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1.  Changes in Muscle Mass, Muscle Strength and Power, but not Physical Function are Related to Testosterone Dose in Healthy Older Men 
To examine the effect of graded doses of testosterone on physical function (PF) and muscle performance in healthy, older men.
Randomized, double-blind, placebo controlled clinical trial.
General Clinical Research Center
Community-dwelling healthy older men aged 60-75 yr, N=44.
Monthly treatment with a gonadotropin releasing hormone agonist plus 25, 50, 125, or 300 mg/wk testosterone enanthate IM for 20 weeks.
Skeletal muscle mass (SMM) was estimated by DEXA. Leg press strength was measured by 1-RM, leg power by Nottingham Leg Rig, and muscle fatigability by repetitions to failure in the leg press exercise. Stair climbing, 6-m and 400-m walking speed, and a timed-up-and-go (TUG) were used to assess PF.
Significant T dose- and concentration-dependent increases were observed in SMM (P<0.001) and maximal strength (P=0.001), but not muscle fatigability. Leg power also increased dose-dependently (P=0.048). In contrast, changes in self-selected normal and fast walking speed over 6-m or 400-m, stair climbing power, and time for the TUG were not significantly related to T-dose, T-concentrations, or changes in muscle strength or power, or SMM.
Testosterone administration was associated with dose-dependent increases in SMM, leg strength and power, but did not improve muscle fatigability or physical function. The observation that physical function scores did not improve linearly with strength suggests that our high functioning older men were already in the asymptotic region of the curve describing the physical function – strength relationship.
PMCID: PMC2585153  PMID: 18795988
stair climb; timed up-and-go; timed walk test
2.  A controlled study of community-based exercise training in patients with moderate COPD 
BMC Pulmonary Medicine  2014;14:125.
The effectiveness of clinic-based pulmonary rehabilitation in advanced COPD is well established, but few data exist for less severe patients treated in alternative settings. The purpose of this study was to investigate whether a novel, community-based exercise program (CBE) was feasible and effective for patients with moderate COPD.
Nineteen patients with moderate COPD (mean FEV1 62%) and self-reported exercise impairment were randomized to 12-weeks of progressive endurance and strength training at a local health club under the guidance of a certified personal trainer, or to continuation of unsupervised habitual physical activity. Outcomes assessed at baseline and 12 weeks included session compliance, intensity adherence, treadmill endurance time, muscle strength, dyspnea, and health status.
Compliance was 94% and adherence was 83%. Comparisons between CBE and control groups yielded the following mean (SEM) differences in favor of CBE: endurance time 134 (74) seconds versus -59 (49) seconds (P = 0.041) and TDI 5.1 (0.8) versus -0.2 (0.5) (P < 0.001). The CBE group increased muscle strength (weight lifted) by 11.8 kilograms per subject per week of training (P < 0.001). SGRQ was not significantly changed.
We demonstrated the feasibility and effectiveness of a novel community-based exercise program involving health clubs and personal trainers for patients with moderate COPD.
Trial registration Identifier NCT01985529.
PMCID: PMC4124480  PMID: 25088030
Community; Exercise rehabilitation moderate COPD
3.  Tests of Muscle Strength and Physical Function: Reliability and Discrimination of Performance in Younger and Older Men and Older Men with Mobility Limitations 
To compare the reliability of muscle strength and physical function measures in younger and older men.
Academic research center.
Thirty younger men, 31 older men and 39 older men with mobility limitations.
Test-retest measures of 1-repetition maximum (1RM), unloaded and loaded 50m walk and stair climb, and a lift and lower task. Reliability was assessed by intra-class correlation (ICC) analysis and the Bland Altman (BA) method.
Leg and chest press 1RM measures identified significant differences between the groups, exhibited excellent test-retest reliability in younger men, older men and older men with mobility limitations (ICCs = 0.946–0.994) and minimal bias between trial 1 and 2 (BA = improvement of 21.1 and 1.1N for leg and chest press, respectively). Test-retest measures of the time to walk 50m and climb 12 steps also demonstrated excellent agreement (ICCs = 0.980–0.988 and 0.942–992, respectively) and minimal bias (BA = 0.755–1.007 and 0.141–0.361 sec faster, respectively). When a subject repeated these measures carrying a modest load ICCs remained > 0.940, bias was similar and the tests better discriminated between the groups. The lift and lower measure demonstrated excellent agreement (ICCs = 0.925–0.947), minimal bias (1.4–2.9 more shelves) and revealed significant differences between groups.
