How Much Testosterone Will Build Muscle
Testosterone Dose-Dependently Increases Maximal Voluntary Strength and Leg Power, but Does Not Affect Fatigability or Specific Tension
Thomas W. Storer, 1Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059 *Address all correspondence and requests for reprints to: Thomas W. Storer, Ph.D., Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059. Search for other works by this author on: 1Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059 Search for other works by this author on: 1Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059 Search for other works by this author on: 1Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059 Search for other works by this author on: 1Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059 Search for other works by this author on: 1Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059 Search for other works by this author on: 1Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059 Search for other works by this author on: 1Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059 Search for other works by this author on:
Accepted:
18 December 2002
Testosterone supplementation in men increases fat-free mass, but whether measures of muscle performance, such as maximal voluntary strength, power, fatigability, or specific tension, are improved has not been determined. Furthermore, the extent to which these measures of muscle performance are related to testosterone dose or circulating concentration is unknown. To examine the relationship between testosterone dose and muscle performance, 61 healthy, eugonadal young men (aged 18–35 yr) were randomized to 1 of 5 groups, each receiving a long-acting GnRH agonist to suppress endogenous testosterone production plus weekly injections of 25, 50, 125, 300, or 600 mg testosterone enanthate for 20 wk. These doses produced mean nadir testosterone concentrations of 253, 306, 542, 1345, and 2370 ng/dl, respectively. Maximal voluntary muscle strength and fatigability were determined by a seated leg press exercise. Leg power was measured using a validated leg power instrument. Specific tension was estimated by the ratio of one repetition maximum muscle strength to thigh muscle volume determined by magnetic resonance imaging. Testosterone administration was associated with a dose-dependent increase in leg press strength and leg power, but muscle fatigability did not change significantly during treatment. Changes in leg press strength were significantly correlated with total (r = 0.46; P = 0.0005) and free (r = 0.38; P = 0.006) testosterone as was leg power (total testosterone: r = 0.38; P = 0.007; free testosterone: r = 0.35; P = 0.015), but not muscle fatigability. Serum IGF-I concentrations were not significantly correlated with leg strength, power, or fatigability. Specific tension did not change significantly at any dose. We conclude that the effects of testosterone on muscle performance are specific; it increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. The changes in leg strength and power are dependent on testosterone dose and circulating testosterone concentrations and exhibit a log-linear relationship with serum total and free testosterone. Failure to observe a significant testosterone dose relationship with fatigability suggests that testosterone does not affect this component of muscle performance and that different components of muscle performance are regulated by different mechanisms.
THERE IS AGREEMENT that testosterone increases fat-free mass when given in physiological replacement doses to healthy, hypogonadal men (1–6), to human immunodeficiency virus-infected men with low testosterone levels (7–9), and to older men with low normal testosterone levels (10–14). However, the data on the effects of testosterone replacement on measures of muscle performance are limited and somewhat contradictory. Some studies have reported greater improvements in grip strength in older men with testosterone supplementation than with placebo. In contrast, in a recent placebo-controlled, randomized clinical trial by Snyder et al. (12), testosterone treatment of older men did not increase muscle strength, even though testosterone administration was associated with gains in fat-free mass. In addition to muscle strength, both power (the rate of force generation) and fatigability (the ability of the muscle to persist in a task) are important measures of muscle performance. The effects of testosterone supplementation on muscle power and fatigability are unknown. Therefore, the first objective of this study was to comprehensively study the effects of testosterone administration on these important measures of muscle performance. We hypothesized that all three measures of muscle function, strength, power, and fatigability, would exhibit a linear response to testosterone dose.
An additional objective measure of qualitative muscle strength is specific tension, the force generated by each unit of muscle volume. Although strength is well accepted to be related to muscle size, it is not known whether testosterone administration induces changes in muscle strength in proportion to testosterone-induced hypertropic changes in muscle volume, or whether it has additional effects on the intrinsic contractile qualities of muscle that are independent of its effects on muscle mass. Therefore, we also determined the effects of testosterone administration on specific tension, a measure of the contractile quality of skeletal muscle, hypothesizing that muscle size and muscle strength would increase in parallel and in proportion to testosterone dose, thus resulting in no change in specific tension.
In a previous study we demonstrated that administration of supraphysiological doses of testosterone to healthy young men was associated with significant increases in muscle size and maximal voluntary strength (15). In contrast, Snyder et al. found no detectable changes in knee extension or knee flexion strength in either healthy, hypogonadal men or older men with low testosterone concentrations (12). Because the increments in testosterone concentrations were modest in the men treated with the testosterone patch used in this study (12), we considered the possibility that doses of testosterone higher than those used in studies of older men might be required to achieve improvements in muscle strength.
