Obesity and Hypogonadism
Conditions
Keywords
Obesity, Hypogonadism, Frailty
Brief summary
The prevalence of obesity in Veterans is greater than in the general population, and even more so among users of the VA Health Care System. In addition, the population of obese older Veterans is rapidly increasing as more baby boomers become senior citizens. In older Veterans, obesity exacerbates the age- related decline in physical function and causes frailty which predisposes to admission to a VA chronic care facility. However, the optimal clinical approach to obesity in older adults is controversial because of the concern that weight loss therapy could be harmful by aggravating the age-related loss of muscle mass and bone mass. In fact, the MOVE (Managing Overweight/Obese Veterans) program does not have any guidelines for eligible Veterans if they are 70 or older. It is possible that the addition of testosterone replacement to lifestyle therapy will preserve muscle mass and bone mass and reverse frailty in obese older Veterans and thus prevent their loss of independence and decrease demand for VA health care services.
Detailed description
Obesity is not only highly prevalent among Americans, but even more so among Veterans using VA medical facilities. Failure to assist Veterans in managing weight and sedentary lifestyle affects current treatment and increases future demand for VA health care services. Decreased muscle mass with aging and the need to carry extra mass due to obesity make it particularly difficult for obese older Veterans to function independently and results in frailty leading to increased nursing home admissions and increased morbidity and mortality. Data from preliminary studies showed that lifestyle therapy resulting in weight loss in this understudied population improves physical function and ameliorates frailty. However, this improvement in physical function is modest at best and most obese older adults remain physically frail. More importantly, there are concerns that lifestyle therapy may exacerbate underlying sarcopenia and osteopenia from weight loss- induced loss of lean body mass and bone mineral density (BMD). As a result, most geriatricians are reluctant to recommend lifestyle therapy that includes weight loss in obese frail elderly patients although the combination of weight loss and exercise is recommended as part of standard care for obese patients in general. Thus, it is not surprising that among Veterans, the MOVE (Managing Overweight/Obese Veterans) program does not have any guidelines for eligible Veterans if they are 70 or older. In addition to overeating and lack of exercise, age-related decline in anabolic hormone (i.e. testosterone) may contribute to sarcopenia and osteopenia, which in turn is exacerbated by obesity. Indeed, preliminary studies discovered that obese older men had markedly low levels of serum testosterone at baseline which remained low throughout the duration of lifestyle therapy. Because testosterone replacement therapy has been shown to increase muscle mass and BMD, it is therefore likely that concomitant testosterone replacement during lifestyle therapy in obese older adults would preserve lean body mass and BMD, and reverse frailty. Accordingly, the optimal management to the problem of sarcopenic obesity and frailty might require a comprehensive approach of a combination of lifestyle intervention and the correction of anabolic hormone deficiency. Therefore, the primary goal of this proposal is to conduct a randomized, comparative efficacy, double-blind, placebo-controlled (for testosterone) trial of the effects of 1) lifestyle therapy (1% diet-induced weight loss and exercise training) + testosterone replacement therapy versus 2) lifestyle therapy without testosterone replacement (testosterone placebo) in obese (BMI e 30 kg/m2) older (age e 65 yrs) male Veterans. The investigators hypothesize that 1) lifestyle therapy + testosterone replacement will cause a greater improvement in physical function than lifestyle therapy without concomitant testosterone replacement; 2) lifestyle therapy + testosterone replacement will cause a greater preservation of fat-free mass and thigh muscle volume than lifestyle therapy without testosterone replacement, 3) lifestyle therapy + testosterone replacement will cause a greater preservation in BMD and bone quality than lifestyle therapy without testosterone replacement, and 4) lifestyle therapy + testosterone replacement will cause a greater reduction in intramuscular proinflammatory cytokines than lifestyle therapy without testosterone replacement. The overarching hypothesis across aims is that a multifactorial intervention by means of lifestyle therapy plus testosterone replacement will be the most effective approach for reversing sarcopenic obesity and frailty in obese older male adults, as mediated by their additive effects in suppressing chronic inflammation, and stimulating muscle and bone anabolism. Obesity in older adults, including many aging Veterans, is a major public health problem. In fact, the public health success that has occurred in recent years could be in danger if lifestyles of older adults are neglected. The novel health outcomes and mechanistic-based data generated from this proposed randomized clinical trial (RCT) will have important ramifications for the standard of care for this rapidly increasing segment of the aging Veteran population.