Measures of muscle strength and physical function can be performed in younger men, older men and older men with mobility limitations with high reliability. In future clinical trials, more challenging measures of performance may better discriminate amongst higher functioning study participants.
PMCID: PMC3031449  PMID: 18811607
Muscle strength; physical function; aging; sarcopenia; anabolic therapies
4.  Eight Weeks of Exercise Training Improves Fitness Measures in Methamphetamine-Dependent Individuals in Residential Treatment 
Journal of addiction medicine  2013;7(2):122-128.
Physical exercise has been shown to benefit diverse medical and behavioral conditions. This study assesses the feasibility and efficacy of an 8-week endurance and resistance training program on fitness measures in individuals undergoing residential treatment for methamphetamine (MA) dependence.
A total of 39 MA-dependent individuals were randomized to 3 days/week of exercise training (ET, n=15) or health education without training (EA, n=14) over 8 weeks. Aerobic performance (VO2max) was measured by indirect calorimetry, body composition by skinfolds, muscle strength by 1-repetition maximum (1-RM) and endurance at 85% of 1-RM for both leg press (LP) and chest press (CP).
A total of 29 individuals completed the study for a 74% adherence rate. Baseline characteristics (mean±SD) were balanced between groups: age 31±7 years; height=1.74±0.07 m; weight 82.0±15.0 kg. The ET group significantly improved VO2max by 0.63±0.22 L/min (+21%), LP strength by 24.4±5.6 kg (+40%) and CP strength by 20.6±5.7 kg (+49%). The ET group increased LP and CP endurance by 120% and 96%, respectively and showed significant reductions in body weight of 1.7±2.4 kg (−2%), % body fat of 2.8±1.3% (−15%) and fat weight 2.8±1.8 kg (−18%). All changes were significant (P<0.001) for ET, and no changes were seen for the EA group.
Individuals recovering from methamphetamine dependence showed substantial improvements in aerobic exercise performance, muscle strength and endurance, and body composition with exercise training. These findings demonstrate the feasibility of an exercise training intervention in these participants and also show excellent responsiveness to the exercise stimulus resulting in physiological changes that might enhance recovery from drug dependency.
PMCID: PMC3617407  PMID: 23552821
Methamphetamine; exercise; addiction
5.  The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men 
Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity.
To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones.
In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention.
LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation.
LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations.
PMCID: PMC4111291  PMID: 22459616
Selective androgen receptor modulators; SARMs; Sarcopenia; Function promoting anabolic therapies; Cachexia
6.  Use of the HR index to predict maximal oxygen uptake during different exercise protocols 
Physiological Reports  2013;1(5):e00124.
This study examined the ability of the HRindex model to accurately predict maximal oxygen uptake (O2max) across a variety of incremental exercise protocols. Ten men completed five incremental protocols to volitional exhaustion. Protocols included three treadmill (Bruce, UCLA running, Wellness Fitness Initiative [WFI]), one cycle, and one field (shuttle) test. The HRindex prediction equation (METs = 6 × HRindex − 5, where HRindex = HRmax/HRrest) was used to generate estimates of energy expenditure, which were converted to body mass-specific estimates of O2max. Estimated O2max was compared with measured O2max. Across all protocols, the HRindex model significantly underestimated O2max by 5.1 mL·kg−1·min−1 (95% CI: −7.4, −2.7) and the standard error of the estimate (SEE) was 6.7 mL·kg−1·min−1. Accuracy of the model was protocol-dependent, with O2max significantly underestimated for the Bruce and WFI protocols but not the UCLA, Cycle, or Shuttle protocols. Although no significant differences in O2max estimates were identified for these three protocols, predictive accuracy among them was not high, with root mean squared errors and SEEs ranging from 7.6 to 10.3 mL·kg−1·min−1 and from 4.5 to 8.0 mL·kg−1·min−1, respectively. Correlations between measured and predicted O2max were between 0.27 and 0.53. Individual prediction errors indicated that prediction accuracy varied considerably within protocols and among participants. In conclusion, across various protocols the HRindex model significantly underestimated O2max in a group of aerobically fit young men. Estimates generated using the model did not differ from measured O2max for three of the five protocols studied; nevertheless, some individual prediction errors were large. The lack of precision among estimates may limit the utility of the HRindex model; however, further investigation to establish the model's predictive accuracy is warranted.
