Testosterone Replacement Increases Fat-Free Mass and Muscle Size in Hypogonadal Men

This open-label nonrandomized study evaluated the effect of intramuscular testosterone enanthate administration on body composition, protein dynamics, and serum hormone concentrations in seven healthy hypogonadal adults 19 to 47 years old. The subjects had been previously treated with androgen replacement therapy (testosterone or gonadotropins) but underwent a 12-week washout period off all androgenic therapy prior to study. During the 10-week treatment period, testosterone enanthate (100 mg IM) was administered weekly in the Clinical Research Center. Subjects were instructed to refrain from moderate to heavy exercise for 4 weeks before study and during the treatment period. All were instructed to consume a standardized daily diet of 36 kcal/kg/d and 1.5 g/ kg/d protein and 100% of the recommended dietary allowance for vitamins.

Study endpoints were determined before and after testosterone therapy. The primary outcome measure was fat-free mass determined by underwater weighing. Body composition (fat-free mass, total body water, and fat mass) was also estimated with use of the deuterium water dilution method. Muscle size was evaluated with use of magnetic resonance imaging (MRI) of the arm and thigh muscles, with cross-sectional areas of the limb, the subcutaneous tissue, and the muscle compartment computed. Muscle strength was assessed by a one-repetition-maximum method for supine bench press and parallel squat exercises. Serial blood hormone measurements included total and free testosterone, luteinizing hormone, follicle-stimulating hormone, and sex-hormone binding globulin determined during weeks 4, 2, and 1 before treatment and an additional eight times during hormone therapy. Finally, the labeled-leucine technique was used to determine protein dynamics (leucine flux, oxidation, and nonoxidative disappearance) before and at the end of treatment.

The etiology of hypogonadism in four subjects was Klinefelter's syndrome (hypergonadotropic hypogonadism), and one each had idiopathic hypogonadotropic hypogonadism, panhypopopituitarism (after resection of a craniopharyngioma), and autoimmune polyglandular failure. There were no significant changes in hemoglobin, hematocrit, serum creatinine, and transaminases before or during testosterone treatment. Serum total testosterone levels increased significantly from baseline values of 2.5 ± 1.0 to 17.7 ± 3.2 nmol/L (mean ± SEM) on day 15, and were maintained in the normal male range for the duration of treatment. Free testosterone levels increased from a baseline of 66 ± 24 to 257 ± 69 pmol/L on day 29 of treatment and were maintained at this level throughout treatment. Blood liver function tests, hematocrit, and creatinine were unaltered by hormone administration.

Body weight and fat-free mass increased significantly from baseline to the posttreatment study. The average weight gain during hormonal treatment was 4.5 ± 0.6 kg or 6% of body weight. The percent body fat did not change with treatment; however, fat-free mass measured by underwater weighing increased significantly from 56 ± 2.5 to 60.9 ± 2.2 kg (or 9% increase). Similar effects on fat-free mass were detected with use of the deuterium-water dilution method. Total body water increased from 40.9 ± 3.3 to 46.0 ± 3.9 kg with testosterone, but percent body water did not change significantly.

Muscle size increased significantly with testosterone for 10 weeks. The triceps muscle area increased by 12% from baseline and the quadriceps musculature increased by 8%, while the amount of subcutaneous fat in arm and thigh did not change. Muscle strength increased significantly with testosterone over the 10 weeks of treatment, as evidenced by a 22% increase in the bench press and a 31% increase in the squat strength measurements. Whole-body leucine flux, oxidation, and nonoxidative disappearance rates did not change with treatment. Testosterone treatment was clinically well tolerated in these hypogonadal men.