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Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science (S.B., L.W., A.B.S., R.P.M., M.L., I.S.-H., C.D., J.D., L.M., T.W.S.), Los Angeles, California 90059; Division of Respiratory Diseases, Pulmonary Physiology, and Critical Care Medicine, Harbor-University of California-Los Angeles Medical Center (R.C.), Torrance, California 90502; Laboratory for Exercise Science, El Camino College (T.W.S.), Torrance, California 90502; and Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine (K.E.Y.), St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Dr. Shalender Bhasin, Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, University of California, Los Angeles, California 90059. E-mail: sbhasin{at}ucla.edu.
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Abstract |
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Introduction |
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There has never been a direct comparison of the androgen responsiveness of young and older men. Furthermore, published data do not consistently support the idea of age-related resistance to androgen effects. Although androgen receptor number in some organs is lower in older animals than in young animals, most of this decrease in androgen receptor number occurs shortly after puberty and not as a function of advancing age (26, 27). Furthermore, older men are more sensitive to the gonadotropin-suppressive effects of testosterone than young men (28). Therefore, our first objective was to compare directly the responsiveness of young and older men to graded doses of testosterone. Because exogenous testosterone administration suppresses endogenous testosterone concentrations unevenly in different individuals, we used a GnRH agonist to suppress endogenous testosterone production to minimize the heterogeneity in circulating testosterone levels. Previously, we demonstrated that in young men, whose testosterone production had been suppressed by a GnRH agonist, testosterone supplementation engendered dose-dependent gains in fat-free mass (FFM) and muscle strength (29). The present study evaluated the responsiveness of healthy, older men, whose endogenous testosterone production had been similarly suppressed, to graded testosterone doses and compared it to that of young men. We recruited healthy young and older men to minimize the confounding influence of physiological derangements in older men with clinical disorders.
Previous studies reported modest gains in FFM and inconsistent changes in muscle strength after testosterone supplementation of older men (16, 17, 18, 19, 20, 23, 25, 29). Because previous studies used relatively small doses of testosterone, we determined whether higher doses would lead to greater FFM and muscle strength gains. We sought to determine the range of testosterone doses that could be safely administered to older men to achieve meaningful gains in FFM and muscle strength.
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Subjects and Methods |
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Participants
We recruited healthy, eugonadal, 60- to 75-yr-old men. Those with prostate cancer, American Urological Association symptom score above 7, prostate-specific antigen (PSA) levels greater than 4 ng/ml, hematocrit above 48%, diabetes mellitus, congestive heart failure, severe sleep apnea, or myocardial infarction in the preceding 6 months were excluded. All participants performed a maximal cycle ergometer test with 12-lead electrocardiogram monitoring to exclude those with cardiovascular symptoms during exercise. We excluded those who in the previous year had taken androgenic steroids, including dehydroepiandrosterone and androstenedione, GH, or other anabolic agents. Men who were participating in sports events, resistance exercise training, or moderate to heavy endurance exercise training were also excluded
Randomization
Testosterone dose assignment was based on randomization tables, with a block size of four. Sixty older and 61 young men were randomized similarly (29). After DSMB discontinued the 600-mg dose in older men in December 2002, subjects were randomized to one of the lower four doses.
Intervention
Men were treated with monthly injections of a long-acting GnRH agonist (Lupron depot, 7.5 mg; TAP, North Chicago, IL) to suppress endogenous testosterone production, and weekly injections of one of five doses of testosterone enanthate (200 mg/ml; Delatestryl, Savient Pharmaceuticals, Inc., Iselin, NJ): 25 mg (13 men), 50 mg (12 men), 125 mg (12 men), 300 mg (14 men), or 600 mg (10 men). Testosterone enanthate was selected because this is the only formulation that could raise testosterone concentrations into the supraphyiological range. The 25-mg dose was selected because this was the smallest dose of testosterone that had been shown to maintain sexual function in men treated with a GnRH antagonist (30). The 600-mg dose was selected because this is the highest dose that had been administered safely to men in clinical trials (29, 31). The General Clinical Research Center staff administered all drug injections to assure compliance.