PMCID: PMC3841054  PMID: 24303190
Cardiorespiratory fitness; exercise testing; prediction equation; resting heart rate
7.  Clinical Meaningfulness of the Changes in Muscle Performance and Physical Function Associated With Testosterone Administration in Older Men With Mobility Limitation 
Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial’s Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant’s perception of change.
Men aged 65 years and older, with mobility limitation, total testosterone 100–350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared.
Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change.
Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.
PMCID: PMC3202898  PMID: 21697501
Testosterone; Minimally important difference; Mobility limitation; Older men; Function promoting therapies
8.  Adverse Events Associated with Testosterone Administration 
The New England journal of medicine  2010;363(2):109-122.
Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied.
Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group.
A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load.
In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy.
PMCID: PMC3440621  PMID: 20592293
9.  Muscle function, physical performance and body composition changes in men with prostate cancer undergoing androgen deprivation therapy 
Asian Journal of Andrology  2012;14(2):204-221.
Prostate cancer (PCa) is the most common visceral malignancy in men with androgen deprivation therapy (ADT) the preferred therapy to suppress testosterone production and hence tumor growth. Despite its effectiveness in lowering testosterone, ADT is associated with side effects including loss of muscle mass, diminished muscle strength, decrements in physical performance, earlier fatigue and declining quality of life. This review reports a survey of the literature with a focus on changes in muscle strength, physical function and body composition, due to short-term and long-term ADT. Studies in these areas are sparse, especially well-controlled, prospective randomized trials. Cross-sectional and longitudinal data (up to 2 years) for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available. Based on limited longitudinal data, the adverse effects of ADT on muscle function, physical performance and body composition occur shortly after the onset of ADT and tend to persist and worsen over time. Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine. Disparities in study duration, types of studies and other patient-specific variables such as time since diagnosis, cancer stage and comorbidities may all affect an understanding of the influence of ADT on health, physical performance and mortality.
PMCID: PMC3735097  PMID: 22367184
androgen deprivation therapy; androgen suppression; exercise prescription; exercise training; functional assessment; lean body mass; older men; prostate cancer
10.  Testosterone Replacement and Resistance Exercise in HIV-Infected Men With Weight Loss and Low Testosterone Levels 
Previous studies of testosterone supplementation in HIV-infected men failed to demonstrate improvement in muscle strength. The effects of resistance exercise combined with testosterone supplementation in HIV-infected men are unknown.
To determine the effects of testosterone replacement with and without resistance exercise on muscle strength and body composition in HIV-infected men with low testosterone levels and weight loss.
Design and Setting
Placebo-controlled, double-blind, randomized clinical trial conducted from September 1995 to July 1998 at a general clinical research center.
Sixty-one HIV-infected men aged 18 to 50 years with serum testosterone levels of less than 12.1 nmol/L (349 ng/dL) and weight loss of 5% or more in the previous 6 months, 49 of whom completed the study.
Participants were randomly assigned to 1 of 4 groups: placebo, no exercise (n = 14); testosterone enanthate (100 mg/wk intramuscularly), no exercise (n = 17); placebo and exercise (n = 15); or testosterone and exercise (n = 15). Treatment duration was 16 weeks.
Main Outcome Measures
Changes in muscle strength, body weight, thigh muscle volume, and lean body mass compared among the 4 treatment groups.