Recently, we used a Leydig cell clamp model to demonstrate for the first time that androgen-dependent processes differ in their testosterone dose-response characteristics (16). The details of the study design, the validation of this model, and the overall findings of this study have been published (16). The present manuscript describes the changes in three measures of muscle performance (voluntary muscle strength, power, and fatigability) as well as changes in muscle contractile quality (specific tension) as a function of testosterone dose.
Materials and Methods
Study design
This was a double-blind, randomized study, approved by the institutional review boards of Charles Drew University and Harbor-UCLA Research and Education Institute. The details of the study design have been previously described (16). The study consisted of a 4-wk control period, 20 wk of treatment, and a 16-wk recovery phase. Treatment consisted of monthly injections of a long-acting GnRH agonist (Decapeptyl, DebioPharm, Geneva, Switzerland) to suppress endogenous testosterone production plus weekly injections of one of five testosterone dosing regimens.
Subjects
A total of 61 healthy men, aged 18–35 yr, participated in this study. All subjects had prior weight-lifting experience, but were not actively involved in strength training during the control or treatment phase of the study. Their characteristics at baseline are described in Table 1. Exclusion criteria included body weight greater than 20% above ideal weight for height, anabolic steroid use within the previous 12 months, or participation in competitive athletics within the previous 12 months. After signing informed consent, subjects underwent a physical examination, including digital rectal examination for evaluation of the prostate. Complete blood counts, blood chemistries, and prostate-specific antigen and serum testosterone levels were measured to determine eligibility. Those who met the eligibility criteria were randomly assigned to receive testosterone enanthate im each week in 1 of 5 testosterone dose regimens (25, 50, 125, 300, or 600 mg/wk). Randomization codes, using a block size of 5, were developed by our biostatistician and used for subject assignment to 1 of the 5 testosterone dose groups. Vials containing each of the 5 testosterone doses were prepared and coded by the research pharmacist. These coded vials were stored at the General Clinical Research Center (GCRC) and administered by GCRC nurses to assure compliance. Investigators, GCRC nurses, and subjects were blinded to the testosterone dose administered throughout the study period. All men received monthly injections of the long-acting GnRH agonist during the treatment phase, starting on d 1. The 5 testosterone doses were chosen such that, when administered weekly in combination with the GnRH agonist, they would produce nadir serum testosterone concentrations below, within, and above the physiological range. The doses selected were determined from published data and our previous experience with different testosterone doses.
Table 1.
Subject characteristics at baseline
| Group (n) | Age (yr) | Weight (kg) | BMI (kg/m−2) | Serum testosterone (nmol/liter−1) | 1-RM (kg) | Leg power (watts) | Fatigability (repetitions) | Specific tension (kg/cm−3) |
|---|---|---|---|---|---|---|---|---|
| 25 mg/wk−1 (12) | 28 ± 5 | 68.0 ± 8.4 | 23 ± 3 | 596 ± 161 | 355 ± 31 | 184 a ± 35 | 23 ± 9 | 2.79 ± 0.58 |
| 50 mg/wk−1 (12) | 29 ± 5 | 77.0 ± 8.1 | 25 ± 3 | 566 ± 220 | 407 ± 22 | 234 ± 40 | 24 ± 9 | 3.13 ± 0.78 |
| 150 mg/wk−1 (12) | 28 ± 3 | 78.9 ± 8.1 | 25 ± 3 | 553 ± 182 | 418 ± 25 | 257 a ± 75 | 22 ± 10 | 2.87 ± 0.82 |
| 300 mg/wk−1 (12) | 24 ± 5 | 78.4 ± 10.6 | 25 ± 3 | 654 ± 157 | 438 ± 26 | 237 ± 58 | 20 ± 7 | 3.06 ± 0.58 |
| 600 mg/wk−1 (13) | 25 ± 4 | 74.8 ± 12.5 | 25 ± 3 | 632 ± 228 | 431 ± 27 | 204 ± 38 | 17 ± 6 | 3.06 ± 0.94 |
| P | 0.058 | 0.101 | 0.368 | 0.709 | 0.215 | 0.015 | 0.392 | 0.839 |
| Group (n) | Age (yr) | Weight (kg) | BMI (kg/m−2) | Serum testosterone (nmol/liter−1) | 1-RM (kg) | Leg power (watts) | Fatigability (repetitions) | Specific tension (kg/cm−3) |
|---|---|---|---|---|---|---|---|---|
| 25 mg/wk−1 (12) | 28 ± 5 | 68.0 ± 8.4 | 23 ± 3 | 596 ± 161 | 355 ± 31 | 184 a ± 35 | 23 ± 9 | 2.79 ± 0.58 |
| 50 mg/wk−1 (12) | 29 ± 5 | 77.0 ± 8.1 | 25 ± 3 | 566 ± 220 | 407 ± 22 | 234 ± 40 | 24 ± 9 | 3.13 ± 0.78 |
| 150 mg/wk−1 (12) | 28 ± 3 | 78.9 ± 8.1 | 25 ± 3 | 553 ± 182 | 418 ± 25 | 257 a ± 75 | 22 ± 10 | 2.87 ± 0.82 |
| 300 mg/wk−1 (12) | 24 ± 5 | 78.4 ± 10.6 | 25 ± 3 | 654 ± 157 | 438 ± 26 | 237 ± 58 | 20 ± 7 | 3.06 ± 0.58 |
| 600 mg/wk−1 (13) | 25 ± 4 | 74.8 ± 12.5 | 25 ± 3 | 632 ± 228 | 431 ± 27 | 204 ± 38 | 17 ± 6 | 3.06 ± 0.94 |
| P | 0.058 | 0.101 | 0.368 | 0.709 | 0.215 | 0.015 | 0.392 | 0.839 |
Group designations represent testosterone enanthate dose. Data are mean ± sd.