Interventions
DRUGTestosterone
Daily testosterone gel applied once daily in the morning to intact skin
OTHERLifestyle Therapy
Weekly behavioral diet to induce \ 10% weight loss in combination with supervised aerobic and exercise training three times a week
DRUGPlacebo
Placebo gel for testosterone
Sponsors
Michael E. DeBakey VA Medical Center
Baylor College of Medicine
Biomedical Research Institute of New Mexico
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
65 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Subjects will be * older (65-85 yr) * obese (BMI 30 kg/m2 or greater) Veteran men with low testosterone (less than 300 mg/dL) as defined by the Endocrine Society * mild to moderately frail * must have stable weight (\ not less than or more than 2 kg) during the last 6 months * sedentary (regular exercise less than 1 h/week or less than 2x/week for the last 6 months)
Exclusion criteria
* Any major chronic diseases, or any condition that would interfere with exercise or dietary restriction, in which exercise or dietary restriction are contraindicated, or that would interfere with interpretation of results. * Examples include, but are not limited to: * cardiopulmonary disease (e.g. recent myocardial infarction (MI), unstable angina, stroke etc) or unstable disease (e.g. CHF) * severe orthopedic/musculoskeletal or neuromuscular impairments * visual or hearing impairments * cognitive impairment (Mini Mental State Exam Score less than 24) * current use of bone active drugs * uncontrolled diabetes (i.e. fasting blood glucose more than 140 mg/dl and/or HbA1c greater than 9.5%). * Any contraindications to testosterone supplementation * history of prostate or breast cancer * history of testicular disease * untreated sleep apnea * hematocrit more than 50% * prostate-related findings of palpable nodule on exam, a serum PSA of 4.0 ng/ml or greater * International Prostate Symptom Sore more than 19 * history of venous thromboembolism * Osteoporosis or a BMD T-score of -2.5 in the lumbar spine or total hip as well as those patients with a history of osteoporosis-related fracture (spine, hip, or wrist)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Physical Performance Test | Baseline and 6 months | The primary functional outcome is the modified physical performance test, which includes seven standardized tasks (walking 50 ft, putting on and removing a coat, picking up a penny, standing up from a chair, lifting a book, climbing one flight of stairs, and performing a progressive Romberg tests) plus two additional tasks (climbing up and down four flights of stairs and performing a 360-degree turn). The score for each task ranges form 0 to 4; a perfect score is 36. Higher scores indicate better physical function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Trabecular Bone Score (Trabecular Bone Quality) | Baseline and 6 months | assessed by trabecular bone score (TBS), a newly developed index for assessing trabecular bone quality and fracture risk. TBS is a bone texture parameter that quantifies cancellous bone microachitecture, which is key in determining bone strength and resistance to fracture, by computing raw data from dual energy x-ray absorptiometry of the lumbar spine. There are no minimum or maximum values. Higher scores mean better outcome. |
| Stroop Interference | Baseline and 6 months | Assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. |
| Change in Word List Fluency | Baseline and 6 months | Measure of verbal production, semantic memory, and language. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. |
| Change in Ray Auditory Verbal Learning Test | Baseline and 6 months | The Rey Auditory Verbal Learning Test (RAVLT) evaluates a wide diversity of functions: short-term auditory-verbal memory, rate of learning, learning strategies, retroactive, and proactive interference, presence of confabulation of confusion in memory processes, retention of information. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. |
| Change in Trail A | Baseline and 6 months | Test of visuospatial scanning, speed of processing, mental flexibility, and executive function (with a greater focus on attention). Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. |
| Change in Trail B | Baseline and 6 months | Test of visuospatial scanning, speed of processing, mental flexibility, and executive function (with a focus on executive function) Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. |
| Change in Symbol Digital Modalities Test | Baseline and 6 months | Assesses key neurocognitive functions that underlie many substitution tasks, including attention, visual scanning, and motor speed. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome. |
| Change in Trabecular Bone Score | Baseline and 6 months | The trabecular bone score is a measure of bone texture correlated with bone microarchitecture and a marker for the risk of osteoporosis. Minimum score is 0, there is no maximum value. Higher scores indicate better bone microarchitecture. |
| Change in C-terminal Telopeptide | Baseline and 6 months | biochemical marker of bone turnover (bone resorption) as measured by immunoassay technique |
| Change in N-terminal Propeptide of Type I Procollagen | Baseline and 6 months | Biochemical marker of bone turnover (bone formation) as measured by radioimmunoassay technique |
| Change in Insulin Growth Factor-1 | Baseline and 6 months | Measured by immunoassay methodology |
| Change in Levels of 25-hydroxyvitamin D | Baseline and 6 months | assessed by using immunoassay methodology |
| Change in Parathyroid Hormone Level | Baseline and 6 months | Measured by immunoassay methodology as marker of bone metabolism |