Nutritional intake
Subjects were prescribed a diet standardized for energy (150 kJ/kg·d) and protein (1.3 g/kg·d). Dietary instructions were reinforced monthly, and compliance was verified using 3-d food records every 4 wk.
Exercise stimulus
The men were asked not to undertake resistance training or moderate to heavy endurance exercise. These instructions were reinforced every 2 wk.
Outcome measures
Fat-free mass (FFM), fat mass, leg press strength, sexual function, mood, and visuospatial cognition were assessed at baseline and after 20 wk. Hormone levels were measured twice during the control period and every month thereafter during the treatment and recovery periods. Safety measures, including complete blood counts, chemistry panels, plasma lipids, and PSA levels, were assessed twice during the control period and every month thereafter.
Hormone assays
Serum total testosterone was measured by a previously validated RIA (29, 31, 32, 33, 34, 35). Free testosterone was separated by an equilibrium dialysis procedure and measured by RIA (32). The sensitivity of the total testosterone assay was 0.02 nmol/liter (0.6 ng/dl), and the lower limit of the normal male range was 9.5 nmol/liter (275 ng/dl); intra- and interassay coefficients of variation were 8.2%, and 13.2%, respectively. For free testosterone assay, the sensitivity was 0.76 pmol/liter (0.22 pg/ml), and intra- and interassay coefficients of variation were 4.2% and 12.3%, respectively. The cross-reactivity of dihydrotestosterone in the testosterone assay was less than 0.1%.
Serum LH and FSH levels were measured by sensitive, two-site-directed, immunofluorometric assays, (Delfia-Wallac, Gaithersburg, MD), as described previously (31). The sensitivity of these assays is 0.04 U/liter for LH and 0.06 U/liter for FSH. The cross-reactivity with TSH, human chorionic gonadotropin, and free 
-subunit of pituitary glycoprotein hormones is less than 1%. Serum SHBG levels were measured by an immunofluorometric assay (31, 35).
Body composition assessment
We measured FFM and fat mass by underwater weighing, dual energy x-ray absorptiometry (DEXA; 4500A, Hologic, Inc., Waltham, MA), and 2H2O dilution. A Hologic QDR4500A DEXA scanner was used to measure total body and appendicular FFM and lean body mass before and after GnRH agonist plus testosterone enanthate treatment. The DEXA scanner was calibrated weekly using the manufacturer’s body composition analysis step phantom (36). Appendicular fat and lean masses were determined by adding the respective bilateral arm and leg masses (37, 38). Skeletal muscle mass was estimated from appendicular muscle mass, using algorithms published by Kim et al. (39).
For estimation of total body water, the men ingested 20 g deuterium oxide, and plasma samples were drawn at –15, 0, 120, 180, and 240 min. We measured deuterium abundance in plasma by nuclear magnetic resonance spectroscopy, using a correction factor of 0.985 for exchangeable hydrogen (35, 40). FFM was estimated as total body water divided by 0.73. We also estimated FFM from measurements of body density obtained by underwater weighing (31). During underwater weighing, the men were asked to exhale to the residual volume, as measured by helium dilution.
Muscle strength
We measured maximal voluntary strength in the leg press exercise by the one-repetition maximum (1-RM) method (41); 1-RM was 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. Because 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 on different days, 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. The 1-RM procedure (41) 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 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 1-min rest period, the load was increased further, and attempts were then made to identify the 1-RM. Attempts were punctuated 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 repeated within 2–7 d after the first test on separate days, with scores 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 1-RM.
Behavioral measurements
Sexual function was assessed by using 7-d logs of sexual activity and desire (42), which have been validated and published previously (29, 43). Visuospatial cognition was assessed by computerized checkerboard test, and mood was assessed by Hamilton depression and Young’s mania scales.
