Testosterone plus megestrol acetate did not increase lean body mass in people with HIV

In HIV patients receiving megestrol acetate treatment, testosterone preserved or improved sexual function.

Issue: April 2007

Megestrol acetate, an oral synthetic progestational agent, stimulates appetite and promotes weight gain in patients with HIV-associated wasting, as well as in elderly patients and patients with cancer and other diseases. Studies have shown, however, that most of the weight gained is fat, possibly because megestrol acetate suppresses testosterone production and action.

Kathleen Mulligan, PhD, of the division of endocrinology at San Francisco General Hospital, and colleagues in the Adult AIDS Clinical Trials Group hoped to correct this effect and add lean body mass in patients with HIV. They added testosterone supplementation to megestrol acetate treatment in a randomized, double-blind, placebo-controlled study. The results were published in the Journal of Clinical Endocrinology and Metabolism.

Seventy-nine men with HIV, aged 18 or older, were randomly assigned to two groups: One group (n=38) received 800 mg megestrol acetate oral suspension (Megace 40 mg/mL, Bristol-Myers Squibb) and placebo daily; the other group (n=41) received the same dose of megestrol acetate plus 200 mg testosterone enanthate every two weeks.

All patients had a BMI <20 or involuntary weight loss of 5% or more; however, baseline BMI, weight and fat were significantly higher in the testosterone group. There were no significant differences in age, CD4 counts or adrenal or gonadal hormone levels at baseline.

Sixty-six patients completed the study and 59 were evaluated for body composition.

Weight and body composition

Body weight increased in both groups (median 7.3 kg in the placebo group and 5.3 kg in the testosterone group). Average lean body mass also increased in both groups by 3.3 kg, as did fat mass (3.8 kg in the placebo group and 3.0 kg in the testosterone group).

After adjusting for differences in baseline weight, lean body mass and fat, the researchers noted no significant differences between the groups in the magnitude or composition of weight gain. In patients who gained 2 kg or more, lean body mass accounted for 45% of weight gain in the placebo group and 49% of the weight gain in the testosterone group.

Megestrol acetate levels increased at week 12 in both groups (1,243 ng/mL on average in the placebo group and 751 ng/mL on average in the testosterone group). The difference between groups in the increase was not statistically significant.

Both groups experienced significant decreases in testosterone, cortisol, dehydroepiandrosterone and androstenendione. At week 12, only the decrease in testosterone differed significantly between groups (12.3 nmol/L on average in the placebo group and 6.1 nmol/L on average in the testosterone group).

Quality of life and toxicity

Sexual functioning at baseline was the same in both groups. At week 12, sexual functioning had improved or remained unchanged in the testosterone group, but had worsened significantly in the placebo group. “The dose of testosterone was sufficient to help people maintain their level of sexual functioning, but not sufficient to accrue additional lean tissue,” Mulligan said in an interview. “This isn’t surprising, as there are different thresholds of serum testosterone levels for different activities that testosterone is involved with.”

Overall health status, based on patient self-assessment, did not differ between groups at either baseline (P=.67) or at week 12 (P=.26).

No significant differences in toxicity rates were reported between groups. At week 12, CD4 counts increased in both groups (49 [–9, 125] cells/mcL in the placebo group and 39 [–14, 104] cells/mcL in the testosterone group), an insignificant difference. At higher doses, Mulligan said toxicity might be a problem. “If we exceed conventional replacement dosing, it would be important to monitor HDL cholesterol and other potential toxicities.”

Mulligan suggested that the primary reason that the combination did not enhance lean body mass accrual is because megestrol acetate “is a very potent suppressor of testosterone. It’s been used to chemically castrate. In fact, when the testosterone levels we measured — even in the people who were supplemented — trough levels on average were below the lower limit of normal.”

The researchers alternatively suggested that megestrol acetate may have interfered with testosterone binding to androgen receptors and decreased the number of receptors in prostate tissue, contributing to the failure of testosterone supplementation to boost lean body mass. – by Carey Cowles

For more information:

Mulligan K, Zackin R, Von Roenn JH, et al. Testosterone supplementation of megestrol therapy does not enhance lean tissue accrual in men with human immunodeficiency virus-associated weight loss: A randomized, double-blind, placebo-controlled, multicenter trial. J Clin Endocrinol Metab. 2007;92:563-570.