| Change in High-sensitivity C-reactive Protein (Inflammatory Marker) | Baseline and 6 months | measured in the peripheral blood using immunoassay technique methodology |
| Change in Interleukin-6 | Baseline and 6 months | Measured from fasting serum using immunoassay technique as marker of inflammation |
| Change in Endurance Capacity | Baseline and 6 months | Assessed by measuring peak oxygen consumption using indirect calorimetry during a treadmill exercise stress test |
| Change in Functional Status | Baseline and 6 months | Assessed by the Functional Status Questionnaire. Score range: 0 to 36 with higher scores indicating better functional status Provides information of the participants ability to perform activities of daily living. |
| Change in Body Weight | Baseline and 6 months | Measured after an overnight fast using calibrated scales |
| Change in Lean Body Mass | Baseline and 6 months | Assessed by using dual-energy x-ray absorptiometry |
| Change in Fat Mass | Baseline and 6 months | Assessed by using dual-energy x-ray absorptiometry |
| Change in Thigh Muscle Volume | Baseline and 6 months | Assessed by using magnetic resonance imaging |
| Thigh Fat Volume | 6 months | Volume of fat in the thigh by measured by magnetic resonance imaging |
| Change in Total Hip Bone Mineral Density | Baseline and 6 months | Assessed by using dual-energy x-ray absorptiometry |
| Change in Lumbar Spine Bone Mineral Density | Baseline and 6 months | As measured by Dual energy x-ray absorptiometry |
| Change in Muscle Strength | Baseline and 6 months | assessed by total1-repetition maximum (the maximal weight lifted at one time; the totals are the sum of the maximal weights lifted in the biceps curl, bench press, 387 seated row, knee extension, knee flexion, and leg press exercises). |
| Change in Static Balance | Baseline and 6 months | assessed by one leg limb stance |
| Change in Dynamic Balance | Baseline and 6 months | Assessed by using the obstacle course |
| Change in Gait Speed | Baseline and 6 months | Determined by measuring the time needed to walk 25 ft. |
| Change in Composite Cognitive Z-score | Baseline and 6 months | Test of overall cognitive performance formed by averaging the standardized scores for several domains of cognitive function (attention, memory, executive, language, global). Higher scores indicate better cognitive status. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the baseline scores (units on a scale). Negative numbers indicate values lower than the reference population and positive numbers indicate values higher than the reference population |
| Change in Modified Mini-mental Exam | Baseline and 6 months | Test of global cognition with components for orientation, registration, attention, language, praxis, and immediate and delayed memory. Score ranges from 0 to 100 with higher scores indicate better cognition. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Hematocrit | Baseline and 6 months | the ratio of the volume of red blood cells to the total volume of blood. |
| Change in Prostate Specific Antigen | Baseline and 6 months | blood test to screen for prostate cancer |
| Change in Short Form Health Survey (SF-36) Quality of Life Physical Component | Baseline and 6 months | Using Short Form-36 of Life Questionnaire Physical Component subscale. Minimum score is 0, Maximum score is 100. Higher scores indicate better outcome. |
| Change in International Prostate Symptom Score | Baseline and 6 months | Using the International Prostate Symptom Scoring (IPS); Minimum score is 0, Maximum score is 35. Higher scores mean worse outcome. |
| Change in Triglyceride Levels | Baseline and 6 months | Blood samples obtained in the fasting state as part of measurements of lipid profile |
| Change in HDL-cholesterol | Baseline and 6 months | Blood samples obtained in the fasting state as part of measurements of lipid profile |
| Change in Waist Circumference | Baseline and 6 months | Waist circumference as measured horizontally at the midpoint between the highest point of the iliac crest and the lowest portion of the 12th rib in the standing position. |
| Change in Glucose | Baseline and 6 months | Measured in the blood after overnight fast |
| Change in Mood | Baseline and 6 months | Using Yesavage Depression Scale Lower scores indicate better mood (range 0 to 30). |
| Number of Participants With Significant Changes in Functional Connectivity in the Default Mode Network | Baseline and 6 months | Functional connectivity was measured with seeds of the DMN (medial prefrontal cortex \[MPFC\] and posterior cingulate cortex \[PCC\]). Correlation coefficients representing the degree of connectivity between hypothesized regions were Fisher transformed. An a priori threshold of p\<.001 at the voxel level and p\<.05, FDR corrected for multiple comparisons across the whole brain, at the cluster level were used to determine significant connectivity. |
| Change in Skeletal Muscle Growth Factor (MYOD1) | Baseline and 6 months | Assessed by using RNA-seq quantification of gene expression in skeletal muscles obtained during muscle biopsies. |
| Change in Peripheral Quantitative Computed Tomography Measures (Volumetric Bone Density) | Baseline and 6 months | assessed by quantitative computed tomography at 4% distal tibia using the following thresholds: 180 mg/cm3 and 45% of the area |
| Change in Estradiol | Baseline and 6 months | As measured by LC-MS/MS |
| Change in Total Testosterone Levels | Baseline and 6 months | as measured in the peripheral blood by liquid chromatography/mass spectrometry |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through advertisements and review of medical records at the Michael E DeBakey VA Medical Center.