Safety monitoring
Blood chemistries, physical examination including prostate examination, and adverse events were evaluated monthly. Serum PSA and lipids were measured during wk 0, 8, 16, and 20. The Data Safety Monitoring Board reviewed the safety data every 3 months. The following rules for treatment discontinuation were established a priori: persistent increase in PSA above 4 µg/ml, increase in PSA more than 1.4 µg/ml above the baseline, hematocrit above 54%, aspartate aminotransferase and alanine aminotransferase more than 3 times upper limit of normal, diagnosis of prostate cancer, palpable prostate abnormality, and urinary retention.
Recovery
After treatment discontinuation, subjects were followed monthly to monitor recovery of hormone levels; subjects whose hormone levels did not return to baseline after 4 months were followed until recovery was complete.
Statistical analyses
All outcome variables were evaluated for distribution and homogeneity of variance; variables that did not meet the assumptions of homogeneity of variance or normal distribution were log-transformed. The primary analysis was a one-way ANOVA in older men. Secondarily, we also performed a two-way ANOVA to compare the change in outcome measures in older and young men; the two factors were age (young or old) and testosterone dose. If ANOVA revealed a significant effect, then the individual groups were compared using Tukey’s multiple comparison procedure. Multiple regression models were used to evaluate the effects of testosterone dose, change in testosterone level, and age. Because testosterone levels during treatment were higher in older men than in younger men, we examined multiplicative interaction of change in testosterone concentration and age to evaluate the parallelism between outcomes and change in testosterone concentrations with respect to age group. Mann-Whitney or Kruskal-Wallis tests compared changes in outcome measures that did not meet assumptions of ANOVA even after transformation. If there was a significant age effect, the values for young and older men for each dose were compared using Tukey’s multiple comparison procedure. Similarly, if the linear model revealed a significant dose effect, then different dose groups were compared using Tukey’s procedure. P < 0.05 for two-tailed comparisons was considered significant.
Assuming a linear relationship between change in FFM, our primary outcome variable, and testosterone concentrations, a sample size of 60 subjects in each age group provided 80% power to detect an effect size (difference between the slopes of the dose-response curves in young and older men) of 0.52 SD and 90% power to detect an effect size of 0.6 SD using a two-sided 5% significance level in a simple two-sample t test. We took into account the fact that multivariate models considered in our analyses adjust for a number of covariates, and these analyses would be expected to show reduced within-group variation compared with the unadjusted model and, therefore, would demonstrate greater power for the given effects. Thus, the study had adequate power to detect a medium effect size.
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Results |
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We evaluated 205 older men for eligibility; 145 men were excluded, because 89 were ineligible, and 56 declined to participate. Sixty older men were randomized; of these, 52 completed all phases of the study: 13 in the 25-mg group, 12 in the 50-mg group, 11 in the 125-mg group, 10 in the 300-mg group, and six in the 600-mg group (Fig. 1
). Eight men did not complete treatment, six because of serious adverse events (three receiving 300 mg and three receiving 600 mg) and one who was lost to follow-up. One subject in the 600-mg group was discontinued when DSMB stopped this study arm.
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Baseline characteristics
Baseline characteristics did not differ among the five dose groups (Table 1). Older men had greater body and fat masses and lower percent FFM and serum total and free testosterone concentrations than young men (Table 2).
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All evaluable men took 100% of the scheduled GnRH agonist injections; one young man in the 125-mg group missed one scheduled testosterone injection.
Nutritional intake
Daily energy and percent protein, carbohydrate, and fat intake were not significantly different among the five groups. There were no significant changes in daily caloric or protein intake during treatment (Table 3).
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During treatment, significant correlations were observed between testosterone dose and nadir total (r = 0.94; P < 0.0001) and free (r = 0.87; P < 0.0001) testosterone levels. Similarly, changes from baseline in total (r = 0.95; P < 0.0001) and free (r = 0.83; P < 0.0001) testosterone levels in older men were positively correlated with testosterone dose. Serum total testosterone levels increased dose-dependently in older men receiving the 125-, 300-, and 600-mg doses.
