Healthy Volunteers
Conditions
Keywords
Testosterone, Bone turnover, Aging, Body composition, Hypogonadism, Sexual function
Brief summary
The purpose of this study is to determine the levels of testosterone and/or estradiol at which changes in bone turnover, body composition, strength, sexual function etc. begin to occur in older men. This information may help determine when to intervene with hormone replacement therapy in aging men.
Detailed description
In this protocol, men age 60-75 will be randomized to one of 6 groups. Groups 1-5 will receive goserelin acetate (Zoladex) plus 0 (placebo gel), 1.25, 2.5, 5, or 10\* g/day of testosterone gel (Androgel). Group 6 will receive placebos for both goserelin acetate and testosterone gel. (\*Note that the 10 g/day dose was reduced to 7.5 g/day part-way through the trial due to reports of possible increased risk of cardiovascular events with testosterone administration). Subjects will be blinded with respect to group assignment. Dietary calcium intake will be assessed by a research dietitian and adjustments made through diet or supplements so that calcium intake is between 1000 and 1200 mg/day. Subjects will be seen on the Clinical Research Center at 4 week intervals for 16 weeks (0, 4, 8, 12, and 16 weeks). At each visit, compliance with Androgel will be assessed by reviewing a medication diary. A standardized series of questions will be posed to each subject to assess potential side effects of the study drugs. Subjects receiving Androgel' will be given a new 4 week supply of medication (except at week 16). A fasting blood and second voided urine sample will be collected. After the blood and urine samples have been obtained, subjects will be given their goserelin injection. The blood and urine tests listed below as well as anthropometric measures, and questionnaires will be performed at each visit. Dual-energy x-ray absorptiometry (DXA), quantitate computed tomography (QCT) scans, and strength assessments will be performed at 0 and 16 weeks only. Subjects who discontinue participation at or after week 8 will be asked if they are willing to have an early discontinuation visit in which all procedures normally done at week 16 will be performed. The following measures will be assessed: * Routine chemistries and prostate specific antigen, PSA (for safety assessment) * Bone turnover using blood and urine tests * Hormones * Lipids * Body composition * Strength * Sexual desire and erectile function * Bone mineral density and bone microarchitecture
Interventions
DRUGTestosterone
Androgel placebo or 1.25, 2.5, 5. or 10\* gms topically each day
DRUGGoserelin acetate
3.6 gms sc every 4 weeks
Sponsors
National Institute on Aging (NIA)
Solvay Pharmaceuticals
AstraZeneca
AbbVie
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
60 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy men age 60 to 75
Exclusion criteria
* History of significant cardiac, renal, pulmonary, hepatic, benign prostatic hyperplasia, or malignant disease, current alcohol or illicit drug abuse, or major psychiatric disorders. * Current diagnoses of disorders known to affect bone metabolism including hyperthyroidism, hyperparathyroidism, osteomalacia, or Paget's disease. * Current use of medications known to affect bone metabolism including estrogens, androgens, anti-estrogens, bisphosphonates, calcitonin, fluoride, oral or inhaled glucocorticoids, suppressive doses of thyroxine, lithium, pharmacological doses of vitamin D (greater than 2000 IU/day), or anti-convulsants. * Cognitive or intellectual impairment that precludes complete understanding of the study protocol. * History of deep vein thrombosis, pulmonary embolism, or clotting disorders. * Serum 25-hydroxyvitamin D \< 15 ng/mL * Serum parathyroid