Pre-assignment details
After obtaining written informed consent, potential participants underwent a comprehensive medical screening procedure, including an exercise stress test. If they were found eligible based on the inclusion/exclusion criteria, they were randomized into one of the two treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Lifestyle Therapy Placebo in combination with behavioral diet to induce \
10% weight loss and supervised aerobic and exercise training
Lifestyle Therapy: Weekly behavioral diet to induce \
10% weight loss in combination with supervised aerobic and exercise training three times a week
Placebo: Placebo gel for testosterone | 41 |
| Testosterone + Lifestyle Therapy Testosterone replacement in combination with behavioral diet to induce \
10% weight loss + supervised aerobic and exercise training
Testosterone: Daily testosterone gel applied once daily in the morning to intact skin
Lifestyle Therapy: Weekly behavioral diet to induce \
10% weight loss in combination with supervised aerobic and exercise training three times a week | 42 |
| Total | 83 |
Baseline characteristics
| Characteristic | Total | Testosterone + Lifestyle Therapy | Placebo + Lifestyle Therapy |
|---|---|---|---|
| Age, Continuous | 73.4 years STANDARD_DEVIATION 3.5 | 73.6 years STANDARD_DEVIATION 3.7 | 72.2 years STANDARD_DEVIATION 3.2 |
| Body mass index | 37.0 kg/m^2 STANDARD_DEVIATION 5.2 | 37.1 kg/m^2 STANDARD_DEVIATION 5.6 | 36.9 kg/m^2 STANDARD_DEVIATION 4.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants | 19 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants | 20 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 3 Participants | 1 Participants |
| Physical Performance Test score | 28.4 units on a scale STANDARD_DEVIATION 2.9 | 28.5 units on a scale STANDARD_DEVIATION 2.8 | 28.3 units on a scale STANDARD_DEVIATION 3.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 34 Participants | 20 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 41 Participants | 19 Participants | 22 Participants |
| Region of Enrollment United States | 83 participants | 42 participants | 41 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 83 Participants | 42 Participants | 41 Participants |
| Total testosterone level | 214 ng/dl STANDARD_DEVIATION 54 | 210 ng/dl STANDARD_DEVIATION 63 | 218 ng/dl STANDARD_DEVIATION 43 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 42 |
| other Total, other adverse events | 12 / 41 | 6 / 42 |
| serious Total, serious adverse events | 1 / 41 | 1 / 42 |
Outcome results
Primary
Change in the Physical Performance Test
The primary functional outcome is the modified physical performance test, which includes seven standardized tasks (walking 50 ft, putting on and removing a coat, picking up a penny, standing up from a chair, lifting a book, climbing one flight of stairs, and performing a progressive Romberg tests) plus two additional tasks (climbing up and down four flights of stairs and performing a 360-degree turn). The score for each task ranges form 0 to 4; a perfect score is 36. Higher scores indicate better physical function.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in the Physical Performance Test | 4.6 units on a scale | Standard Error 0.3 |
| Testosterone + Lifestyle Therapy | Change in the Physical Performance Test | 4.9 units on a scale | Standard Error 0.3 |
p-value: 0.58Mixed Models Analysis
Secondary
Change in Body Weight
Measured after an overnight fast using calibrated scales
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Body Weight | -10.6 kilograms | Standard Error 0.6 |
| Testosterone + Lifestyle Therapy | Change in Body Weight | -9.8 kilograms | Standard Error 0.6 |
p-value: 0.56Mixed Models Analysis
Secondary
Change in Composite Cognitive Z-score
Test of overall cognitive performance formed by averaging the standardized scores for several domains of cognitive function (attention, memory, executive, language, global). Higher scores indicate better cognitive status. The Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of the baseline scores (units on a scale). Negative numbers indicate values lower than the reference population and positive numbers indicate values higher than the reference population
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Composite Cognitive Z-score | .273 z-score | Standard Error 0.061 |
| Testosterone + Lifestyle Therapy | Change in Composite Cognitive Z-score | .557 z-score | Standard Error 0.065 |
p-value: 0.003Mixed Models Analysis
Secondary
Change in C-terminal Telopeptide
biochemical marker of bone turnover (bone resorption) as measured by immunoassay technique
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in C-terminal Telopeptide | 0.530 µg/L | Standard Error 0.012 |
| Testosterone + Lifestyle Therapy | Change in C-terminal Telopeptide | 0.002 µg/L | Standard Error 0.012 |
