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Measurements of total and free testosterone levels in women have lacked precision and accuracy because of limited assay sensitivity. The paucity of normative data on total and free testosterone levels in healthy women has confounded interpretation of androgen levels in women with human immunodeficiency virus (HIV) infection and other disease states. Therefore, the objectives of this study were to develop sensitive assays for the measurement of the low total and free testosterone levels in women to define the range for these hormones during the normal menstrual cycle and assess the total and free testosterone levels in HIV-infected women. By using a larger volume of serum, increasing the incubation time, and reducing the antibody concentration, the sensitivity of the total testosterone assay was increased to 0.008 nmol/L, and that of the free testosterone assay was increased to 2 pmol/L. The mean percent free testosterone was 1.0 +/- 0.1% of the total testosterone. Serum total and free testosterone levels in the follicular and luteal phases were not significantly different, but both demonstrated a modest preovulatory increase, 3 days before the LH peak. Serum total [0.50 +/- 0.32 (14.60 +/- 9.22) vs. 1.2 +/- 0.7 nmol/L (34.3 +/- 21.0 ng/dL); P < 0.0001] and free testosterone levels (5.56 +/- 2.70 (1.58 +/- 0.80) vs. 12.8 +/- 5.5 pmol/L (3.4 +/- 1.7 pg/mL); P < 0.0001) were significantly lower in HIV-infected women (n = 37) than in healthy women (n = 34). Serum total and free testosterone levels were also significantly lower in HIV-infected women who were menstruating normally. There were no significant differences in serum total and free testosterone levels between those who had lost weight and those who had not. Testosterone levels correlated inversely with plasma HIV ribonucleic acid copy number. Serum FSH, but not LH, levels were significantly higher in HIV-infected women than in controls. Using assays with sufficient sensitivity, we defined the range for total and free testosterone levels during the normal menstrual cycle. Serum total and free testosterone levels are lower in HIV-infected women and correlate inversely with plasma HIV ribonucleic acid levels. The hypothesis that androgen deficiency contributes to wasting in HIV-infected women remains to be tested.
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PMID:The use of a sensitive equilibrium dialysis method for the measurement of free testosterone levels in healthy, cycling women and in human immunodeficiency virus-infected women. 1129 35

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.
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PMID: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 study. 958 52

Wasting is a state of nonvolitional weight loss that frequently afflicts patients with cancer or those infected with the human immunodeficiency virus. Body composition measurements afford a more clinically relevant assessment of an individual's functional capacity, energy stores, and prognosis. Several techniques of body composition measurements exist, each with selected advantages and disadvantages. This review summarizes the methods and the utility of body composition analysis.
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PMID:The role of body composition measurements in wasting syndromes. 962 78

Diarrhea and malabsorption are common findings in patients with the acquired immunodeficiency syndrome (AIDS). The pathogenesis and consequences of malabsorption in human immunodeficiency virus (HIV) infection are similar to those found in non-HIV-related conditions, and are related to both direct intestinal damage and alterations in the coordination of the body's response to feeding. The pathogenesis of malabsorption is multifactorial and includes primary enterocyte injury with partial villus atrophy and crypt hyperplasia, ileal dysfunction with bile salt wasting and fat malabsorption, and exudative enteropathy. Clinical studies show that intestinal cryptosporidiosis leads to excess fecal losses of about 20% for protein and fat. The consequences of malabsorption include decreased appetite; "enterogastrone" effects including dry mouth, decreased gastric acid secretion, decreased rate of gastric emptying, and slowed intestinal transit; anemia resulting from iron, folate, or vitamin B12 malabsorption; and metabolic effects including osteomalacia, gallstones, renal stones, and hypocholesterolemia. Few studies of nutritional therapy have been applied specifically to AIDS patients with malabsorption. Total parenteral nutrition promotes weight gain, although the response to this therapy depends on the underlying clinical problem, with body cell mass repletion noted in patients with malabsorption but predominantly fat gain in patients with systemic infections. Nutritional stabilization also was noted in response to oral administration of a semielemental diet.
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PMID:Human immunodeficiency virus-related wasting: malabsorption syndromes. 962 87

Wasting is a debilitating complication of the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and is a major cause of morbidity and mortality. The etiology of wasting in HIV/AIDS is complex and its origins are multifactorial. Both patterns of simple starvation and the more complex metabolic and endocrine alterations associated with stress and trauma have been described in patients with the AIDS wasting syndrome. Observations suggest that the pathophysiology of the wasting in individual patients with HIV/AIDS may vary according to the primary cause of wasting and underlying disease activity. Optimal treatment of the AIDS wasting syndrome will depend on a thorough evaluation of all possible contributing factors. This review addresses the pathophysiologic basis of weight loss in HIV/AIDS, based on the current literature.
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PMID:The etiology of wasting in the human immunodeficiency virus and acquired immunodeficiency syndrome. 962 88