a P < 0.05.
Table 1.
Subject characteristics at baseline
| Group (n) | Age (yr) | Weight (kg) | BMI (kg/m−2) | Serum testosterone (nmol/liter−1) | 1-RM (kg) | Leg power (watts) | Fatigability (repetitions) | Specific tension (kg/cm−3) |
|---|---|---|---|---|---|---|---|---|
| 25 mg/wk−1 (12) | 28 ± 5 | 68.0 ± 8.4 | 23 ± 3 | 596 ± 161 | 355 ± 31 | 184 a ± 35 | 23 ± 9 | 2.79 ± 0.58 |
| 50 mg/wk−1 (12) | 29 ± 5 | 77.0 ± 8.1 | 25 ± 3 | 566 ± 220 | 407 ± 22 | 234 ± 40 | 24 ± 9 | 3.13 ± 0.78 |
| 150 mg/wk−1 (12) | 28 ± 3 | 78.9 ± 8.1 | 25 ± 3 | 553 ± 182 | 418 ± 25 | 257 a ± 75 | 22 ± 10 | 2.87 ± 0.82 |
| 300 mg/wk−1 (12) | 24 ± 5 | 78.4 ± 10.6 | 25 ± 3 | 654 ± 157 | 438 ± 26 | 237 ± 58 | 20 ± 7 | 3.06 ± 0.58 |
| 600 mg/wk−1 (13) | 25 ± 4 | 74.8 ± 12.5 | 25 ± 3 | 632 ± 228 | 431 ± 27 | 204 ± 38 | 17 ± 6 | 3.06 ± 0.94 |
| P | 0.058 | 0.101 | 0.368 | 0.709 | 0.215 | 0.015 | 0.392 | 0.839 |
| Group (n) | Age (yr) | Weight (kg) | BMI (kg/m−2) | Serum testosterone (nmol/liter−1) | 1-RM (kg) | Leg power (watts) | Fatigability (repetitions) | Specific tension (kg/cm−3) |
|---|---|---|---|---|---|---|---|---|
| 25 mg/wk−1 (12) | 28 ± 5 | 68.0 ± 8.4 | 23 ± 3 | 596 ± 161 | 355 ± 31 | 184 a ± 35 | 23 ± 9 | 2.79 ± 0.58 |
| 50 mg/wk−1 (12) | 29 ± 5 | 77.0 ± 8.1 | 25 ± 3 | 566 ± 220 | 407 ± 22 | 234 ± 40 | 24 ± 9 | 3.13 ± 0.78 |
| 150 mg/wk−1 (12) | 28 ± 3 | 78.9 ± 8.1 | 25 ± 3 | 553 ± 182 | 418 ± 25 | 257 a ± 75 | 22 ± 10 | 2.87 ± 0.82 |
| 300 mg/wk−1 (12) | 24 ± 5 | 78.4 ± 10.6 | 25 ± 3 | 654 ± 157 | 438 ± 26 | 237 ± 58 | 20 ± 7 | 3.06 ± 0.58 |
| 600 mg/wk−1 (13) | 25 ± 4 | 74.8 ± 12.5 | 25 ± 3 | 632 ± 228 | 431 ± 27 | 204 ± 38 | 17 ± 6 | 3.06 ± 0.94 |
| P | 0.058 | 0.101 | 0.368 | 0.709 | 0.215 | 0.015 | 0.392 | 0.839 |
Group designations represent testosterone enanthate dose. Data are mean ± sd.
a P < 0.05.
Controlling exercise and nutritional intake
Subjects were advised to refrain from all resistance exercise training and intense, prolonged endurance exercise, but were allowed to continue other habitual activities throughout the study. Two weeks before the initiation of the study, subjects were prescribed a diet standardized for energy intake at 150 kJ/kg/d and a protein intake of 1.3 g/kg/d. These instructions were reinforced every 4 wk during a meeting with our dietitian in which the subject's actual nutrient intake was verified by analysis of 3-d food logs.
