral therapy. Seventy-six percent of patients had previously had an opportunistic infection. Appendix Figure. Flow of participants through the study. Table 1. Results of Factorial Analysis Changes in response to testosterone therapy and training are shown in Table 1. Lean body mass and muscle area increased significantly in response to training and testosterone therapy. Muscle strength on elbow flexion and shoulder extension and overall upper-extremity Z score increased in response to testosterone therapy. The change in muscle area correlated with the change in muscle strength (R =0.48; P =0.001 for mid-thigh muscle area and strength on knee extension). No interaction was found between testosterone therapy and training. Levels of high-density lipoprotein (HDL) cholesterol increased in response to training but decreased in response to testosterone therapy. Levels of total and free testosterone increased in response to testosterone therapy, and levels of gonadotropin and sex hormonebinding globulin decreased. Caloric intake did not change significantly between the groups. The CD4 count did not change significantly in response to training or testosterone therapy (P >0.2). Viral load decreased in testosterone-treated patients. Use of antiretroviral therapy did not change in any study group. Levels of aspartate aminotransferase or prostate-specific antigen did not change significantly (P >0.2). No patient developed new prostate nodules. Three patients developed breast tenderness or gynecomastia (two were receiving testosterone and one was receiving placebo). Compliance with the training program was 78% among patients who completed the study; compliance with testosterone therapy was 98%. Discussion Previous studies suggest that testosterone therapy, alone (4, 5) and in combination with resistance training, increases lean body mass in hypogonadal men with AIDS wasting (6). However, recent data indicate that androgen levels are normal in most HIV-infected men (7), and the independent effects of testosterone and supervised exercise in eugonadal men with AIDS wasting are not known. The patients in our study generally had normal body weight and a normal Karnofsky score but had lost substantial weight. Most patients had a history of opportunistic infection, and although they were not cachectic or malnourished, they had reduced muscle mass (2). Previous studies have shown that resistance training in combination with testosterone or anabolic steroid therapy increases lean body mass (6, 14, 15). In contrast, we found that training had a significant effect (increase of 2.3 kg) on lean bod

Potassium depletion in hepatic cirrhosis. A reversible cause of impaired growth-hormone and insulin response to stimulation.

Abstract Seven of 17 patients with cirrhosis and impaired carbohydrate tolerance were found to have potassium depletion as judged by rises of body potassium from 12.7 to 35.8 per cent of the initial value during potassium chloride administration. Plasma insulin and growth-hormone response to the administration of glucose or arginine was initially below normal in the potassium-depleted patients but elevated above normal in those without potassium depletion. Administration of 180 mEq of potassium chloride daily for a period of two or more weeks resulted in increased body potassium, improved glucose tolerance and increased insulin and growth-hormone responses in the seven potassium-depleted cirrhotic patients, but no significant change in any of these measurements in the others. These observations indicate that potassium depletion in cirrhotic patients is associated with a diabetic glucose tolerance test and reduced output of both insulin and growth hormone and that potassium repletion may be accompanied by ...

BODY FLUID AND ELECTROLYTE COMPOSITION IN ARTERIAL HYPERTENSION. I. STUDIES IN ESSENTIAL, RENAL AND MALIGNANT HYPERTENSION

In previous studies in this laboratory it was found that the capacity to excrete sodium as indicated by the rate of excretion of an intravenously administered sodium load was significantly increased in essential and renal hypertension (1, 2). Sodium excretory capacity was reduced by antihypertensive therapy and was correlated significantly with the level of arterial pressure. However, the absence of a high degree of correlation, together with the ability of dietary sodium intake to influence the renal capacity to excrete sodiun-m, suggested that in addition to an elevated blood pressure other factors such as an increase in body sodium and fluid volume might enhance sodium excretion in hypertensive individuals. Studies in Cushings syndrome and Addisons disease by other workers suggest that the level of adrenal cortical activity may influence not only the renal capacity to excrete sodium but also the arterial pressure as well as the bodys content of fluids and electrolytes (3, 4). In line with these observations are recent relports indicating that an increase in aldosterone activity occurs in certain groups of hypertensive subjects (5-7). To clarify the relationship of arterial hypertension to alterations in adrenal cortical function and in electrolyte and water metabolism, it was decided to study body fluid and electrolyte composition in various forms of hypertension, including that associated with primary aldosteronism (8). The present report describes the findings in essential, renal and malignant hypertension. The observa-

