Study Design

This study was approved by the institutional review boards of the Harbor–UCLA Research and Education Institute and the Charles R. Drew University of Medicine and Science. All the study subjects gave informed written consent. The subjects were normal men weighing 90 to 115 percent of their ideal body weights; they were 19 to 40 years of age and had experience with weight lifting. They were recruited through advertisements in local newspapers and community colleges. None had participated in competitive sports in the preceding 12 months. Men who had ever taken anabolic agents or recreational drugs or had had a psychiatric or behavioral disorder were excluded from the study.

Of 50 men who were recruited, 7 dropped out during the control period because of problems with scheduling or compliance. The remaining 43 men were randomly assigned to one of four groups: placebo with no exercise, testosterone with no exercise, placebo plus exercise, and testosterone plus exercise. The study was divided into a 4-week control period, a 10-week treatment period, and a 16-week recovery period. During the four-week control period, the men were asked not to lift any weights or engage in strenuous aerobic exercise.

Of the 43 men, 3 dropped out during the treatment phase: 1 because of problems with compliance, 1 because illicit-drug use was detected by routine drug screening, and 1 because of an automobile accident. Forty men completed the study: 10 in the placebo, no-exercise group; 10 in the testosterone, no-exercise group; 9 in the placebo-plus-exercise group; and 11 in the testosterone-plus-exercise group.

Standardization of Protein and Energy Intake

Two weeks before day 1, the men were instructed to begin following a standardized daily diet containing 36 kcal per kilogram of body weight, 1.5 g of protein per kilogram, and 100 percent of the recommended daily allowance of vitamins, minerals, and trace elements. Compliance with the diet was verified every four weeks by three-day records of food consumption. The dietary intake was adjusted every two weeks on the basis of changes in body weight.

Treatment

The men received either 600 mg of testosterone enanthate in sesame oil or placebo intramuscularly each week for 10 weeks in the Clinical Research Center. This dose is six times higher than the dose usually given as replacement therapy in men with hypogonadism and is therefore supraphysiologic. Doses as high as 300 mg per week have been given to normal men for 16 to 24 weeks without major toxic effects.34

Training Stimulus

The men in the exercise groups received controlled, supervised strength training three days per week during the treatment period. All the men trained at equivalent intensities in relation to their strength scores before the training. The training consisted of a cycle of weight lifting at heavy intensity (90 percent of the maximal weight the man lifted for one repetition before the start of training), light intensity (70 percent of the pretraining one-repetition maximal weight), and medium intensity (80 percent of this maximal weight) on three nonconsecutive days each week.35 Regardless of the actual weights lifted, the training was held constant at four sets with six repetitions per set (a set is the number of complete repetitions of an exercise followed by rest). Because previous research had demonstrated increases in strength of approximately 7 percent for the bench-press exercise and 12 percent for the squatting exercise after four to five weeks of training,35 the weights were increased correspondingly during the final five weeks of training in relation to the initial intensity. The number of sets was also increased from four to five, but the number of repetitions per set remained constant. The men were advised not to undertake any resistance exercise or moderate-to-heavy endurance exercise in addition to the prescribed regimen.

Evaluation and Outcome Measures

The primary end points were fat-free mass, muscle size as measured by magnetic resonance imaging (MRI), and muscle strength as based on the one-repetition maximal weight lifted during the bench-press and squatting exercises before and after the 10-week treatment period. Serum concentrations of total and free testosterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin were measured on days 14 and 28 of the control period and days 2, 3, 7, 14, 28, 42, 56, and 70 of the treatment period. Blood counts, blood chemistry (including serum aminotransferases), serum concentrations of prostate-specific antigen, and plasma concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured at the start of the control period and on day 4; on days 28, 56, and 70 of the treatment period; and four months after the discontinuation of treatment. Periodic evaluations to identify adverse effects were performed by examiners unaware of the study-group assignments on days 1 and 28 of the control period; days 28, 56, and 70 of the treatment period; and four months after the discontinuation of treatment. Mood and behavior were evaluated during the first week of the control period and after 6 and 10 weeks of treatment. Sexual function and semen characteristics were not assessed.

Assessment of Muscle Size

Muscle size was measured by MRI of the arms and legs at the humeral or femoral mid-diaphyseal level, the junction of the upper third and middle third of the bone, and the junction of the middle third and lower third. The cross-sectional areas of the arms and legs, the subcutaneous tissue, the muscle compartment, and the quadriceps and triceps muscles were computed, and the areas at the three levels were averaged.

Analysis of Body Composition

Fat-free mass was estimated on the basis of measurements of body density obtained by underwater weighing. During weighing, the men were asked to exhale to the residual volume, as measured by helium dilution.

Measures of Muscle Strength

The effort-dependent performance of muscle was assessed on the basis of the maximal weight lifted for one repetition during the bench-press and squatting exercises.36 Each man completed increasingly more difficult lifts with the same weights and bars that he used during training; in each exercise, the maximal weight lifted (the one-repetition maximum) was recorded as a measure of muscle strength.

Hormone Measurements

Serum concentrations of luteinizing hormone and follicle-stimulating hormone were measured by immunofluorometric assays,36 each with a sensitivity of 0.05 IU per liter. Serum testosterone was measured by immunoassay,37 and free testosterone was measured by equilibrium dialysis.37 Serum concentrations of sex hormone–binding globulin and prostate-specific antigen were measured by immunoassays using reagents purchased from Delphia–Wallac (Turku, Finland) and Hybritech (San Diego, Calif.), respectively.

Assessment of Mood and Behavior

A standardized Multidimensional Anger Inventory38 that includes 38 questions to measure the frequency, duration, magnitude, and mode of expression of anger, arousal of anger, hostile outlook, and anger-eliciting situations and a Mood Inventory that includes questions pertaining to general mood, emotional stability, and angry behavior were administered before, during (week 6), and after the treatment (unpublished data). For each man a live-in partner, spouse, or parent answered the same questions about the man's mood and behavior.

Statistical Analysis

The Shapiro and Wilk test was used to test whether the outcome variables had a normal distribution. Changes were computed for each subject as the difference between the values for each variable at the beginning and end of the treatment period (from day 0 to day 70). These values were averaged among the subjects in each group to obtain the group means. Analysis of variance was used to determine whether there were base-line differences among the four groups. Two-tailed, paired t-tests were used to test for changes in each outcome variable in each group. If there was a change, an analysis of variance was used to test for differences between groups in the amount of change, and then Scheffé's test was used to assess pairwise differences. This test adjusts for multiple comparisons, but it does not yield exact P values for pairwise comparisons between groups.