Sarcopenia associated with chronic illnesses

Several studies on the effects of androgen supplementation in HIV-infected men have been reported (Bhasin et al. 1998; 2000; Coodley et al. 1994; Coodley and Coodley 1997; Dobs etal. 1999; Grinspoon etal. 1998; 2000; Sattler etal. 1999; 2002; Strawford et al. 1999a; 1999b; Van Loan et al. 1999). However, many of these studies were not controlled clinical trials. Most of the studies were of short duration ranging from 12-24 weeks. Several androgenic steroids have been studied in a limited fashion, including nandrolone decanoate, oxandrolone, oxymetholone, stanozolol, testosterone cypionate, and testosterone enanthate.

Of the five placebo-controlled studies of testosterone replacement in HIV-infected men with weight loss, three (Bhasin et al. 1998; 2000; Grinspoon et al. 1998) demonstrated an increase in fat-free mass and two (Coodley and Coodley 1997; Dobs et al. 1999) did not. The three studies (Bhasin et al. 1998; 2000; Grinspoon et al. 1998) that showed gains in fat-free mass selected patients with low testosterone levels. Coodley and Coodley (1997) examined the effects of

200 mg testosterone cypionate given every two weeks for three months to 40 HIV seropositive patients with weight loss of greater than 5% of usual body weight and CD4 cell counts of <2 x 105/l in a double-blind, placebo controlled study. Among the 35 patients who completed the first three months of the study, there was no significant difference between the effects of testosterone and placebo treatment on weight gain. However, testosterone supplementation improved overall sense of well-being (p = 0.03). Body composition was not assessed.

In two placebo-controlled, double-blind, clinical trials, we have demonstrated that testosterone replacement in HIV-infected men with low testosterone levels is associated with significant gains in fat-free mass (Bhasin et al. 1998; 2000). There were no significant changes in liver enzymes, plasma HIV-RNA copy number, and CD4 and CD8+ T cell counts with testosterone administration in either of the two trials. In one study (Bhasin et al. 2000), we determined the effects of testosterone replacement, with or without a program of resistance exercise, on muscle strength and body composition in androgen-deficient, HIV-infected men with weight loss and low testosterone levels. This was a placebo-controlled, doubleblind, randomized, clinical trial in HIV-infected men with serum testosterone less than 350 ng/dl, and weight loss of 5% or more in the previous six months. Participants were randomly assigned to one of four groups: placebo, no exercise; testosterone, no exercise; placebo plus exercise; or testosterone plus exercise (Bhasin et al. 2000). Placebo or 100 mg testosterone enanthate were given intramuscularly weekly for 16 weeks. The exercise program was a thrice-weekly, progressive, supervised strength-training program. Effort-dependent muscle strength in five different exercises was measured using the 1RM method. In the placebo-only group, muscle strength did not change in any of the five exercises (-0.3 to -4.0%). This indicates that this strategy was effective in minimizing the influence of the learning effect. Men treated with testosterone alone, exercise alone, or combined testosterone and exercise, experienced significant increases in maximum voluntary muscle strength in the leg press (+22 to 30%), leg curls (+18 to 36%), bench press (+19 to 33%), and latissimus dorsi pulldowns (+17 to 33%) exercises. The gains in strength in all the exercises were greater in men receiving testosterone, or exercise alone compared to those receiving placebo alone. The change in leg press strength was correlated with change in muscle volume (R = 0.44, P = 0.003) and change in fat free mass (R = 0.55, P < 0.001). We conclude that when the confounding influence of the learning effect is minimized and appropriate androgen-responsive measures of muscle strength are selected, testosterone replacement is associated with demonstrable increase in maximal voluntary strength in HIV-infected men with low testosterone levels.

Strength training also promotes gains in lean body mass and muscle strength (Bhasin et al. 1996; 2000). Further, supraphysiologic doses of androgens augment the anabolic effects of resistance exercise on lean body mass and maximal voluntary strength (Sattler etal. 2002; Strawford etal. 1999).

These data suggest that testosterone can promote weight gain and increase in lean body mass, as well as muscle strength in HIV-infected men with low testosterone levels. We do not know, however, whether physiological androgen replacement can produce meaningful improvement in quality of life, utilization of health care resources, or physical function in HIV-infected men. Some studies have reported improvements in mood and depression indices in HIV-infected men after testosterone administration. Emerging data indicate that testosterone does not affect HIV replication, but its effects on virus shedding in the genital tract are not known.

There is a high frequency of low total and free testosterone levels, sexual dysfunction, infertility, delayed puberty, and growth failure in patients with end-stage renal disease (Handelsman etal. 1981; 1985; 1986). Fat free mass is decreased and physical function is markedly impaired in men with end-stage renal disease who are receiving maintenance hemodialysis (Johansen 1999; Painter and Johansen 1999). Androgen administration does not consistently improve sexual dysfunction in these patients (Handelsman 1985). Similarly, the effects of androgen treatment on growth and pubertal development in children with end-stage renal disease remain unclear (Jones et al. 1980; Kassmann et al. 1992). Controlled clinical trials of nandrolone decanoate have reported increased hemoglobin levels with androgen treatment in men with end-stage renal disease who are on hemodialysis (Buchwald et al. 1977; Berns et al. 1992; Johansen et al. 1999). Prior to the advent of erythropoietin, testosterone was commonly used to treat anemia associated with end-stage renal disease. Testosterone increases red cell production by stimulating erythropoietin, augmenting erythropoietin action, and by its direct action on stem cells. Further studies are needed to determine whether testosterone administration can reduce blood transfusion and erythropoietin requirements in patients with end-stage renal disease on hemodialysis.

Patients with autoimmune disorders, particularly those receiving glucocorti-coids, often experience a reduction in circulating testosterone concentrations, muscle wasting and bone loss (MacAdams etal. 1986; Reid 1987; Reid etal. 1994; 1996). In a placebo-controlled study, Reid etal. (1996) administered a replacement dose of testosterone to men receiving glucocorticoids. Testosterone replacement was associated with a greater increase in fat free mass and bone density than placebo.

Chronic obstructive pulmonary disease (COPD) is a chronic debilitating disease for which there are few effective therapies. Muscle wasting and dysfunction are recognized as correctable causes of exercise intolerance in these patients. It has been speculated that low levels of anabolic hormones such as testosterone, growth hormone and insulin-like growth factor-1 may contribute to muscle atrophy and dysfunction (Casaburi et al. 1996). Human growth hormone increases nitrogen retention and lean body muscle in patients with COPD; however, the effects of hrGH on respiratory muscle strength and exercise tolerance remain to be established (B├╝rdet etal. 1997;Pape etal. 1991;Pichard etal. 1996). Schols etal. (1995) examined the effects of a low dose of nandrolone or placebo in 217 men and women with COPD; these authors reported modest increases in lean body mass and respiratory muscle strength. Casaburi etal. (2001) have recently demonstrated that physiologic testosterone replacement increases fat free mass, muscle size, and muscle strength in men with COPD who have low testosterone levels.

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