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The Use of Testosterone in the AIDS Wasting Syndrome

The AIDS wasting syndrome (AWS) is a devastating complication of advanced HIV disease that is characterized by the disproportionate loss of lean body mass in men and gender-specific changes in body composition in women. The precise mechanisms of the wasting syndrome are largely unknown, but include malabsorption, reduced caloric intake, and increased energy expenditure. Recent data suggest that a defect in muscle protein synthesis is also involved.¹ In this setting, loss of potent endogenous anabolic hormones, such as testosterone, may contribute to muscle loss. Treatment with testosterone and testosterone analogues has therefore become an important treatment strategy in HIV-infected patients.

Significant progress has been made in the development of successful anabolic strategies to reverse the loss of weight and lean body mass in patients with AWS. However, wasting remains a significant clinical problem, even in the era of HAART. For example, significant loss of lean body mass was recently shown to occur with weight loss of only 5% in a Community Program for Clinical Research on AIDS (CPCRA) cohort.² Another recent report demonstrated significantly reduced cross-sectional muscle area in patients with wasting, and no difference among patients receiving protease inhibitor (PI) therapy.³ Furthermore, decreased muscle mass was shown to correlate directly with functional status among men with AWS, suggesting that anabolic therapies are much needed in this population.⁴ An important question in this regard is whether PI therapy itself builds lean body mass among patients with wasting. Recently published longitudinal data over 12 months suggest that patients indeed gain weight in response to PI therapy, but not lean body mass.⁵ Furthermore, abnormalities in fat distribution have been reported with PI use, but further research is needed in this area.

The Role of Hypogonadism in the AIDS Wasting Syndrome

The loss of endogenous anabolic hormones such as testosterone is a contributing factor to the striking loss of lean body mass in HIV-infected patients. Early studies demonstrated that testosterone levels were low in over half of all men with AIDS4 and that the prevalence of hypogonadism increased with the severity of the illness. The mechanisms of gonadal dysfunction in HIV-infected men may be primary (related to testicular dysfunction) or secondary (related to hypothalamic/pituitary dysfunction). Primary hypogonadism, seen in approximately 25% of hypogonadal HIV-infected men, is most often idiopathic, but can be caused by anatomic destruction of testicular tissue due to opportunistic infections such as cytomegalovirus, toxoplasmosis, or Kaposi's sarcoma, though this is relatively rare.⁶ More commonly, hypogonadism is secondary, which may be related to the effects of severe illness and undernutrition on gonadotropin production. In addition, medications such as megestrol acetate, a synthetic progestational agent, may result in profound hypogonadism. Rarely, mass lesions of the pituitary and hypothalamus are seen and may represent opportunistic infections, such as toxoplasmosis or HIV-related malignancies, including lymphoma. Recent data suggest that HAART has lowered the prevalence of hypogonadism to 25% of HIV-infected men.⁷ Androgen deficiency is also prevalent in seropositive women. In a recent study, 33% of HIV-infected women without wasting and 66% of women with wasting demonstrated free testosterone levels below the normal range for healthy women.⁸

The diagnosis of hypogonadism is best made by determining the serum free or bioavailable testosterone levels in both men and women. Increased levels of sex hormone binding globulin result in increased total or bound testosterone levels. Measurement of gonadotropin levels is a useful way to differentiate primary from secondary hypogonadism in men. Imaging of the hypothalamus and pituitary glands is recommended in the setting of headache or visual changes or if there are other signs and symptoms of pituitary disease.

