Effects Of Androgen Replacement On Body Composition And Muscle Function In Hiv Infection

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Several different anabolic interventions have been examined as treatments for HIV-related wasting, including appetite stimulants (such as dronabinol) (54) and meges-

terol acetate) (55), anabolic hormones (such as human growth hormone (56,57), insulin-like growth factor (IGF)-1 (57), and androgens (44,52,53,58-67); and immune response modulators, such as thalidomide. Dronabinol increases appetite but does not increase lean body mass. Similarly, megesterol acetate treatment produces a modest weight gain but no significant change in lean body mass. Importantly, this progestational agent decreases serum testosterone levels and may produce androgen deficiency symptoms.

In two recently published clinical trials, treatment of HIV-infected men with human growth hormone (hGH) was associated with a 1.5-kg increase in lean body mass (56,57). Although greater gains in weight were recorded after 6 wk of hGH treatment, these gains were not sustained with continued treatment for 12 wk. The reasons for the failure to sustain weight gains during hGH treatment are not clear, although it is conceivable that weight gain early in the course of treatment results from water retention. Growth hormone (GH) administration is often associated with side effects, including edema, arthralgias, myalgias, and jaw pain. Not surprisingly, treatment-discontinuation rates were high (21-40%) in the two hGH studies. The annual cost of treating HIV-infected men with hGH is substantially greater than that of testosterone replacement therapy using any of the available androgen formulations.

Several studies of the effects of androgen supplementation in HIV-infected men have been reported and are summarized in Table 1 (6,44,52,53,58-60,62-67). However, many of these studies were not controlled clinical trials. In addition, most studies were of short duration, ranging from 12 to 24 wk. 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 (see Table 1) (52,60,68) demonstrated an increase in fat-free mass, and two (59,62) did not. The three studies (60,68,69) that showed gains in fat-free mass selected patients with low testosterone levels. Coodley et al. (59) examined the effects of 200-mg testosterone cypionate given every 2 wk for 3 mo to 40 HIVseropositive patients with weight loss of greater than 5% of usual body weight and CD4 cell counts of less than 2 x 105/L in a double-blind, placebo-controlled study. Of the 35 patients who completed the first 3 mo of the study, there was no significant difference in weight gain between testosterone and placebo treatment. However, testosterone supplementation improved overall sense of well-being (p = 0.03). Body composition was not assessed.

In a placebo-controlled, double-blind, clinical trial, we examined the effects of physiological testosterone replacement by means of the nonscrotal patch (60). Forty-one HIV-positive men with serum testosterone levels less than 400 ng/dL were randomly assigned to receive either two placebo patches nightly or two testosterone patches, designed to release 5 mg testosterone during a 24-h period. Testosterone replacement was associated with a 1.34-kg increase in lean body mass (p = 0.02), as well as a significantly greater reduction in fat mass than that observed with placebo treatment. There were no significant changes in liver enzymes, plasma HIV-RNA copy number, or CD4 and CD8+ T-cell counts. Both placebo and testosterone-treatment were associated with a significant increase in muscle strength. Because most of the participants in this study did not have prior weight-lifting experience, we hypothesized that the apparent increase in muscle strength in the placebo group reflected a learning

Table 1

Placebo-Controlled Studies of Androgen Supplementation in HIV-infected Men

Subjects

Treatment Regimen

Changes in Body Composition

Changes in Muscle Function

Comments

Grinspoon et al., 1998 (61)

Grinspoon et al., 2001 (72)

HIV-infected men with serum testosterone <400 ng/dL

HIV-infected men with AIDS wasting syndrome and free-testosterone levels <42 pmol/L

HIV-infected men with >5% weight loss and serum testosterone less than 350 ng/dL

HIV-infected men with AIDS wasting syndrome

HIV-infected men with AIDS and 5-10% weight loss, and baseline testosterone <400 ng/dL or free testosterone <16 pg/mL HIV-infected men with >5% weight loss, and CD4 counts <200/cmm

Testosterone patch (5-mg d) vs placebo patch x 10 wk

300-mg every 3 wk x 6 mo

100-mg testosterone enanthate weekly x 16 wk, with or without resistance training; placebo controlled 200-mg testosterone enanthate weekly, with or without strength training; placebo controlled x 12-wk

Testoderm 6-mg scrotal patch vs placebo patch x 12 wk

Testosterone cypionate 200 mg every 2 wk x 12 wk vs placebo in a crossover design

+1.3 kg gain in FFM after testosterone replacement

+2 kg increase in FFM; no change in fat mass

+2.9 kg gain in testosterone-treated

Greater increments in muscle mass and volume in response to testosterone and resistance exercise training as compared to placebo

Changes in body weight or body cell mass by bioelectrical impedance not significantly different between testosterone and placebo groups

No significant differences in change in body weight between testosterone and placebo periods

Strength gains in placebo and testosterone-treated men not significantly different Muscle strength not measured; no change in exercise functional capacity

Significantly greater gains in muscle strength with testosterone treatment than with placebo Strength gains not significantly greater in testosterone or resistance training groups in comparison to placebo group

Not measured

Not measured

Strength measurements confounded by learning effect

Testosterone-treated patients reported feeling better, improved quality of life and appearance

Quality-of-life measure not changed

Testosterone treatment associated with improved well-being men

Strawford et al., 1999 (53)