Recent improvements in the management of people living with human immunodeficiency virus (HIV) disease in the United States have led to remarkable reductions in HIV-related morbidity and mortality. The Centers for Disease Control and Prevention recently reported substantial reductions in acquired immunodeficiency syndrome (AIDS)-related opportunistic infections and conditions, including HIV-related wasting. These achievements followed the introduction of the new class of antiretroviral therapies, the aspartyl protease inhibitors, and their use in combination with nucleoside inhibitors in so-called highly active antiretroviral therapies. In an effort to provide guidance for clinicians in HIV care, the Office of AIDS Research, United States Department of Health and Human Services recently convened a panel of experts to set clinical practice guidelines for the use of antiretroviral therapy in adults and adolescents. This article summarizes the new standard of care for the use of HIV therapies. It also reviews recent data suggesting that combination therapy has altered the natural history of HIV infection and has reduced the incidence of HIV-related nutritional disturbances and wasting.
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PMID:Current antiretroviral therapy and its impact on human immunodeficiency virus-related wasting. 962 90

Weight loss and wasting are significant contributors to morbidity in patients infected with the human immunodeficiency virus (HIV). The approach to the patient with HIV and weight loss needs to be proactive and comprehensive, as early intervention may be beneficial and the weight loss may be multifactorial. Evaluation for weight loss needs to be directed at any apparent contributing cause and can include dietary evaluation, treatment of intercurrent complicating infections or malignancies, and maximization of HIV therapy. Some patients will also benefit from an evaluation of the gastrointestinal tract to document malabsorption and/or opportunistic enteric infections. It is also prudent to evaluate testosterone levels in male patients. Interventions in the patient who is not able to take in sufficient calories should include dietary advice and/or nutritional supplements, as well as the use of appetite stimulants. Megace (Bristol-Myers Squibb, Princeton, NJ) has been shown to effectively increase appetite, oral intake, and body weight. For the patient with malabsorption and/or diarrhea, treatment of enteric infections should be attempted. These patients may benefit from the replacement of some dietary fat with medium-chain triglycerides, either in a nutritional product or to replace cooking oils. Other patients may benefit from the use of anabolic agents such as growth hormone, nandrolone, testosterone, or oxandrolone, which are all effective at increasing lean body mass. For select patients, agents such as thalidomide might be of benefit, although its mechanism of action is not clear. There are few data from prospective, controlled trials of combinations of these agents, but these studies are underway. It is likely that the optimal interventions for patients will be combinations of agents to improve oral intake and add lean body mass, which will permit a reduction in morbidity from weight loss and an improvement in quality of life for the HIV-infected patient.
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PMID:Single-agent/combination therapy of human immunodeficiency virus-related wasting. 962 91

The major acquired immunodeficiency syndrome (AIDS) clinical trials groups in the Division of AIDS of the National Institutes of Health have been investigating weight loss and wasting in persons with the human immunodeficiency virus (HIV) and AIDS. Both the AIDS Clinical Trials Group (ACTG) and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) have developed research projects to study the pathogenesis, diagnosis, prevention, and treatment of HIV-related malnutrition and wasting. This article reviews multicenter trials concerning HIV-related malnutrition and wasting conducted by the AIDS clinical trials groups. CPCRA trials will examine the effects of caloric supplements and triglycerides, or the use of megestrol acetate, oxandrolone, and progressive resistance training, on weight loss in patients with HIV-associated wasting. Planned ACTG trials will study the effects of the combination of megestrol acetate and testosterone, the testosterone derivative nandrolone decanoate, or highly active antiretroviral therapy on weight loss. Results from these studies may also have relevance to clinical oncologists who are treating patients with cancer-related cachexia.
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PMID:Clinical trials update in human immunodeficiency virus wasting. 962 92