hormone (PTH) \< 10 or \> 65 pg/mL * Serum thyroid stimulating hormone (TSH) \< 0.5 or \> 5.0 U/L * Serum calcium \> 10.6 mg/dL * Serum creatinine \> 2 mg/dL * Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \> 2x the upper limit of normal * Serum bilirubin \> 2 mg/dL * Serum alkaline phosphatase \> 150 U/L * Plasma hemoglobin \< 11 gm/dL * Hematocrit \> 50 * Fracture within the last 6 months. * Serum testosterone level \< 270 or \> 1070 ng/dL * Serum prostate specific antigen (PSA) level \> 4 ug/L. * International Prostate Symptom Score (IPSS) \> 19 * Systolic blood pressure \> 160 or diastolic blood pressure \> 95 * Framingham risk score greater than or equal to 20 * Difficulty walking 2 blocks
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX) | Baseline and 16 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Body Composition: Fat Mass | Baseline and 16 weeks | — |
| Percentage Change in Thigh Muscle Area | Baseline and 16 weeks | Assessed by quantitative computed tomography (QCT) |
| Change in Erectile Function Symptoms | Baseline and 16 weeks | Based on International Index of Erectile Function (IIEF) scale, question #15, which asked subjects to rate their confidence that they could achieve and maintain an erection. Scores range from 1 to 5, with higher scores being better. |
| Change in Libido / Sexual Desire | 16 weeks | Change in libido from baseline (scale ranges from -2 to +2), with -2 being much less, -1 somewhat less, 0 same, +1 somewhat more, +2 much more |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1: 0 g/Day Zoladex plus Placebo T gel | 26 |
| Group 2: 1.25 g/Day Zoladex plus 1.25 g/day T gel | 25 |
| Group 3: 2.5 g/Day Zoladex plus 2.5 g/day T gel | 31 |
| Group 4: 5 g/Day Zoladex plus 5 g/day T gel | 35 |
| Group 5: 10* g/Day Zoladex plus 10\* g/day T gel; \*Note that the 10 g/day dose was reduced to 7.5 g/day part-way through the trial | 29 |
| Group 6: PBO/PBO Placebo Zoladex plus Placebo T gel | 31 |
| Total | 177 |
Baseline characteristics
| Characteristic | Total | Group 6: PBO/PBO | Group 5: 10* g/Day | Group 2: 1.25 g/Day | Group 4: 5 g/Day | Group 1: 0 g/Day | Group 3: 2.5 g/Day |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 3.9 | 65 years STANDARD_DEVIATION 4 | 65 years STANDARD_DEVIATION 3 | 64 years STANDARD_DEVIATION 3 | 65 years STANDARD_DEVIATION 4 | 66 years STANDARD_DEVIATION 5 | 64 years STANDARD_DEVIATION 4 |
| Body-mass Index | 27.3 kg/m^2 STANDARD_DEVIATION 4.1 | 26.9 kg/m^2 STANDARD_DEVIATION 4.2 | 28.2 kg/m^2 STANDARD_DEVIATION 3.5 | 27.3 kg/m^2 STANDARD_DEVIATION 4.3 | 27.1 kg/m^2 STANDARD_DEVIATION 4.2 | 28.0 kg/m^2 STANDARD_DEVIATION 3.9 | 26.3 kg/m^2 STANDARD_DEVIATION 4.3 |
| Estradiol | 27 pg/mL STANDARD_DEVIATION 9 | 28 pg/mL STANDARD_DEVIATION 7 | 26 pg/mL STANDARD_DEVIATION 6 | 26 pg/mL STANDARD_DEVIATION 11 | 30 pg/mL STANDARD_DEVIATION 11 | 27 pg/mL STANDARD_DEVIATION 7 | 25 pg/mL STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 39 Participants | 0 Participants | 0 Participants | 1 Participants | 35 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 135 Participants | 30 Participants | 28 Participants | 23 Participants | 0 Participants | 25 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 176.2 cm STANDARD_DEVIATION 7 | 176.7 cm STANDARD_DEVIATION 6.5 | 175.4 cm STANDARD_DEVIATION 5 | 175.1 cm STANDARD_DEVIATION 8.7 | 177.5 cm STANDARD_DEVIATION 7.6 | 175.2 cm STANDARD_DEVIATION 5.7 | 176.5 cm STANDARD_DEVIATION 7.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 0 Participants | 1 Participants | 3 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 165 Participants | 29 Participants | 28 Participants | 22 Participants | 31 Participants | 26 Participants | 29 Participants |
