Testosterone threshold levels and lean tissue mass targets needed to enhance skeletal muscle strength and function: the HORMA trial

Abstract

Background: In the HORMA (Hormonal Regulators of Muscle and Metabolism in Aging) Trial, supplemental testosterone and recombinant human growth hormone (rhGH) enhanced lean body mass, appendicular skeletal muscle mass, muscle performance, and physical function, but there was substantial interindividual variability in outcomes.

Methods: One hundred and twelve men aged 65-90 years received testosterone gel (5 g/d vs 10 g/d via Leydig cell clamp) and rhGH (0 vs 3 vs 5 μg/kg/d) in a double-masked 2 × 3 factorial design for 16 weeks. Outcomes included lean tissue mass by dual energy x-ray absorptiometry, one-repetition maximum strength, Margaria stair power, and activity questionnaires. We used pathway analysis to determine the relationship between changes in hormone levels, muscle mass, strength, and function.

Results: Increases in total testosterone of 1046 ng/dL (95% confidence interval = 1040-1051) and 898 ng/dL (95% confidence interval = 892-904) were necessary to achieve median increases in lean body mass of 1.5 kg and appendicular skeletal muscle mass of 0.8 kg, respectively, which were required to significantly enhance one-repetition maximum strength (≥ 30%). Co-treatment with rhGH lowered the testosterone levels (quantified using liquid chromatography-tandem mass spectrometry) necessary to reach these lean mass thresholds. Changes in one-repetition maximum strength were associated with increases in stair climbing power (r = .26, p = .01). Pathway analysis supported the model that changes in testosterone and insulin-like growth factor 1 levels are related to changes in lean body mass needed to enhance muscle performance and physical function. Testosterone's effects on physical activity were mediated through a different pathway because testosterone directly affected Physical Activity Score of the Elderly.

Conclusions: To enhance muscle strength and physical function, threshold improvements in lean body mass and appendicular skeletal muscle mass are necessary and these can be achieved by targeting changes in testosterone levels. rhGH augments the effects of testosterone. To maximize functional improvements, the doses of anabolic hormones should be titrated to achieve target blood levels.

Figure 1.

Changes in serum testosterone and insulin-like growth factor 1 (IGF-1) levels by dose assignment. The box plots represent the distribution of changes from baseline to week 16 for testosterone participants who received 5 or 10 g/d doses and IGF-1 for participants who received rhGH at 0, 3, and 5 μg/kg/d. The solid line within each box represents the median and hatched line the mean of the distribution change. The upper and lower boundaries of the boxes represent the 75th and 25th percentiles of the distribution, respectively. The upper and lower whiskers represent the 90th and 10th percentiles, respectively. Dots above and below the 90th and 10th percentiles, respectively, are individual values outside this range. For Panel A (total testosterone) and Panel B (free testosterone), within dose group changes were significant (p < .0001) as were differences between groups (p < .0001). For Panel C (IGF-1), within group changes were significant for the 3 and 5 μg/kg doses (p < .0001) as was the Wald trend across the groups (p < .0001).

Figure 2.

Pathway analysis. This figure shows the result of the pathway analysis based on our hypotheses. Numbers associated with arrows are the estimated regression coefficients of the predictors/mediators with their corresponding mediators and outcomes; each is significant at p < .05. Predictors are changes (Δ) in serum testosterone and insulin-like growth factor 1 (IGF-1) levels; mediators are changes in lean body mass (LBM) and one-repetition maximum (1-RM) strength; and outcomes are changes in Physical Activity Score of the Elderly (PASE) and Margaria stair climbing power.

Figure 3.

Changes in total lean body and appendicular skeletal muscle mass related to changes in testosterone and insulin-like growth factor 1 (IGF-1) levels. Panels A and B shows changes in lean tissue mass for four groups of participants for whose change in total testosterone (T) and IGF-1 levels from baseline to week 16 were dichotomized as “high” (greater than median) or “low” (below median). For Panel A (change in total lean body mass), the Wald trend across the four groups was <0.0001. For pairwise comparisons with Tukey adjustment, asterisk represents difference (p < .0001) between high/high and low/low groups, double asterisks represent difference (p = .004) between high/high and low/high groups, and dagger represent difference (p = .02) between high/high and high/low groups. For Panel B (change in appendicular skeletal muscle mass), the Wald trend across the four groups was p = .0001. For pairwise comparisons with Tukey adjustment, asterisk represents difference (p < .0001) between high/high and low/low groups and double asterisk represent difference (p = .04) between high/high and low/high groups.