The sequelae of hypogonadism among HIV-infected patients include decreased muscle mass and functional capacity, fatigue, and reduced quality of life. Decreased lean body mass is a significant predictor of increased mortality and reduced survival among HIV-infected patients and is therefore an important clinical endpoint in this population. Among men with aws, testosterone levels are highly correlated with lean body mass.⁴ Furthermore, such patients demonstrate a disproportionate loss of muscle mass in comparison to weight. For example, in one study of hypogonadal HIV-infected men, weight was 93% of predicted, but muscle mass only 77% of predicted.⁴ Importantly, significant loss of muscle mass (sarcopenia) correlates directly with functional status among men with aws. Similarly, among women, serum testosterone and dehydroepiandrosterone levels correlate with muscle mass.⁸

Effects of Testosterone on AIDS-Related Wasting

HIV-Infected Men

The effects of testosterone administration in hypogonadal HIV-infected men with wasting were recently investigated. In a randomized, placebo-controlled trial, patients received 300 mg of testosterone intramuscularly every three weeks for six months. Muscle and lean body mass increased significantly in testosterone-treated relative to placebo-treated patients, by approximately 2 to 3 kg.⁹ Importantly, patients reported subjective benefits with respect to improved overall quality of life, appearance, and well being. The testosterone was well tolerated and no patients experienced adverse effects. In an open label extension for six additional months, a sustained anabolic effect of testosterone administration on lean body mass was demonstrated. Patients initially randomized to placebo gained lean body mass only after the cross-over to open-label testosterone, whereas those initially randomized to testosterone continued to gain lean body mass during the last six months. At the end of the year, those who received placebo during months 0 to 6 gained a total of 1.0 kg (2.4%), whereas those receiving testosterone the entire 12 months gained an average of 3.7 kg (7.6%) of lean body mass.¹⁰ No adverse effects on the prostate or prostate-specific antigen levels were seen, and hematocrit increased 3.5% over this time period.

There are important questions as to the efficacy of androgen therapy in eugonadal men with AWS. Although short-term supraphysiologic testosterone dosing has been shown to increase muscle mass in HIV-negative men,¹¹ supraphysiologic dosing cannot yet be endorsed because of potential risks to the prostate, detrimental effects on mood, and acne. Studies being performed under carefully controlled conditions are underway to determine the efficacy of larger dose of testosterone in HIV-infected patients.

Questions remain as to whether combining exercise with anabolic therapy increases functional status in HIV-infected men. Data in non-HIV-infected men suggest an additive effect,¹² but this strategy has not been studied among men with AWS.

Transdermal delivery of testosterone is now an alternative to intramuscular dosing for HIV-infected patients. Two transdermal products, Androderm and Testoderm, are now commercially available. The recommended dose for each is 5 mg/day. Bhasin et al. recently demonstrated that transdermal testosterone (5 mg/day) significantly increases lean body mass by 1.4 kg over three months in hypogonadal men with HIV infection.¹² Potential advantages of transdermal dosing include more stable, steady-state testosterone levels. However, further studies are necessary to ensure that mean and peak testosterone levels are sufficient in response to transdermal dosing. At the present time, either route is acceptable for hypogonadal men with HIV infection. Serum testosterone levels should be checked at least once after initiation of transdermal therapy to ensure that levels are within the normal range.

HIV-Infected Women

Administration of anabolic agents to women with AWS is a relatively new area of clinical research. A significant percentage of seropositive women demonstrate androgen deficiency. To test the hypothesis that androgen supplementation will be effective for HIV-infected women with wasting, a 12-week, double-blind, placebo-controlled pilot study of a transdermal testosterone delivery system for women was conducted. Relatively androgen-deficient women (free testosterone less than the mean of the normal range) were randomized to receive either placebo or a testosterone skin patch delivering testosterone doses of 150 to 300 µg/day. These doses are comparable with the known production rate of testosterone in women. The patch was well tolerated, and side effects were minimal. No virilizing effects on hair growth or lipids were observed. Testosterone concentrations within the physiologic range were achieved only with the 150-µg dose. Patients randomized to the physiologic dose of 150 µg/day¹³ gained 1.9 kg on average. This group also showed significant trends toward improved quality of life and energy. In contrast, patients receiving the higher dose of 300 µg reported less improvement in quality of life measures.¹³ Longer-term studies of physiologic androgen dosing in HIV-infected women are now underway.