We studied the effects of enteral supplements on protein and energy intakes, body composition, energy expenditure, and gastrointestinal histology in 49 subjects with human immunodeficiency virus-associated weight loss (12.7 +/- 0.9% of body wt). We also determined whether a stable-isotope mass spectrometric measurement at baseline might predict the short-term response of fat-free mass (FFM) measured by bioelectrical impedance analysis. Thirty-nine subjects completed the study after being randomly assigned to receive either a whole-protein-based (n = 22) or a peptide-based (n = 17) formula. A nonsupplemented, nonrandomly assigned group (n = 13) was followed concurrently. Both formulas were well tolerated. Voluntary intakes of energy and protein from nonsupplement sources decreased significantly during supplementation [by 819-1638 kJ (196-382 kcal)/d and 5.6-14.4 g protein/d, respectively; P < 0.01] but to a lesser extent than the intake from the supplement [2300-2510 kJ(550-600 kcal)/d and 19-28 g protein/d, respectively], so that net increases in intakes of protein and energy (P < 0.03), as well as of several vitamins and trace elements were increased. Nevertheless, the mean FFM did not increase for the group as a whole, although there was considerable interindividual heterogeneity. Changes in FFM at 6 wk were significantly inversely correlated (r = 0.65, P < 0.01) with baseline synthesis of fat (de novo hepatic lipogenesis), but not with other potential measures of energy intake (insulin-like growth factor 1 or its binding protein) or inflammation (soluble tumor necrosis factor receptors I or II). The prospective identification of FFM response by measurement of de novo hepatic lipogenesis supported the hypothesis that the subset of wasting patients whose FFM is unresponsive to nutrient supplementation have altered nutrient metabolism.
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PMID:De novo lipogenesis predicts short-term body-composition response by bioelectrical impedance analysis to oral nutritional supplements in HIV-associated wasting. 966 9

Although human immunodeficiency virus (HIV) disease is increasing rapidly among women, no prior studies have investigated gender-based therapeutic strategies for the treatment of acquired immunodeficiency syndrome (AIDS) and its complications in this population. Markedly decreased serum androgen levels have been demonstrated in women with AIDS and may be a contributing factor to the wasting syndrome in this population. To assess the effects of androgen replacement therapy in women with AIDS wasting, we conducted a randomized, placebo-controlled, pilot study of transdermal testosterone administration. The primary aim of the study was to determine efficacy in terms of the change in serum testosterone levels, safety parameters and tolerability. A secondary aim of the study was to investigate testosterone effects on weight, body composition, quality of life, and functional indexes. Fifty-three ambulatory women with the AIDS wasting syndrome defined as weight less than 90% of ideal body weight or weight loss of more than 10% of the preillness maximum, free of new opportunistic infection within 6 weeks of study initiation, and with screening serum levels of free testosterone less than the mean of the normal reference range (< 3 pg/mL) were enrolled in the study. Subjects were age 37 +/- 1 yr old (mean +/- SEM), weighed 92 +/- 2% of ideal body weight, and had lost 17 +/- 1% of their maximum weight. CD4 count was 324 +/- 36 cells/mm3, and viral burden was 102,382 +/- 28,580 copies. Subjects were randomized into three treatment groups, in which two placebo patches (PP), one active/one placebo patch (AP group), or two active patches (AA group) were applied twice weekly to the abdomen for 12 weeks. The expected nominal delivery rates of testosterone were 150 and 300 microg/day, respectively, for the AP and AA groups. Forty-five subjects completed the study (PP group, n = 13; AP group, n = 14; AA group, n = 18). Two additional subjects from the PP group and two from the AP group were included in the intent to treat analysis. Serum free testosterone levels increased significantly from 1.2 +/- 0.2 to 5.9 +/- 0.8 pg/mL (AP) and from 1.9 +/- 0.4 to 12.4 +/- 1.6 pg/mL (AA) in response to testosterone administration (P < 0.0001 for comparison of AA vs. PP and AP vs. PP; normal range, 1.3-6.8 pg/mL). Testosterone administration was generally well tolerated locally and systemically, with no adverse trends in hirsutism scores, lipid profiles, or liver function tests. Weight increased significantly in the AP group (1.9 +/- 0.7 kg) vs. the PP group (0.6 +/- 0.8 kg; P = 0.043), but did not increase significantly in the AA group (0.9 +/- 0.4 kg; P = 0.263 vs. PP, by mixed effects model assessing the interaction of time and treatment on all available data, one-tailed test). Improved social functioning (P = 0.024, by one-tailed test) and a trend toward improved pain score (P = 0.059) were observed in the AP vs. the PP-treated patients (RAND 36-Item Health Survey questionnaire). Five of six previously amenorrheic patients in the AP group had spontaneous resumption of menses compared to only one of four amenorrheic patients in the AA group (P = 0.045 for comparison of actual number of periods during the study). This study is the first investigation of testosterone administration in women with AIDS wasting. We demonstrate a novel method to augment testosterone levels in such patients that is safe and well tolerated during short term administration. At the lower of the two doses administered in this study, testosterone therapy was associated with positive trends in weight gain and quality of life. Higher, more supraphysiological, dosing was not associated with positive trends in weight or overall well-being. These data suggest that testosterone administration may improve the status of women with AIDS wasting. Further studies are needed to assess the effects of testosterone on weight in HIV-infected women and to define the optimal therapeutic window for test
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PMID:Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study. 970 37


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