Baseline total and free testosterone levels were lower in older men than in young men (Table 2
). Secondary analysis revealed that after adjusting for dose, serum total and free testosterone levels during treatment were significantly higher in older men than young men (age effect, P < 0.0001 for each; Table 4 and Fig. 2). Increments above baseline in total and free testosterone levels were significantly greater in older men than young men (age effect, P < 0.0001 for each).
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). Baseline SHBG levels did not change in older men with treatment (Table 4). On d 252, 16 wk after treatment discontinuation, serum LH, total and free testosterone levels were not significantly different from baseline (LH, 5.8 ± 0.5 U/liter; total testosterone, 296 ± 12 ng/dl; free testosterone, 32 ± 2 pg/ml).
Adverse events
Older men had 147 adverse and 12 serious adverse events. Twelve serious adverse events occurred in nine older men and included hematocrit greater than 54% (six events), leg edema with shortness of breath (one event), urinary retention (one event), and prostate cancer (two events). There were dose-dependent increases in hemoglobin and hematocrit (dose effect, P < 0.0001; see Table 6 and Fig. 3). One older man receiving the 125-mg dose, three receiving the 300-mg dose, and two receiving the 600-mg dose had hematocrits greater than 54%. Leg edema occurred in eight older men: one receiving 50 mg, four receiving 300 mg, and three receiving 600 mg.
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). Two older men were found to have prostate cancer; one man receiving the 300-mg dose underwent biopsy because of a PSA level greater than 4 µg/ml, and a second man receiving the 50-mg dose underwent biopsy because of prostate irregularity that was palpated on digital rectal examination on the last recovery day.
There were 55 adverse events, but no serious adverse events, in young men (12). The frequency of total and serious adverse events and prostate events by testosterone dose was not statistically different between young and older men, although the total number of adverse events was numerically greater in older men than young men. The older men had significantly greater increments in hemoglobin and hematocrit than young men after adjusting for testosterone levels (age effect, P = 0.0001; Table 6 and Fig. 3).
Body composition
Changes in FFM in older men, measured by DEXA, correlated with testosterone dose (r = 0.77; P < 0.001) and total (r = 0.74; P < 0.001) and free (r = 0.72; P < 0.001) testosterone concentrations in older men (Table 5 and Fig. 4). Administration of 125-, 300-, and 600-mg doses in older men was associated with average FFM gains of 4.2, 5.6, and 7.3 kg, respectively; the gains in FFM were significantly greater in older men receiving 125-, 300-, and 600-mg doses than in those receiving 25- or 50-mg doses. Changes in FFM by underwater weighing also revealed a significant dose effect (P < 0.0001). Changes in skeletal muscle mass correlated with testosterone dose (r = 0.76; P < 0.001). The ratio of total body water to FFM did not change significantly at any dose in older men (change from baseline, –0.05 ± 0.05, –0.06 ± 0.03, 0.10 ± 0.04, –0.02 ± 0.03, and –0.09 ± 0.03).
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Changes in fat mass by DEXA were correlated inversely with testosterone dose (r = –0.54; P < 0.001) and total (r = –0.50; P < 0.001) and free (r = –0.48; P < 0.001) testosterone concentrations in older men (Table 5). Older men receiving 125-, 300-, and 600-mg doses lost greater amounts of fat mass than those receiving the 25-mg dose (P < 0.05 for each comparison). There was a significant age effect on change in fat mass (P < 0.0001) after adjusting for testosterone levels; young men receiving 25- and 50-mg doses gained more fat mass than older men receiving similar doses (P = 0.0006).
Muscle strength
Testosterone administration was associated with dose-dependent gains (P < 0.001) in leg press strength in older men (Table 5 and Fig. 4); men receiving 125-, 300-, and 600-mg doses gained more leg press strength than those receiving the 25-mg dose. Changes in muscle strength in older men correlated with total (r = 0.51; P = 0.0001) and free (r = 0.44; P = 0.001) testosterone levels. Multiple regression revealed no significant age effect or age by change in testosterone level interactive effect on change in leg press strength (P = 0.29).