Assessment of muscle function
Muscle function may be described with three primary performance components: strength, power, and endurance (17, 18). So as not to confuse the term endurance when applied to muscle function with endurance in a cardiorespiratory context, the term fatigability will be used to infer local muscle endurance. Strength is defined as the maximal force-generating capacity of a muscle or muscle group in performing a movement (19). In this study maximal voluntary strength in the leg press exercise was measured as the one repetition maximum (1-RM) defined as the maximum amount of weight that a subject was able to lift once and only once using a seated leg press machine (Keiser Sport, Fresno, CA) with pneumatic resistance. Recognizing that maximal voluntary strength measurements are highly effort dependent, several strategies were used to assure reliability and reproducibility and to minimize the confounding influence of the learning effect. Tests were performed in duplicate or triplicate, with careful attention to positioning so that starting knee flexion (90° by goniometry), the ensuing hip angles, and foot placement on the leg press footplate were standardized and held constant. In addition, the 1-RM procedure (20) included a familiarization period in which subjects were instructed in and then practiced the proper execution of the seated leg press exercise. After this familiarization, subjects completed a generalized warm-up consisting of 5 min of cycle ergometer or treadmill exercise plus stretching of the quadriceps, hamstrings, lower back, and triceps surae. Immediately after this warm-up, subjects were positioned on the leg press machine with position measurements recorded for subsequent testing. The initial load was set at 50% of the subject's estimated 1-RM using reference values established for this exercise in our laboratory. Subjects were first asked to perform eight repetitions of the leg press exercise at this load. After 1 min of rest, the subjects performed four repetitions at a load that was increased by approximately 20 kg. After a 2-min rest period, the load was increased further, and attempts were then made to identify the 1-RM. Attempts were interspersed with 2-min rest intervals and continued until the 1-RM was identified as the greatest amount of weight lifted through the complete range of motion. Strength tests were conducted in duplicate on nonconsecutive days, and scores were required to be within 5%. Failure to meet this criterion required a third test. Only 15% of our subjects required a third test, and none required a fourth. In all cases, the highest value in the duplicate or triplicate trails was taken as the criterion measure.
Power is defined as the rate of doing work or generating force. We used a specially designed and validated (21) leg power instrument (University of Nottingham Medical College, Nottingham, UK) to measure lower extremity knee and hip extensor power. The test was performed with subjects' right foot on the foot pedal with the right knee flexed to 90°. Subjects were instructed to push the foot pedal as hard and as fast as possible. The instrument's data acquisition and processing routines calculated peak power (watts) using the mass of the flywheel and its revolution frequency. As with the 1-RM tests, subjects were first familiarized with the procedures, completed a warm-up, and were positioned to achieve the desired 90° of knee flexion. The seat position required to achieve the desired knee angle was recorded to the nearest 0.5 cm for subsequent testing. Trials were continued until a plateau in peak power was reached, in which case the highest value was recorded as the peak power. Typically, 5–15 trials were required to achieve peak power. As the duration of effort required for each trial was less than 1 sec, approximately 30 sec of rest were provided between trials.
Muscle fatigability refers to the ability to sustain a submaximal contraction or to make repetitive dynamic contractions before fatiguing. The Keiser leg press was used for this test, with the resistance set at 75% of the subject's pretreatment 1-RM. The same warm-up and positioning controls used in the 1-RM tests were enforced for the fatigability tests. The criterion measure was the total number of repetitions to failure, with failure defined as the inability to complete a repetition through the complete range of motion.
Specific tension
The ratio of muscle strength to muscle volume is often referred to as specific force (22) or specific tension (23) and represents the qualitative attributes of a muscle's intrinsic ability to develop tension. We calculated specific tension as the ratio of the maximal voluntary strength in the leg press exercise to thigh muscle cross-sectional area derived from magnetic resonance imaging (MRI) scans of the thigh. Images were taken with the subjects in the supine position, entering the body coil feet first, with the heels in a neutral position. MRI scans were obtained for the thigh musculature (flexor and extensor compartments), with the first slice taken at the distal border of the lateral femoral condyle. A total of 17 slices were taken, with each slice 10 mm thick and 15 mm between slices. Thigh muscle volume was calculated by integrating five transverse slices: two above the midline, one at the midline, and two below the midline of the widest cross-sectional area of the thigh. Commercially available software (AW version 3.1, volume analysis software, General Electric, Milwaukee, WI) was used to perform these calculations. The accuracy of the volume analysis software was determined by analyzing scans of a phantom cylinder of known dimensions. Duplicate manual tracings were drawn around the outermost edge of the entire thigh (total thigh), the skeletal musculature (to subtract out sc fat), and the femur (to subtract out femoral bone areas). All analyses were performed by the same investigator in a blinded fashion.
