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1 Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, 90059; and 2 Division of Respiratory and Critical Care Physiology and Medicine, Harbor-University of California at Los Angeles Medical Center, Torrance, California 90509
Administration
of replacement doses of testosterone to healthy hypogonadal men and
supraphysiological doses to eugonadal men increases muscle size. To
determine whether testosterone-induced increase in muscle size is due
to muscle fiber hypertrophy, 61 healthy men, 18-35 yr of age,
received monthly injections of a long-acting gonadotropin-releasing
hormone (GnRH) agonist to suppress endogenous testosterone secretion
and weekly injections of 25, 50, 125, 300, or 600 mg testosterone
enanthate (TE) for 20 wk. Thigh muscle volume was measured by magnetic
resonance imaging (MRI) scan, and muscle biopsies were obtained from
vastus lateralis muscle in 39 men before and after 20 wk of combined
treatment with GnRH agonist and testosterone. Administration of GnRH
agonist plus TE resulted in mean nadir testosterone concentrations of 234, 289, 695, 1,344, and 2,435 ng/dl at the 25-, 50-, 125-, 300-, and
600-mg doses, respectively. Graded doses of testosterone administration were associated with testosterone dose and concentration-dependent increase in muscle volume measured by MRI (changes in vastus lateralis volume, 
4, +7, +15, +32, and +48 ml at 25-, 50-, 125-, 300-, and
600-mg doses, respectively). Changes in cross-sectional areas of both
type I and II fibers were dependent on testosterone dose and
significantly correlated with total (r = 0.35, and
0.44, P < 0.0001 for type I and II fibers,
respectively) and free (r = 0.34 and 0.35, P < 0.005) testosterone concentrations during
treatment. The men receiving 300 and 600 mg of TE weekly experienced
significant increases from baseline in areas of type I (baseline vs. 20 wk, 3,176 ± 186 vs. 4,201 ± 252 µm2,
P < 0.05 at 300-mg dose, and 3,347 ± 253 vs.
4,984 ± 374 µm2, P = 0.006 at
600-mg dose) muscle fibers; the men in the 600-mg group also had
significant increments in cross-sectional area of type II (4,060 ± 401 vs. 5,526 ± 544 µm2, P = 0.03) fibers. The relative proportions of type I and type II fibers did
not change significantly after treatment in any group. The myonuclear
number per fiber increased significantly in men receiving the 300- and
600-mg doses of TE and was significantly correlated with testosterone
concentration and muscle fiber cross-sectional area. In conclusion, the
increases in muscle volume in healthy eugonadal men treated with graded
doses of testosterone are associated with concentration-dependent
increases in cross-sectional areas of both type I and type II muscle
fibers and myonuclear number. We conclude that the testosterone induced
increase in muscle volume is due to muscle fiber hypertrophy.
androgen; muscle hypertrophy; satellite cells; mechanism of action
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