Behavioral measures
Visuospatial cognition, and mood did not change significantly either in young or older men (data not shown).
Blood chemistries
Baseline PSA levels were higher in older men than young men (P < 0.05); however, there was no significant dose (P = 0.58) or age (P = 0.65) effect on PSA levels (Table 6) in older men. Serum aspartate aminotransferase, alanine aminotransferase, and bilirubin did not change significantly at any dose. Serum creatinine increased significantly in correlation with testosterone dose (r = 0.38; P = 0.005).
Plasma lipids
Total and high-density lipoprotein (HDL) cholesterol levels decreased dose-dependently in older men; a significant decrease in HDL cholesterol was observed in men receiving the 600-mg dose (Table 6). Changes in low-density lipoprotein (LDL) cholesterol or triglyceride levels were not significant. Secondary analysis revealed no significant age effect on changes in plasma lipids.
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Discussion |
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Aging is associated with loss of skeletal muscle mass and strength and impaired physical function (43, 44, 45, 46, 47, 48, 49, 50, 51). Age-related sarcopenia increases the risk of falls, fractures, and disability (26, 27, 28, 29, 30, 31). Therefore, anabolic interventions that prevent or reverse age-related loss of muscle mass and strength are desirable. Low bioavailable testosterone levels correlate with decreased FFM and muscle strength. Conversely, testosterone supplementation, especially when given in supraphysiological doses, induces remarkable gains in muscle mass and strength in older men, similar to those observed in young men. Gains in leg press strength in older men receiving 125-, 300-, and 600-mg doses averaged 28–50 kg. Thus, skeletal muscle in older men is capable of undergoing considerable hypertrophy in response to androgenic stimulus.
Mechanisms of androgen action on muscle are poorly understood. Testosterone supplementation increases muscle protein accretion (24, 52, 53, 54, 55, 56, 57) by increasing fractional muscle protein synthesis and facilitating the reutilization of amino acids by the muscle. Testosterone has also been reported to decrease muscle protein degradation. Testosterone supplementation induces hypertrophy of both type 1 and 2 skeletal muscle fibers (58), associated with a dose-dependent increase in the number of myonuclei and satellite cells (59). The muscle protein synthesis hypothesis does not easily explain the reciprocal change in fat mass during testosterone administration. Emerging data suggest that testosterone promotes commitment of pluripotent, mesenchymal cells into myogenic lineage and inhibits adipogenesis (60, 61).
Although testosterone administration in castrated rats induces salt and water retention, these effects are transient. We have shown in a number of experiments in hypogonadal men (34), healthy eugonadal men (34), and human immunodeficiency virus-infected men (35) that the ratio of FFM determined by DEXA to total body water does not change during testosterone administration. These observations along with the significant, dose-related strength gains indicate that the apparent increase in FFM is not due to water retention in excess of that associated with protein accretion.
This is the first direct comparison of testosterone dose-responsiveness of young and older men. The study provided comprehensive assessment of androgen-induced body composition changes in older men, using multiple methods in the controlled setting of a clinical research center which allowed standardization of energy and protein intake. Combined administration of GnRH agonist and testosterone suppressed LH and consequently endogenous testosterone production; this minimized heterogeneity in testosterone levels due to uneven suppression of endogenous testosterone production by exogenous androgen.
Increments in total and free testosterone levels above baseline were higher in older men than young men. Higher testosterone levels suggest that testosterone clearance is lower in older men than young men. The mechanisms of decreased testosterone clearance in older men are unknown.
Sexual function did not change significantly at any dose in either age group. Thus, these data are consistent with previous observations that sexual function in men (29, 42) and male rats (62) is maintained at testosterone concentrations at the lower end of the male range. Testosterone dose-response relationships differ for different androgen-dependent outcomes; sexual function and PSA levels are maintained at lower testosterone concentrations than those required to induce muscle accretion.