Body weight increased significantly by 2.6 kg (P<.001) in men receiving testosterone alone and by 2.2 kg (P = .02) in men who exercised alone but did not change in men receiving placebo alone (−0.5 kg; P = .55) or testosterone and exercise (0.7 kg; P = .08). Men treated with testosterone alone, exercise alone, or both experienced significant increases in maximum voluntary muscle strength in leg press (range, 22%–30%), leg curls (range, 18%–36%), bench press (range, 19%–33%), and latissimus pulls (range, 17%–33%). Gains in strength in all exercise categories were greater in men assigned to the testosterone-exercise group or to the exercise-alone group than in those assigned to the placebo-alone group. There was a greater increase in thigh muscle volume in men receiving testosterone alone (mean change, 40 cm3; P<.001 vs zero change) or exercise alone (62 cm3; P = .003) than in men receiving placebo alone (5 cm3; P = .70). Average lean body mass increased by 2.3 kg (P = .004) and 2.6 kg (P<.001), respectively, in men who received testosterone alone or testosterone and exercise but did not change in men receiving placebo alone (0.9 kg; P = .21). Hemoglobin levels increased in men receiving testosterone but not in those receiving placebo.
Our data suggest that testosterone and resistance exercise promote gains in body weight, muscle mass, muscle strength, and lean body mass in HIV-infected men with weight loss and low testosterone levels. Testosterone and exercise together did not produce greater gains than either intervention alone.
PMCID: PMC3173037  PMID: 10683055
11.  Habitual Physical Activity Levels are Associated with Performance in Measures of Physical Function and Mobility in Older Men 
To determine whether objectively measured physical activity levels are associated with physical function and mobility in older men.
Academic research center.
Eighty-two community-dwelling men ≥ 65 years of age with self-reported mobility limitations were divided into a low activity and a high activity group based on the median average daily physical activity counts of the whole sample.
Physical activity by triaxial accelerometers; physical function and mobility by the Short Physical Performance Battery (SPPB), gait speed, stair climb time, and a lift and lower task; aerobic capacity by maximum oxygen consumption (VO2max); and leg press and chest press maximal strength and peak power.
Older men with higher compared to lower physical activity levels demonstrated a > 1.4 point higher mean SPPB score and a 0.35 m/s faster walking speed. They also climbed a standard flight of stairs 1.85 sec faster and completed 60% more shelves in a lift and lower task (all p < 0.01). Muscle strength and power measures, however, were not significantly different between the low and high activity group. Correlation analyses and multiple linear regression models showed that physical activity is positively associated with all physical function and mobility measures, leg press strength, and VO2max.
Older men with higher physical activity levels demonstrate better physical function and mobility than less active peers. Moreover, in older men physical activity levels are predictive of performance in measures of physical function and mobility. Future work is needed to determine whether modifications in physical activity levels can improve or preserve physical performance in later-life.
PMCID: PMC2945416  PMID: 20738436
aging; sarcopenia; muscle strength; disability; exercise
12.  Effects of Testosterone Therapy on Muscle Performance and Physical Function in Older Men with Mobility Limitations (The TOM Trial): Design and Methods 
Contemporary clinical trials  2008;30(2):133-140.
The TOM study is the first, single-site, placebo-controlled, randomized clinical trial designed to comprehensively determine the effects of testosterone administration on muscle strength and physical function in older men with mobility limitations. A total of 252 community dwelling individuals aged 65 and older with low testosterone levels and self-reported limitations in mobility and short physical performance battery (SPPB) score between 4 and 9 will be randomized to receive either placebo or testosterone therapy for 6 months. The primary objective is to determine whether testosterone therapy improves maximal voluntary muscle strength as quantified by the one repetition maximum. Secondary outcomes will include measures of physical function (walking, stair climbing and a lifting and lowering task), habitual physical activity and self-reported disability. The effects of testosterone on affect, fatigue and sense of well being will also be assessed. Unique aspects of the TOM Trial include selection of men with self-reported as well as objectively demonstrable functional limitations, community-based screening and recruitment, adjustment of testosterone dose to ensure serum testosterone levels in the target range while maintaining blinding, and inclusion of a range of self-reported and performance-based physical function measures as outcomes. identifier: NCT00240981.
PMCID: PMC3031114  PMID: 18996225
testosterone; mobility limitations; physical function; strength; aging; sarcopenia; anabolic therapies
13.  Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging 
Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with β-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging.
PMCID: PMC2072878  PMID: 16932274
anabolic therapies; androgens; sarcopenia; selective androgen receptor modulators; testosterone

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