Oxandrolone and Nandrolone

Synthetic testosterone analogues have also been studied for their potential anabolic effects on patients with AWS. Oxandrolone, an oral analogue of 17-methyldihydrotestosterone, was studied in a 16-week, double-blind, placebo-controlled preliminary trial. HIV-infected men were randomized to receive either 5 or 15 mg/day of oxandrolone. A significant weight gain was demonstrated in the patients receiving the 15-mg dose, whereas patients on the 5-mg dose maintained their weight but did not have a statistically significant weight gain as compared with the group receiving placebo.¹⁴ Body composition data were not collected in the study. In an open label study of oxandrolone at a dose of 20 mg, patients demonstrated a 5.2-kg weight gain at 12 months and a 3.2-kg gain in body cell mass.¹⁵ However, a significant increase in intracellular water was observed.

Nandrolone decanoate, an injectable 17-alkylated anabolic steroid, was also studied. In a 16-week open label trial in men, nandrolone administration resulted in a 2.3-kg weight gain with a statistically significant increase in lean body mass.¹⁶ However, total body water also increased, and definitive conclusions cannot be drawn from the study because of its open label design.

The risk of liver damage due to oral anabolic agents is significant. These agents must be used with caution, particularly in patients with preexisting liver dysfunction, and effects on the liver may be dose related.

Other anabolic agents under investigation for treatment of aws include topically applied testosterone gels, dehydroepiandrosterone, and dihydrotestosterone (DHT), a nonaromatizable 5- reductase derivative of testosterone, whose levels are reduced in some HIV-infected patients. Preliminary open label studies of DHT suggest that it may have beneficial effect on weight, but further studies are needed.

Treatment Recommendations

All HIV-infected men, particularly those with weight loss and wasting, should be screened for hypogonadism and given physiologic replacement, intramuscularly (200 to 300 mg every two to three weeks) or via transdermal patch (5 mg/day) for at least one year. However, no data on long-term therapy beyond one year are available, and periodic discontinuation of testosterone and reassessment of gonadal function, particularly among men who have recovered weight, may be considered. Serial monitoring of the prostate-specific antigen levels is important with long-term testosterone administration. Among patients who have achieved stable weight and are less ill, testosterone may be discontinued and gonadal function reassessed, as androgen levels may improve with nutritional and immunologic recovery. Use of anabolic steroids as androgen replacement in eugonadal men is not recommended. Studies are now underway to determine the utility of testosterone administration in eugonadal men with wasting, but such a practice cannot now be endorsed outside of a research study. Use of anabolic steroids in this population may also prove beneficial, but further studies are needed.

Conclusions

Although the advent of HAART has changed the face of AIDS for many, it is unlikely that AWS will be eliminated. Patients may fail HAART, and potent antiviral therapy is unable to diminish the severe muscle wasting that characterizes HIV disease. For this reason, anabolic agents that build lean body mass are a reasonable approach to AWS. Hypogonadism, seen in a substantial number of HIV-infected men and women, may contribute to loss of muscle mass, and therefore, to fatigue and diminished quality of life in this population. A significant effect of physiologic testosterone administration on lean body and muscle mass has now been shown in hypogonadal HIV-infected men. This effect is sustained during one year of therapy, and testosterone therapy is well tolerated. Preliminary data in women also shows a significant effect of physiologic testosterone administration on weight and quality of life. Although limited data exists for testosterone analogues such as nandrolone and oxandrolone, further studies are needed to determine their effects at higher doses (especially regarding liver function) as well as their effects on women.

— Colleen Corcoran, MSN, ANP, and Steven Grinspoon, MD

Colleen Corcoran is an Adult Nurse Practitioner at the Massachusetts General Hospital. Dr. Grinspoon is an Assistant Professor of Medicine at Harvard Medical School and a member of the Neuroendocrine Unit at the Massachusetts General Hospital

Published in AIDS Clinical Care April 1, 1999

Citation(s):

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