Hormone assays
Serum testosterone (immunoassay) and free testosterone (equilibrium dialysis) were measured as previously reported (16). Serum IGF-I levels were measured by acid-ethanol extraction and immunoassay (24). The sensitivities and intra- and interassay coefficients of variation for IGF-I assays were 80 ng/ml, 4%, and 6%, respectively.
Statistical analysis
Subject characteristics were summarized with descriptive statistics and displayed as the mean ± sd. Baseline differences between groups were evaluated by one-way ANOVA. Within-group changes from baseline in the measures of muscle performance and physical function due to testosterone dose were analyzed using paired t tests. Differences among the groups were evaluated with analysis of covariance (ANCOVA). If change scores for any variable were not normally distributed, they were log-transformed. Subanalyses of any group differences were based on the Student-Newman-Keuls multiple comparison procedure, using a global 5% significance level. Relationships between serum testosterone level and measures of muscle function and physical performance are described with Pearson Product-Moment correlations. The Number Cruncher Statistical System (NCSS 2000, NCSS Statistical Software, Kaysville, UT) was used for all statistical analyses with P ≤ 0.05 required for significance.
Results
Of the 61 subjects originally enrolled, 54 completed the study (16). One subject withdrew from the 25 mg/wk dose group, 4 from the 50 mg/wk dose group, and 2 from the 300 mg/wk dose group. None of these subjects withdrew because of adverse effects. Furthermore, none of the 54 subjects completing the study experienced serious adverse effects attributable to treatment.
The subjects' baseline characteristics are presented in Table 1. Overall, our subjects averaged 26 yr of age with a body mass index (BMI) of 25 mg/wk. Although the subjects' BMI was on the borderline between ideal weight for height and overweight as defined by current NIH recommendations (25), the subjects' relative percentage body fat by underwater weighing (14%) indicated that, on the average, these men were lean. Their serum testosterone levels before treatment were in the midnormal range for healthy young men.
Hormone levels for these subjects have been previously reported (16). Mean ± se serum total testosterone concentrations in the five groups, 7 d after previous testosterone injection (nadir levels), were 253 ± 66, 306 ± 58, 570 ± 75, 1345 ± 139, and 2370 ± 150 ng/dl, respectively; the corresponding free testosterone concentrations were 29 ± 5, 32 ± 3, 52 ± 8, 138 ± 21, and 275 ± 30 pg/dl, respectively. Serum total and free testosterone levels, measured during the last treatment week after the previous injection, were linearly related to the testosterone dose administered (P = 0.0001). In men receiving the 25- and 50-mg doses, nadir total and free testosterone concentrations decreased from baseline and were at the lower limit of the normal range for healthy young men. In contrast, serum total and free testosterone concentrations increased significantly from baseline and were in the supraphysiological range in men receiving the 300- and 600-mg doses. These values indicate that our experimental model was successful in creating graded ranges of serum testosterone concentrations. Mean ± se changes in serum IGF-I were −7 ± 18, −17 ± 9, −18 ± 17, 58 ± 29, and 72 ± 13 ng/ml for the 25, 50, 125, 300, and 600 mg/wk testosterone doses, respectively (P < 0.001). Post hoc analysis indicted that the mean increase in the 600 mg/wk group was significantly greater than that in the 25, 50, and 125 mg/wk doses. The increase in the 300 mg/wk group was greater than that in subjects receiving the 125 mg/wk dose. The only statistically significant change from baseline was noted in subjects receiving the 600 mg/wk dose. The change in IGF-I was significantly related to testosterone dose (r = 0.50; P < 0.001).
Figure 1A illustrates individual changes in leg press strength within each of the five testosterone dose groups. Overall, changes in maximal voluntary strength in the leg press exercise were dependent upon testosterone dose and significantly correlated with both serum total (P = 0.0005) and free testosterone (P = 0.006) concentrations as illustrated in Fig. 1, B and C, respectively. Surprisingly, changes in leg press strength were not significantly correlated with circulating IGF-I concentrations (P = 0.22), as shown in Fig. 1D. The overall ANCOVA for change in leg press strength among the five treatment groups was significant (P = 0.0002). The changes in leg press strength from baseline in men treated with the 300 and 600 mg/wk testosterone doses were significantly greater than for the other three groups, but not significantly different from each other. Significant changes from baseline in leg press strength were observed in the 50, 300, and 600 mg/wk dose groups, but not for the 25 and 125 mg/wk groups.
Figure 1.
