The New England Journal of Medicine -- July 4, 1996 -- Vol. 335, No. 1

The Anabolic Action of Testosterone

The paper by Bhasin et al. (1) in this issue of the Journal shows that a dose of testosterone enanthate (600 mg weekly for 10 weeks) that produces supraphysiologic serum concentrations of testosterone in men increases muscle size and strength and that the effects of exercise are additive to
those of testosterone. Even though athletes have suggested for years that androgens increase muscle mass, there are two main reasons why it has taken until 1996 for this fact to be demonstrated in a clinical trial. First, most earlier studies did not control for the independent effects of testosterone and exercise. Bhasin et al. studied the effects of placebo and testosterone treatment with and without a regimen of standardized weight lifting three times weekly. The men in all four groups were instructed to eat a standard diet, and their compliance was checked. Second, although the muscles of humans are sensitive to androgens, muscle response is difficult to measure in relation to the response of other androgen-sensitive tissues. In women the skin is very responsive to testosterone, so that hirsutism occurs when there is only two to three times as much testosterone production as in normal women, (2) and obvious virilization appears in response to a moderate additional increase. In contrast,
a small increase in muscle mass can be detected only with advanced techniques of imaging. (1) The response of muscle is small; there is only a 30 percent difference between men and women in muscle mass, whereas their rates of testosterone production differ by a factor of 100. (2) To understand the work of Bhasin et al., it is important to relate the amount of testosterone that enters the blood after the intramuscular administration of testosterone enanthate with the rate at which the hormone is produced in normal men. (3) In men with hypogonadism, serum testosterone concentrations increased to 1400 ng per deciliter (48.5 nmol per liter) two days after the intramuscular administration of 100 mg of testosterone enanthate and declined to 800 ng per deciliter (27.7 nmol per liter) one week after treatment. (3) From these data and the rate of metabolic clearance of testosterone in men, (4) the amount of testosterone that enters the blood after an injection of testosterone enanthate can be
estimated. Thus, an injection of 100 mg of testosterone enanthate results in a dose of testosterone almost double that produced by the testes of normal men (75 vs. 42 mg per week). It is impossible to estimate the exact amount of testosterone that entered the blood after the 600-mg dose of testosterone enanthate used by Bhasin et al. was administered, because serum testosterone was measured only after the final week of treatment. (1) The dose could have been as high as 450 mg per week -- 6 times the amount absorbed from a 100-mg dose, or more than 10 times the amount produced in normal men -- or as low as 300 mg per week, or 7 times the amount produced in normal men, given that serum testosterone concentrations were only 4 times higher one week after the 600-mg dose than they were after the 100-mg dose. It may be inferred that testosterone enanthate can increase muscle mass in normal men if the dose increases the amount of testosterone entering the blood to approximately 10 times the amount normally produced. (1) One of the
reasons that testosterone had no effect on muscle mass in other studies in humans is that the doses were too small.

The concern that testosterone may be hazardous stems from beliefs that it is partly responsible for the higher risk of coronary artery disease in men than in women; that little, if any, prostate cancer develops in men without active Leydig cells; and that androgens induce rage and anger. The doses of testosterone that affect these end points in normal men are not known. In the short term, 3.0 to 4.5 g of testosterone given over a period of 10 weeks adds additional risk, but were the drug to be given for a longer time, the increase over the 130 g of testosterone produced by the testes in men 15 to 75 years of age would of course be greater. The fact that a large dose of testosterone enanthate did not affect serum concentrations of
lipids and prostate-specific antigen or measures of mood and behavior (1) should provide some short-term reassurance.

In animals, testosterone-induced increases in muscle mass, protein and RNA synthesis, and glycogen accumulation in muscle have been used as measures of the anabolic effects of this steroid. (5,6) For years the anabolic effects of androgens in humans were measured by changes in nitrogen balance, (7) a method that lacked precision, sensitivity, and specificity and required that the subjects be confined to a metabolic ward. The ability
of magnetic resonance imaging to detect with accuracy a change as small as 6 percent in the cross-sectional area of muscle in response to treatment with testosterone is a great advance and indicates the relative ease with which further studies can be conducted in outpatients. Whether testosterone can be administered to prevent the wasting of muscle in immobilized patients or patients with cancer or cachexia caused by the
human immunodeficiency virus must await the outcome of controlled trials similar to this one. (1)

C. Wayne Bardin, M.D.
National Institute of Child Health and Human Development
Bethesda, MD 20892-7510

Copyright � 1996 by the Massachusetts Medical Society. All rights reserved.