p-value: 0.03Mixed Models Analysis
Secondary
Change in Dynamic Balance
Assessed by using the obstacle course
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Dynamic Balance | -2.9 seconds | Standard Error 0.3 |
| Testosterone + Lifestyle Therapy | Change in Dynamic Balance | -3.2 seconds | Standard Error 0.4 |
p-value: 0.46Mixed Models Analysis
Secondary
Change in Endurance Capacity
Assessed by measuring peak oxygen consumption using indirect calorimetry during a treadmill exercise stress test
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Endurance Capacity | 2.8 ml/kg/min | Standard Error 0.3 |
| Testosterone + Lifestyle Therapy | Change in Endurance Capacity | 4.0 ml/kg/min | Standard Error 0.3 |
p-value: 0.03Mixed Models Analysis
Secondary
Change in Fat Mass
Assessed by using dual-energy x-ray absorptiometry
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Fat Mass | -8.2 kg | Standard Error 0.4 |
| Testosterone + Lifestyle Therapy | Change in Fat Mass | -8.0 kg | Standard Error 0.5 |
p-value: 0.91Mixed Models Analysis
Secondary
Change in Functional Status
Assessed by the Functional Status Questionnaire. Score range: 0 to 36 with higher scores indicating better functional status Provides information of the participants ability to perform activities of daily living.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Functional Status | 2.9 units on a scale | Standard Error 0.4 |
| Testosterone + Lifestyle Therapy | Change in Functional Status | 3.1 units on a scale | Standard Error 0.4 |
p-value: 0.97Mixed Models Analysis
Secondary
Change in Gait Speed
Determined by measuring the time needed to walk 25 ft.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Gait Speed | 8.6 m/min | Standard Error 1.3 |
| Testosterone + Lifestyle Therapy | Change in Gait Speed | 8.2 m/min | Standard Error 1.4 |
p-value: 0.96Mixed Models Analysis
Secondary
Change in High-sensitivity C-reactive Protein (Inflammatory Marker)
measured in the peripheral blood using immunoassay technique methodology
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in High-sensitivity C-reactive Protein (Inflammatory Marker) | .19 mg/dl | Standard Error 0.05 |
| Testosterone + Lifestyle Therapy | Change in High-sensitivity C-reactive Protein (Inflammatory Marker) | .18 mg/dl | Standard Error 0.05 |
p-value: 0.58Mixed Models Analysis
Secondary
Change in Insulin Growth Factor-1
Measured by immunoassay methodology
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Insulin Growth Factor-1 | 11.8 ng/mL | Standard Error 2.8 |
| Testosterone + Lifestyle Therapy | Change in Insulin Growth Factor-1 | 16.9 ng/mL | Standard Error 3 |
p-value: 0.35Mixed Models Analysis
Secondary
Change in Interleukin-6
Measured from fasting serum using immunoassay technique as marker of inflammation
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Interleukin-6 | -1.1 pg/mL | Standard Error 0.2 |
| Testosterone + Lifestyle Therapy | Change in Interleukin-6 | -1.0 pg/mL | Standard Error 0.2 |
p-value: 0.9Mixed Models Analysis
Secondary
Change in Lean Body Mass
Assessed by using dual-energy x-ray absorptiometry
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Lean Body Mass | -2.4 kg | Standard Error 0.2 |
| Testosterone + Lifestyle Therapy | Change in Lean Body Mass | -1.2 kg | Standard Error 0.2 |
p-value: 0.01Mixed Models Analysis
Secondary
Change in Levels of 25-hydroxyvitamin D
assessed by using immunoassay methodology
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Levels of 25-hydroxyvitamin D | 6.2 ng/mL | Standard Error 1.1 |
| Testosterone + Lifestyle Therapy | Change in Levels of 25-hydroxyvitamin D | 8.3 ng/mL | Standard Error 1.2 |
p-value: 0.27Mixed Models Analysis
Secondary
Change in Lumbar Spine Bone Mineral Density
As measured by Dual energy x-ray absorptiometry
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Lumbar Spine Bone Mineral Density | 0.004 gm/cm^2 | Standard Error 0.004 |
| Testosterone + Lifestyle Therapy | Change in Lumbar Spine Bone Mineral Density | 0.007 gm/cm^2 | Standard Error 0.004 |
p-value: 0.69Mixed Models Analysis
Secondary
Change in Modified Mini-mental Exam
Test of global cognition with components for orientation, registration, attention, language, praxis, and immediate and delayed memory. Score ranges from 0 to 100 with higher scores indicate better cognition.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Modified Mini-mental Exam | 1.2 units on a scale | Standard Error 0.3 |
| Testosterone + Lifestyle Therapy | Change in Modified Mini-mental Exam | 2.1 units on a scale | Standard Error 0.3 |
p-value: 0.16Mixed Models Analysis
Secondary
Change in Muscle Strength
assessed by total1-repetition maximum (the maximal weight lifted at one time; the totals are the sum of the maximal weights lifted in the biceps curl, bench press, 387 seated row, knee extension, knee flexion, and leg press exercises).