STUDIES OF ALKALOSIS. II. ELECTROLYTE ABNORMALITIES IN ALKALOSIS RESULTING FROM PYLORIC OBSTRUCTION

It has been clearly established in experimental animals with pyloric obstruction that the stomach contents contain both sodium and chloride, but because the chloride loss exceeds that of sodium, that alkalosis results (1). More recently, in addition to extracellular water and electrolyte deficits, intracellular deficits of potassium-and partial replacement of these deficits by sodiumhave been demonstrated in experimentally induced alkalosis (2, 3), and in patients with alkalosis from vomiting (4). This report describes abnormalities of water and electrolyte metabolism, and discusses some mechanisms of their production, in patients with alkalosis resulting primarily from loss of upper gastrointestinal contents. Renal insufficiency, which occurred in a number of them, was the subject of a previous report (5).

The effects of L-thyroxine sodium on nontoxic goiter, on myxedema and on the thyroid uptake of radioactive iodine.

SYNTHETIC thyroxine is apparently absorbed and physiologically active when ingested, although it has generally been used intravenously.1 2 3 4 5 6 Clinical studies employing oral administration of ...

I131-Diodrast Studies in Unilateral Renal Disease

A procedure utilizing I131-Diodrast with carrier Diodrast and a ratiometer has been evaluated for the early diagnosis of unilateral renal disease. Relative differences in function between kidneys demonstrated by this procedure correlated well with findings at surgical exploration or autopsy. In 3 patients with unilateral renal arterial stenosis who had normal intravenous pyelograms, I131-Diodrast results were abnormal. Although normal I131-Diodrast results may rule out unilateral renal disease, an abnormal result with I131-Diodrast may be seen with any lesion resulting in urine flow differences between kidneys.

Body fluid and electrolyte composition in cardiac patients with severe heart disease but without peripheral edema.

A LTHOUGH excessive retention of sodium and water is a striking feature in frank congestive heart failure, little is known about the abnormalities in body fluid and electrolyte metabolism in cardiac patients with severe heart disease prior to the development of obvious peripheral edema. Previous studies in nonedematous cardiac patients have not revealed any impairment in the handling of oral or intravenous sodium loads prior to the appearance of edema.2 3 Therefore, the present study was undertaken to determine whether any abnormality in body fluid and electrolyte metabolism might be present in such patients even though they might appear to handle sodium loads normally. When it was found that these nonedematous cardiac patients had significant increases in exchangeable sodium and radiosulfate space, it was decided to attempt to correlate such changes in body fluids and electrolytes with cardiovascular and renal hemodynamic function.

The renogram: Physiologic basis and current clinical use

Externally monitored radioisotopic renal function studies have proven to be diagnostically useful in a variety of urinary tract disorders. Controversy, however, concerning everything from equipment and patient preparation to information content and interpretation has surrounded the procedure since its inception. The theses presented here are that the choice of equipment is determined by the intended use, that a few major physiologic events determine the shape of the curves produced in the studies, that the information content exceeds what has been extracted to date, and that subtle renal abnormalities are better detected by intercomparison of a patients two kidneys than by comparison to values derived from a selected normal population. Choice of patient preparation and interpretation of the results depend on understanding the physiology involved in the procedure.

The use of radioactive isotopes in the diagnosis of hypertension

Summary Although radioisotopic technics for the diagnosis of renovascular hypertension have been available for less than a decade, they have been demonstrated to provide unique information with a minimum of inconvenience and discomfort to the patient. Kinetic data, obtained with I 131 -Hippuran, and scans, showing the anatomical location of a labeled mercurial, are of established value as screening procedures for renovascular hypertension and may, in addition, be useful in predicting the outcome of surgery in an individual patient.