The best trade-off between anabolic effects and adverse effects was achieved with the 125-mg dose. These data suggest that in efficacy trials for aging-associated sarcopenia, serum testosterone levels should be raised into high end of the normal male range to maximize anabolic effects; the long-term safety of such an approach has not been tested. Also, lower testosterone levels might be sufficient for efficacy trials in men with sexual dysfunction. These data should not be interpreted to justify the 125-mg dose as the replacement dose in clinical practice. Because older men have lower plasma testosterone clearance than young men, it is likely that older men would need lower doses of testosterone than younger men to achieve the desired serum testosterone levels.
Administration of 300- and 600-mg testosterone doses was associated with a high frequency of serious adverse events in older men. An increase in hematocrit was the most frequent dose-limiting adverse event in older men. Testosterone stimulates erythropoietin production and erythropoietic stem cell replication (63, 64, 65, 66, 67). The reasons for greater hematocrit increment in older men are unknown. High hematocrit levels are associated with increased plasma viscosity and risk of stroke and hypertension. Leg edema developed in some older men receiving 300- or 600-mg doses. Testosterone administration to castrated male rats causes transient salt and water retention (57). In older men with preexisting heart disease, high testosterone doses may induce edema. Androgen administration induces myocardial hypertrophy (68); we do not know whether androgen-induced myocardial hypertrophy is beneficial or deleterious.
Two older men were diagnosed with prostate cancer (Gleason grade 4 in one man in whom information was available). There is concern that testosterone administration may induce subclinical prostate cancers to grow (69). More intensive PSA monitoring during testosterone administration might lead to the detection of a greater number of prostate cancers.
Because supraphysiological doses of testosterone (300 and 600 mg) were associated with a high frequency of adverse events, it is unlikely that these doses can be used in long-term human trials. However, these data provide compelling rationale for the development of selective androgen receptor modulators with anabolic properties that are free of dose-limiting adverse effects of testosterone (70). The Institute of Medicine committee on assessing the need for clinical trial of testosterone replacement therapy recommended studies of testosterone replacement in older men with low testosterone levels and symptoms attributable to androgen deficiency, such as sexual dysfunction, sarcopenia, or depression (71). Our study was designed to compare the androgen responsiveness of healthy, young and older men, and was not an efficacy trial. The study did not have adequate power to demonstrate improvements in clinical outcomes or risks of testosterone supplementation. We do not know whether testosterone-induced gains in muscle mass and strength translate into improved physical function or quality of life, or whether these gains in muscle mass and strength obtained in the controlled setting of a clinical research center can be replicated in a community setting. Thus, no claims about the efficacy or long-term risks of testosterone replacement in older men can be based on these results. However, these data provide evidence that some age-related changes in body composition and muscle strength are reversible, and that remarkable alterations in muscle mass and strength and fat mass are achievable in older men with androgen administration.
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Acknowledgments |
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Footnotes |
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First Published Online November 23, 2004
Abbreviations: FFM, Fat-free mass; HDL, high-density lipoprotein; PSA, prostate-specific antigen; 1-RM, one-repetition maximum.
Received June 21, 2004.
Accepted November 12, 2004.
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) and older (
) men in response to graded doses of testosterone enanthate. Healthy, young and older men were randomized to receive a long-acting GnRH agonist plus one of five different doses of testosterone enanthate (25, 50, 125, 300, and 600 mg weekly, im) for 20 wk. Serum testosterone levels were measured 7 d after the previous testosterone injection and represent nadir levels during wk 16. Data are the mean ± SEM. If there was a significant age effect, the values for young and older men for each dose were compared using Tukey’s multiple comparison procedure. *, Significant differences between young and older men receiving that dose (P < 0.05). Similarly, if the linear model revealed a significant dose effect, then different dose groups were compared using Tukey’s multiple comparison procedure. To convert serum total testosterone levels from conventional units (nanograms per deciliter) to Systeme International units (nanomoles per liter), multiply values in nanograms per deciliter by 0.03467. To convert free testosterone levels from conventional units (picograms per milliliter) to Systeme International units (picomoles per liter), multiply values in picograms per milliliter by 3.467.