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Muscle Strength | 72 kg | Standard Error 5 |
| Testosterone + Lifestyle Therapy | Change in Muscle Strength | 68 kg | Standard Error 5 |
p-value: 0.94Mixed Models Analysis
Secondary
Change in N-terminal Propeptide of Type I Procollagen
Biochemical marker of bone turnover (bone formation) as measured by radioimmunoassay technique
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in N-terminal Propeptide of Type I Procollagen | -4.7 µg/L | Standard Error 1.4 |
| Testosterone + Lifestyle Therapy | Change in N-terminal Propeptide of Type I Procollagen | 1.5 µg/L | Standard Error 1.5 |
p-value: 0.04Mixed Models Analysis
Secondary
Change in Parathyroid Hormone Level
Measured by immunoassay methodology as marker of bone metabolism
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Parathyroid Hormone Level | 12.9 pg/mL | Standard Error 2 |
| Testosterone + Lifestyle Therapy | Change in Parathyroid Hormone Level | 9.0 pg/mL | Standard Error 2 |
p-value: 0.39Mixed Models Analysis
Secondary
Change in Ray Auditory Verbal Learning Test
The Rey Auditory Verbal Learning Test (RAVLT) evaluates a wide diversity of functions: short-term auditory-verbal memory, rate of learning, learning strategies, retroactive, and proactive interference, presence of confabulation of confusion in memory processes, retention of information. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Ray Auditory Verbal Learning Test | 3.1 units on a scale | Standard Error 0.9 |
| Testosterone + Lifestyle Therapy | Change in Ray Auditory Verbal Learning Test | 7.0 units on a scale | Standard Error 1 |
p-value: 0.03Mixed Models Analysis
Secondary
Change in Static Balance
assessed by one leg limb stance
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Static Balance | 4.5 seconds | Standard Error 0.9 |
| Testosterone + Lifestyle Therapy | Change in Static Balance | 5.0 seconds | Standard Error 0.9 |
p-value: 0.41Mixed Models Analysis
Secondary
Change in Symbol Digital Modalities Test
Assesses key neurocognitive functions that underlie many substitution tasks, including attention, visual scanning, and motor speed. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Symbol Digital Modalities Test | 1.1 units on a scale | Standard Error 0.5 |
| Testosterone + Lifestyle Therapy | Change in Symbol Digital Modalities Test | 2.8 units on a scale | Standard Error 0.5 |
p-value: 0.1Mixed Models Analysis
Secondary
Change in Thigh Muscle Volume
Assessed by using magnetic resonance imaging
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Thigh Muscle Volume | -68 cm^3 | Standard Error 10 |
| Testosterone + Lifestyle Therapy | Change in Thigh Muscle Volume | -25 cm^3 | Standard Error 10 |
p-value: 0.04Mixed Models Analysis
Secondary
Change in Total Hip Bone Mineral Density
Assessed by using dual-energy x-ray absorptiometry
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Total Hip Bone Mineral Density | -0.013 gm/cm^2 | Standard Error 0.002 |
| Testosterone + Lifestyle Therapy | Change in Total Hip Bone Mineral Density | 0.007 gm/cm^2 | Standard Error 0.002 |
p-value: 0.003Mixed Models Analysis
Secondary
Change in Trabecular Bone Score
The trabecular bone score is a measure of bone texture correlated with bone microarchitecture and a marker for the risk of osteoporosis. Minimum score is 0, there is no maximum value. Higher scores indicate better bone microarchitecture.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Trabecular Bone Score | 0.12 units on a scale | Standard Error 0.01 |
| Testosterone + Lifestyle Therapy | Change in Trabecular Bone Score | .11 units on a scale | Standard Error 0.01 |
p-value: 0.65Mixed Models Analysis
Secondary
Change in Trabecular Bone Score (Trabecular Bone Quality)
assessed by trabecular bone score (TBS), a newly developed index for assessing trabecular bone quality and fracture risk. TBS is a bone texture parameter that quantifies cancellous bone microachitecture, which is key in determining bone strength and resistance to fracture, by computing raw data from dual energy x-ray absorptiometry of the lumbar spine. There are no minimum or maximum values. Higher scores mean better outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Trabecular Bone Score (Trabecular Bone Quality) | 0.11 units on a scale | Standard Error 0.01 |