A, Change in maximal voluntary leg press strength after 20 wk of treatment with a GnRH agonist plus one of five weekly doses of testosterone. ○, Individual changes; ▪, group mean ± se. A significant linear correlation was observed for change in maximal voluntary leg press strength and testosterone dose. The overall ANCOVA for difference in mean change between groups was significant (P < 0.0002). *, Significant change from baseline, P < 0.05; †, change from baseline in the 300 and 600 mg/wk groups was significantly greater than change from baseline in the 25, 50, and 125 mg/wk groups, P < 0.05. B–D, Significant relationships between change in maximal voluntary leg press strength and serum testosterone concentration (B), serum free testosterone concentration (C), and change in serum IGF-I concentration (D) at the end of 20 wk of treatment.
Figure 1.
A, Change in maximal voluntary leg press strength after 20 wk of treatment with a GnRH agonist plus one of five weekly doses of testosterone. ○, Individual changes; ▪, group mean ± se. A significant linear correlation was observed for change in maximal voluntary leg press strength and testosterone dose. The overall ANCOVA for difference in mean change between groups was significant (P < 0.0002). *, Significant change from baseline, P < 0.05; †, change from baseline in the 300 and 600 mg/wk groups was significantly greater than change from baseline in the 25, 50, and 125 mg/wk groups, P < 0.05. B–D, Significant relationships between change in maximal voluntary leg press strength and serum testosterone concentration (B), serum free testosterone concentration (C), and change in serum IGF-I concentration (D) at the end of 20 wk of treatment.
Figure 2A displays individual subject changes in leg power with testosterone dose. Changes in leg power were dependent on testosterone dose and were significantly correlated with total and free testosterone concentrations during treatment (Fig. 2, B and C, respectively). However, as illustrated in Fig. 2D, changes in leg power were not significantly correlated with IGF-I concentrations. The overall ANCOVA for differences between dose groups was significant (P = 0.038). Post hoc analysis indicated that the mean change from baseline in the 600 mg/wk group was significantly greater than those in all the other groups (P < 0.05). The pattern of change in leg power was similar to that shown in Fig. 1A for strength, with the greatest increases in power noted for the 300- and 600-mg/wk dose groups (Fig. 2A). Both of these groups exhibited greater increases than subjects in the 25, 50, and 125 mg/wk groups.
Figure 2.
A, Change in leg power after 20 wk of treatment with a GnRH agonist plus one of five weekly doses of testosterone. ○, Individual changes; ▪, group mean ± se. The relationship between change in leg power and testosterone dose was significant, P = 0.002. The overall ANCOVA was significant (P = 0.038). **, Significant change from baseline, P < 0.01; †, change from baseline in the 600 mg/wk group was significantly greater than change from baseline in the 25, 50, 125, and 300 mg/wk groups, P < 0.05. B–D, Significant relationships between change in leg power and serum testosterone concentration (B), serum free testosterone concentration (C), and change in serum IGF-I concentration (D) at the end of 20 wk of treatment.
Figure 2.
A, Change in leg power after 20 wk of treatment with a GnRH agonist plus one of five weekly doses of testosterone. ○, Individual changes; ▪, group mean ± se. The relationship between change in leg power and testosterone dose was significant, P = 0.002. The overall ANCOVA was significant (P = 0.038). **, Significant change from baseline, P < 0.01; †, change from baseline in the 600 mg/wk group was significantly greater than change from baseline in the 25, 50, 125, and 300 mg/wk groups, P < 0.05. B–D, Significant relationships between change in leg power and serum testosterone concentration (B), serum free testosterone concentration (C), and change in serum IGF-I concentration (D) at the end of 20 wk of treatment.
Figure 3A illustrates the individual subject changes in muscle fatigability in performing the leg press exercise with each of the five testosterone dose groups. The overall ANCOVA for changes in fatigability among the five treatment groups was P = 0.067, suggesting a trend toward significance (Fig. 3A). Changes in muscle fatigability were not significantly correlated with either serum total (P = 0.17) or free (P = 0.35) testosterone concentrations (Fig. 3, B and C, respectively) or with IGF-I (Fig. 3D).
Figure 3.
A, Change in leg press fatigability after 20 wk of treatment with a GnRH agonist plus one of five weekly doses of testosterone. ○, Individual changes; ▪, group mean ± se. The relationship between change in fatigability and testosterone dose was not significant. The overall ANOVA was not significant (P = 0.35). *, Significant change from baseline, P < 0.05. B–D, The change in leg press fatigability was not significantly related to serum testosterone concentration (B), serum free testosterone concentration (C), or change in serum IGF-I concentration at the end of 20 wk of treatment.
Figure 3.