Batterham and Garsia

HIV-infected men with CD4+ cell count <400/cmm

HIV-infected men with weight loss >5% in the preceding 2 yr

HIV-infected men with AIDS wasting syndrome and borderline low testosterone concetrations

HIV-infected men with >5% weight loss

HIV-infected men with chronic cachexia cachexia

Nandrolone 600 mg weekly alone or nandrolone plus resistance training exercise for 12 wk All subjects received resistance exercise training plus testosterone enanthate 100 mg weekly, and randomized to 20-mg oxan-drolone or placebo daily Placebo, 65 mg nandrolone weekly, or 200 mg nandrolone weekly

Randomized to nutritional supplementation alone, megesterol acetate 400 mg daily or nandrolone 100 mg every 15 d

Oxymetholone monotherapy, oxymetholone plus ketotifen, compared to historical controls

+3.9 kg gain in FFM after nandrolone treatment alone, and 5.2 kg in combined treatment group +6.9 kg mean increase in LBM in oxandrolone group; 3.8 kg gain in placebo group

Greater increments in nitrogen retention in both nandrolone groups compared to placebo

Greater LBM gain in association with nandrolone than placebo

8.2 kg weight gain in the oxymetholone group, 6.1 kg gain in combination group, compared with a weight loss of 1.8 kg in historical controls

Strength gains greater with combined treatment than with nandrolone alone

Greater muscle strength gains in oxandrolone group than in placebo group

LBM increased by 3.1 kg in 10 men in open-label treatment phase

Muscle strength not measured

Body composition and muscle performance not measured

No placebo alone group

Significant drop in plasma HDL cholesterol in oxandrolone

Small sample size

Controls not concurrent; no placebo group

FFM, fat free body mass; LBM, lean body mass; HDL, high-density lipoprotein

Testosterone Replacement Effects

Fig. 1. Change in fat-free mass during testosterone administration with or without resistance exercise training in HIV-infected men with weight loss and low testosterone concentrations. Data are mean +/-SEM. Fat-free mass was measured by dual energy X-ray absorptiometry. *, significantly greater than placebo. (Reproduced from ref. 69.)

Fig. 1. Change in fat-free mass during testosterone administration with or without resistance exercise training in HIV-infected men with weight loss and low testosterone concentrations. Data are mean +/-SEM. Fat-free mass was measured by dual energy X-ray absorptiometry. *, significantly greater than placebo. (Reproduced from ref. 69.)

effect. Most other studies of testosterone replacement in HIV-infected men have also failed to demonstrate significant increases in muscle strength.

Therefore, in a subsequent study (52) (see Figs. 1 and 2), the subjects returned to the exercise laboratory on two or more occasions until they were familiar with the equipment and technique and stability of measurement had been achieved. In this study, 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, double-blind, randomized, clinical trial in HIV-infected men with serum testosterone levels less than 350 ng/dL and weight loss of 5% or more in the previous 6 mo. Men were randomly assigned to one of four groups: placebo, no exercise; testosterone, no exercise; placebo plus exercise; or testosterone plus exercise. Placebo or 100-mg testosterone enanthate were given intramuscular weekly for 16 wk. The exercise program was a thrice weekly, progressive, supervised strength-training program. Effort-dependent muscle strength in five different exercises was measured by the 1-repetition maximum method. In the placebo alone group, muscle strength did not change for 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 who were treated

Testosterone Replacement Effects

Fig. 2. Change in maximal voluntary muscle strength in the leg-press exercise during testosterone administration with or without resistance exercise training in HIV-infected men with weight loss and low testosterone concentrations. Data are mean +/-SEM. Muscle strength was measured as the 1-repetition maximum in the leg press exercise. (Reproduced from ref. 69.)

Fig. 2. Change in maximal voluntary muscle strength in the leg-press exercise during testosterone administration with or without resistance exercise training in HIV-infected men with weight loss and low testosterone concentrations. Data are mean +/-SEM. Muscle strength was measured as the 1-repetition maximum in the leg press exercise. (Reproduced from ref. 69.)

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%) (see Fig. 2), leg curls (+18 to 36%), bench press (+19 to 33%), and latis-simus pulls (+17 to 33%) exercises. The gains in strength in all exercises were greater in men receiving testosterone or exercise alone than in those receiving placebo alone. The change in leg press strength correlated positively with an increase in muscle volume (r = 0.44, p = 0.003) and fat-free mass (r = 0.55, p < 0.001).

We conclude that when the confounding influence of the learning effect is minimized, as in this study, 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 (52,70). Supraphysiological doses of androgens augment the anabolic effects of resistance exercise on lean body mass and maximal voluntary strength (53,67).

A systematic review of the randomized, placebo-controlled trials that compared the effects of testosterone therapy with placebo in HIV patients with wasting was conducted (71). This analysis showed a difference of 1.04 kg (-0.01-2.10) between the testosterone treatment group and the placebo group by random effect, and 0.63 kg (-0.01-1.28) for fixed effect models. The meta-analysis of the six trials that included measurements of lean body mass revealed a difference in lean body mass between the testosterone group and the placebo group of 1.22 kg (95% CI 0.23-2.22) for the random effect model and 0.51 kg (0.09-0.93) for fixed effect. The difference in lean body mass between the testosterone and placebo groups was much greater in the three trials that used the im route of administration (-3.34 kg) in the post hoc analysis, presumably because of the higher testosterone dose used in these trials.

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.

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