| Testosterone + Lifestyle Therapy | Change in Trabecular Bone Score (Trabecular Bone Quality) | 0.12 units on a scale | Standard Error 0.01 |
p-value: 0.65Mixed Models Analysis
Secondary
Change in Trail A
Test of visuospatial scanning, speed of processing, mental flexibility, and executive function (with a greater focus on attention). Minimum score is 0, there is no maximum value. Higher scores indicate better outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Trail A | -7.7 units on a scale | Standard Error 1.4 |
| Testosterone + Lifestyle Therapy | Change in Trail A | -13.9 units on a scale | Standard Error 1.5 |
p-value: 0.03Mixed Models Analysis
Secondary
Change in Trail B
Test of visuospatial scanning, speed of processing, mental flexibility, and executive function (with a focus on executive function) Minimum score is 0, there is no maximum value. Higher scores indicate better outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Trail B | -10.2 units on a scale | Standard Error 2.9 |
| Testosterone + Lifestyle Therapy | Change in Trail B | -19.5 units on a scale | Standard Error 3 |
p-value: 0.18Mixed Models Analysis
Secondary
Change in Word List Fluency
Measure of verbal production, semantic memory, and language. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Word List Fluency | 0.2 units on a scale | Standard Error 0.5 |
| Testosterone + Lifestyle Therapy | Change in Word List Fluency | 0.9 units on a scale | Standard Error 0.5 |
p-value: 0.41Mixed Models Analysis
Secondary
Stroop Interference
Assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. Minimum score is 0, there is no maximum value. Higher scores indicate better outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Stroop Interference | 4.6 score on a scale | Standard Error 0.7 |
| Testosterone + Lifestyle Therapy | Stroop Interference | 3.1 score on a scale | Standard Error 0.7 |
p-value: 0.21Mixed Models Analysis
Secondary
Thigh Fat Volume
Volume of fat in the thigh by measured by magnetic resonance imaging
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Thigh Fat Volume | -292 cm^3 | Standard Error 31 |
| Testosterone + Lifestyle Therapy | Thigh Fat Volume | -262 cm^3 | Standard Error 32 |
p-value: 0.67Mixed Models Analysis
Other Pre-specified
Change in Estradiol
As measured by LC-MS/MS
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Estradiol | -3.0 pg/dL | Standard Error 2.7 |
| Testosterone + Lifestyle Therapy | Change in Estradiol | 22.1 pg/dL | Standard Error 2.9 |
p-value: <0.001Mixed Models Analysis
Other Pre-specified
Change in Glucose
Measured in the blood after overnight fast
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Glucose | -22.5 mg/dl | Standard Error 3.7 |
| Testosterone + Lifestyle Therapy | Change in Glucose | -17.1 mg/dl | Standard Error 3.8 |
p-value: 0.23Mixed Models Analysis
Other Pre-specified
Change in HDL-cholesterol
Blood samples obtained in the fasting state as part of measurements of lipid profile
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in HDL-cholesterol | 5.4 mg/dl | Standard Error 1 |
| Testosterone + Lifestyle Therapy | Change in HDL-cholesterol | 0.2 mg/dl | Standard Error 1.1 |
p-value: 0.01Mixed Models Analysis
Other Pre-specified
Change in Hematocrit
the ratio of the volume of red blood cells to the total volume of blood.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Hematocrit | -0.5 percentage of red blood cells | Standard Error 0.3 |
| Testosterone + Lifestyle Therapy | Change in Hematocrit | 2.4 percentage of red blood cells | Standard Error 0.4 |
p-value: <0.001Mixed Models Analysis
Other Pre-specified
Change in International Prostate Symptom Score
Using the International Prostate Symptom Scoring (IPS); Minimum score is 0, Maximum score is 35. Higher scores mean worse outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in International Prostate Symptom Score | -0.2 units on a scale | Standard Error 0.5 |
| Testosterone + Lifestyle Therapy | Change in International Prostate Symptom Score | -0.1 units on a scale | Standard Error 0.5 |
p-value: 0.69Mixed Models Analysis
Other Pre-specified
Change in Mood
Using Yesavage Depression Scale Lower scores indicate better mood (range 0 to 30).