A, Change in leg press fatigability after 20 wk of treatment with a GnRH agonist plus one of five weekly doses of testosterone. ○, Individual changes; ▪, group mean ± se. The relationship between change in fatigability and testosterone dose was not significant. The overall ANOVA was not significant (P = 0.35). *, Significant change from baseline, P < 0.05. B–D, The change in leg press fatigability was not significantly related to serum testosterone concentration (B), serum free testosterone concentration (C), or change in serum IGF-I concentration at the end of 20 wk of treatment.
The changes in specific tension in men treated with the five different weekly testosterone dose regimens were 9 ± 3%, 4 ± 2%, −7 ± 6%, 1 ± 3%, and −1 ± 5% (mean ± se) for the 25, 50, 125, 300, and 600 mg/wk dose groups, respectively. None of these changes was significant (P > 0.05), nor were the changes significantly different from each other (P = 0.82). The change in specific tension was not significantly correlated with testosterone dose or serum total or free testosterone concentrations (data not shown).
Discussion
Our data demonstrate that when the confounding factors in the measurements of muscle performance are controlled, testosterone administration increases maximal voluntary strength and leg power. In contrast, testosterone does not improve muscle fatigability, indicating that testosterone effects may be specific to certain characteristics of muscle performance, but not all. The effects of testosterone administration on muscle strength and leg power are dose and concentration dependent.
Previous studies of testosterone supplementation in androgen-deficient, young and older men have yielded conflicting results. Some studies in which physiological testosterone replacement was administered to healthy young hypogonadal men have reported significant gains in maximal voluntary strength and fat-free mass; however, a recent study reported no change in muscle strength after long-term testosterone administration even though fat-free mass increased significantly (4). The data on the effects of testosterone replacement in older men have also been contradictory. Tenover (13) and Sih et al. (26) reported that testosterone replacement of older men with low testosterone levels was associated with a greater improvement in grip strength than that associated with placebo administration. Recently, Ferrando et al. (11) reported significant gains in muscle strength in older men treated with testosterone. In contrast, in a well-designed, placebo-controlled, randomized clinical trial, Snyder et al. (12) found no significant differences in changes in knee extensor or knee flexor strength between placebo- and testosterone-treated men. The older men included in this study were not uniformly hypogonadal. In addition, their muscle strength was measured by a method (Biodex dynamometer) that did not demonstrate a response even in frankly hypogonadal younger men treated with testosterone (4). The Biodex dynamometer measures isokinetic strength using an open kinematic chain exercise that does not mimic natural movements in activities of daily living. Isokinetic strength, measured with an open kinematic chain exercise (leg extension) by this instrument, may assess a different measure of muscle performance than the variable resistance one-repetition maximum strength measured in the leg press exercise using the Keiser equipment with its closed kinematic chain movement. These data are consistent with the proposal that the effects of testosterone on muscle performance are specific to different measures of muscle performance. Therefore, failure of some previous studies to demonstrate improvements in some components of muscle performance should not be interpreted as evidence that testosterone has no effect on muscle performance. Our data provide unequivocal evidence that increasing testosterone concentrations in healthy young men are associated with dose- and concentration-dependent gains in maximal voluntary strength.
Our data constitute the first demonstration that testosterone improves leg power. Power is required in quick, explosive movements and has been shown to be correlated with functional activities in older persons (27–30). Jozsi et al. (31) stressed the contribution of the decline in leg power to the age-related impairment of physical function. Kraemer and Newton (32) emphasized that the ability to generate power is the most important attribute of muscle performance in performing many sports and everyday activities. Because testosterone improves leg power, it is possible that testosterone might improve those aspects of physical function that are dependent upon leg power; this hypothesis needs to be tested in prospective studies.
Muscle fatigability was not significantly related to testosterone dose or serum concentration, although there was a trend toward significance. Although testosterone administration was associated with net accrual of muscle mass, additional peripheral adaptations, including increases in capillarization, mitochondrial density, and oxidative enzyme activity, that determine muscle fatigability might not be affected by testosterone. However, it is possible that the study did not have sufficient power to exclude a type II error (power for this test was 0.64).
The gains in maximal voluntary strength and muscle power were not significantly correlated with serum IGF-I concentrations. Observations that testosterone supplementation augments fat-free mass and muscle strength even in hypophysectomized men (1) suggest that testosterone-induced increases in circulating GH and IGF-I levels may not be essential for mediating testosterone effects on the muscle. It is possible that the increments in circulating GH and IGF-I concentrations during testosterone administration might indirectly contribute to nitrogen retention and augment the overall anabolic effects of androgens (33). Several studies are in agreement that testosterone directly stimulates im IGF-I mRNA and down-regulates respective binding proteins (34).