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Mood | -1.43 score on a scale | Standard Error 0.38 |
| Testosterone + Lifestyle Therapy | Change in Mood | -1.39 score on a scale | Standard Error 0.39 |
p-value: 0.69Mixed Models Analysis
Other Pre-specified
Change in Peripheral Quantitative Computed Tomography Measures (Volumetric Bone Density)
assessed by quantitative computed tomography at 4% distal tibia using the following thresholds: 180 mg/cm3 and 45% of the area
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Peripheral Quantitative Computed Tomography Measures (Volumetric Bone Density) | -3.1 mg/cm^3 | Standard Error 1.3 |
| Testosterone + Lifestyle Therapy | Change in Peripheral Quantitative Computed Tomography Measures (Volumetric Bone Density) | -0.3 mg/cm^3 | Standard Error 1.3 |
p-value: 0.05Mixed Models Analysis
p-value: 0.3Mixed Models Analysis
Other Pre-specified
Change in Prostate Specific Antigen
blood test to screen for prostate cancer
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Prostate Specific Antigen | 0.2 ng/mL | Standard Error 0.1 |
| Testosterone + Lifestyle Therapy | Change in Prostate Specific Antigen | 0.5 ng/mL | Standard Error 0.1 |
p-value: 0.31Mixed Models Analysis
Other Pre-specified
Change in Short Form Health Survey (SF-36) Quality of Life Physical Component
Using Short Form-36 of Life Questionnaire Physical Component subscale. Minimum score is 0, Maximum score is 100. Higher scores indicate better outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Short Form Health Survey (SF-36) Quality of Life Physical Component | 5.5 units on a scale | Standard Error 0.8 |
| Testosterone + Lifestyle Therapy | Change in Short Form Health Survey (SF-36) Quality of Life Physical Component | 7.1 units on a scale | Standard Error 0.8 |
p-value: 0.42Mixed Models Analysis
Other Pre-specified
Change in Skeletal Muscle Growth Factor (MYOD1)
Assessed by using RNA-seq quantification of gene expression in skeletal muscles obtained during muscle biopsies.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Skeletal Muscle Growth Factor (MYOD1) | 0.23 log2fold | Standard Error 0.05 |
| Testosterone + Lifestyle Therapy | Change in Skeletal Muscle Growth Factor (MYOD1) | 0.53 log2fold | Standard Error 0.12 |
Comparison: 6 months vs Baselinep-value: 0.37t-test, 2 sided
Comparison: 6 months vs Baselinep-value: 0.02t-test, 2 sided
Other Pre-specified
Change in Total Testosterone Levels
as measured in the peripheral blood by liquid chromatography/mass spectrometry
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Total Testosterone Levels | 60 ng/dL | Standard Error 21 |
| Testosterone + Lifestyle Therapy | Change in Total Testosterone Levels | 306 ng/dL | Standard Error 23 |
p-value: <0.001Mixed Models Analysis
Other Pre-specified
Change in Triglyceride Levels
Blood samples obtained in the fasting state as part of measurements of lipid profile
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Triglyceride Levels | -39 mg/dl | Standard Error 5.4 |
| Testosterone + Lifestyle Therapy | Change in Triglyceride Levels | -31 mg/dl | Standard Error 5 |
p-value: 0.23Mixed Models Analysis
Other Pre-specified
Change in Waist Circumference
Waist circumference as measured horizontally at the midpoint between the highest point of the iliac crest and the lowest portion of the 12th rib in the standing position.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Change in Waist Circumference | -9.4 cm | Standard Error 0.5 |
| Testosterone + Lifestyle Therapy | Change in Waist Circumference | -8.4 cm | Standard Error 0.6 |
p-value: 0.36Mixed Models Analysis
Other Pre-specified
Number of Participants With Significant Changes in Functional Connectivity in the Default Mode Network
Functional connectivity was measured with seeds of the DMN (medial prefrontal cortex \[MPFC\] and posterior cingulate cortex \[PCC\]). Correlation coefficients representing the degree of connectivity between hypothesized regions were Fisher transformed. An a priori threshold of p\<.001 at the voxel level and p\<.05, FDR corrected for multiple comparisons across the whole brain, at the cluster level were used to determine significant connectivity.
Time frame: Baseline and 6 months
Population: The number of subjects per group is less than the overall number of subjects enrolled in the trial because this was an add-on outcome later in the study. Moreover, the analyses are limited to subjects with complete evaluable pre and post-MRI data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Lifestyle Therapy | Number of Participants With Significant Changes in Functional Connectivity in the Default Mode Network | DMN (MPFC seed) | 0 Participants |
| Placebo + Lifestyle Therapy | Number of Participants With Significant Changes in Functional Connectivity in the Default Mode Network | DMN (PCC seed) | 0 Participants |
| Testosterone + Lifestyle Therapy | Number of Participants With Significant Changes in Functional Connectivity in the Default Mode Network | DMN (MPFC seed) | 0 Participants |
| Testosterone + Lifestyle Therapy | Number of Participants With Significant Changes in Functional Connectivity in the Default Mode Network | DMN (PCC seed) | 0 Participants |
p-value: >0.05t-test, 2 sided