Our data show that testosterone administration alone increased maximal voluntary strength, but did not improve specific tension. Using similar methodology to determine specific tension, Welle et al. (23) reported significant 38% and 32% increases in knee extensor specific tension after 3 mo of resistance exercise training in their young (22–31 yr) and old (62–72 yr) subjects, respectively. Taken together, these data suggest that strength training improves the contractile quality of muscle, but testosterone does not. There are several important corollaries to these observations. First, the improvements in maximal voluntary strength during testosterone administration are proportional to the gains in muscle mass. Second, the mechanisms by which testosterone and resistance training each improves muscle strength must not be entirely similar. While there may be some common mechanistic pathways by which both testosterone and resistance exercise induce gains in muscle size and strength, the effects of resistance exercise on muscle function probably involve additional mechanisms that are not affected by testosterone.
We recognize that the errors in the measurement of both maximal voluntary strength and muscle volume contribute to variance in the estimates of specific tension. Although computerized tomography (35) and MRI (36–38) scans are often used to estimate muscle cross-sectional area or volume, these measurements will only be accurate in fibers that have a parallel orientation (10). Although we used an MRI-determined index of muscle size that has been found to correlate well with maximal voluntary isometric contractions (36), our in vivo estimates of specific tension may not reflect measurements obtained in vitro with individual muscle fibers. Because direct measurements of the length, diameter, and orientation of muscle fibers that are contributing to force generation cannot be made in vivo, some inherent, unmeasurable uncertainty in the estimates of specific tension in human studies is introduced (22). The present data, generated in healthy young men, are similar to those reported earlier in a frog model, in which castration or testosterone administration had no effect on specific tension (39).
This study demonstrates that gains in maximal voluntary muscle strength and muscle power are related to testosterone dose and to serum and free testosterone concentrations. A single log-linear, dose-response curve best described the relationship between circulating testosterone concentrations and changes in fat-free mass and muscle size. Our data are consistent with Forbes's hypothesis of a linear relationship between testosterone dose and muscle mass and strength gains (4, 12, 13).
Generally, biological dose-response curves span a range of 2 log units. Within the constraints imposed by safety considerations, we only tested a relatively limited range of doses extending from 25–600 mg weekly. In light of what is known about biological dose-response curves, it is anticipated that a plateau would be achieved at doses that are approximately 2 log units higher than the minimal effective dose of testosterone enanthate. In that perspective, it is not surprising that a plateau was not observed within the relatively narrow range of doses that we studied. However, because of ethical and safety concerns, it is unlikely that doses higher than 600 mg would ever be tested in humans within the framework of a clinical research protocol.
The existence of a defined relationship between the administered dose and the gains in muscle strength and leg power suggests that in clinical disorders characterized by loss of muscle mass and function, it should be possible to predictably maximize gains in these measures of muscle performance by increments in testosterone dose. Our data predict that administration of supraphysiological doses to human immunodeficiency virus-infected men with weight loss, or men with cancer-associated cachexia would be associated with greater gains in muscle strength and power than those associated with physiological testosterone replacement. Although short-term administration of testosterone in physiological and slightly supraphysiological doses is relatively safe, the long-term effects of testosterone administration on the risk of prostate cancer and atherosclerotic heart disease are unknown. Long-term studies are needed to determine the range of serum testosterone concentrations that can be safely achieved to realize maximal anabolic effects without adversely affecting the risk to benefit ratio.
Our data were generated in healthy young men; we do not know whether similar dose-response relationships are operative in older men, men with chronic illness, or women. It is possible that testosterone dose-response curves might be shifted to the right in illness and old age. Testosterone dose-response relationships in women remain unknown.
The mechanisms by which testosterone exerts its anabolic effects on muscle function are not well understood, but probably involve alterations in the expression of many muscle growth regulators, including IGF-I, IGF-binding protein-3, and myostatin. Testosterone has also been shown to alter neuromuscular transmission. We do not know whether these effects are mediated through androgen receptor-mediated mechanisms or through an antiglucocorticoid effect. The effects of testosterone on muscle bioenergetics, capillarization and local blood flow, and mitochondrial function are not known and are the subjects of ongoing investigation.
BioTechnology General (Iselin, NJ) provided testosterone enanthate, and DebioPharma (Geneva, Switzerland) provided the GnRH agonist.
This work was supported by NIH Grants 1RO1-AG-14369 and 1RO1-DK-59627-01, FDA Grant ODP 1397, General Clinical Research Center Grant MO1-RR-00425, and RCMI Grants P20-RR-11145-01 (RCMI Clinical Research Initiative) and G12RR03026.
R.C. is the Grancell-Burns Chair in the Rehabilitative Sciences at the Harbor-University of California-Los Angeles Research and Education Institute.
Abbreviations:
-
ANCOVA,
-
BMI,
-
GCRC,
General Clinical Research Center;
-
MRI,
magnetic resonance imaging;
-
1-RM,
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