| Region of Enrollment United States | 177 participants | 31 participants | 29 participants | 25 participants | 35 participants | 26 participants | 31 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 177 Participants | 31 Participants | 29 Participants | 25 Participants | 35 Participants | 26 Participants | 31 Participants |
| Testosterone | 490 ng/dL STANDARD_DEVIATION 150 | 505 ng/dL STANDARD_DEVIATION 155 | 484 ng/dL STANDARD_DEVIATION 148 | 485 ng/dL STANDARD_DEVIATION 117 | 483 ng/dL STANDARD_DEVIATION 165 | 496 ng/dL STANDARD_DEVIATION 176 | 491 ng/dL STANDARD_DEVIATION 142 |
| Thigh-muscle area | 15531 mm^2 STANDARD_DEVIATION 2424 | 15572 mm^2 STANDARD_DEVIATION 2157 | 15771 mm^2 STANDARD_DEVIATION 2145 | 16006 mm^2 STANDARD_DEVIATION 2515 | 15367 mm^2 STANDARD_DEVIATION 2820 | 15272 mm^2 STANDARD_DEVIATION 2026 | 15281 mm^2 STANDARD_DEVIATION 2645 |
| Total body fat mass | 21471 g STANDARD_DEVIATION 8564 | 19931 g STANDARD_DEVIATION 7574 | 22803 g STANDARD_DEVIATION 7459 | 20827 g STANDARD_DEVIATION 7208 | 23062 g STANDARD_DEVIATION 11123 | 22773 g STANDARD_DEVIATION 8693 | 19396 g STANDARD_DEVIATION 7567 |
| Total-body Lean Mass | 55784 g STANDARD_DEVIATION 7444 | 55867 g STANDARD_DEVIATION 6637 | 56081 g STANDARD_DEVIATION 6116 | 55553 g STANDARD_DEVIATION 8218 | 55653 g STANDARD_DEVIATION 9206 | 56177 g STANDARD_DEVIATION 6417 | 55428 g STANDARD_DEVIATION 8054 |
| Weight | 84.8 kg STANDARD_DEVIATION 13.9 | 83.9 kg STANDARD_DEVIATION 13 | 86.8 kg STANDARD_DEVIATION 12.2 | 83.9 kg STANDARD_DEVIATION 15 | 85.7 kg STANDARD_DEVIATION 15.1 | 86.2 kg STANDARD_DEVIATION 14.1 | 82.0 kg STANDARD_DEVIATION 14.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 25 | 0 / 31 | 0 / 35 | 0 / 29 | 0 / 31 |
| other Total, other adverse events | 3 / 26 | 0 / 25 | 0 / 31 | 1 / 35 | 2 / 29 | 0 / 31 |
| serious Total, serious adverse events | 0 / 26 | 0 / 25 | 0 / 31 | 0 / 35 | 0 / 29 | 0 / 31 |
Outcome results
Primary
Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX)
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: 0 g/Day | Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX) | 103 percentage change | Standard Error 12 |
| Group 2: 1.25 g/Day | Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX) | 41 percentage change | Standard Error 6 |
| Group 3: 2.5 g/Day | Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX) | 29 percentage change | Standard Error 6 |
| Group 4: 5 g/Day | Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX) | 15 percentage change | Standard Error 7 |
| Group 5: 10* g/Day | Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX) | 4 percentage change | Standard Error 5 |
| Group 6: Placebo/Placebo (PBO/PBO) | Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX) | 11 percentage change | Standard Error 6 |
Secondary
Change in Erectile Function Symptoms
Based on International Index of Erectile Function (IIEF) scale, question #15, which asked subjects to rate their confidence that they could achieve and maintain an erection. Scores range from 1 to 5, with higher scores being better.
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: 0 g/Day | Change in Erectile Function Symptoms | -1.4 units on a scale | Standard Error 0.2 |
| Group 2: 1.25 g/Day | Change in Erectile Function Symptoms | -0.5 units on a scale | Standard Error 0.2 |
| Group 3: 2.5 g/Day | Change in Erectile Function Symptoms | -0.2 units on a scale | Standard Error 0.2 |
| Group 4: 5 g/Day | Change in Erectile Function Symptoms | -0.1 units on a scale | Standard Error 0.2 |
| Group 5: 10* g/Day | Change in Erectile Function Symptoms | 0.2 units on a scale | Standard Error 0.2 |
| Group 6: Placebo/Placebo (PBO/PBO) | Change in Erectile Function Symptoms | -0.3 units on a scale | Standard Error 0.2 |
Secondary
Change in Libido / Sexual Desire
Change in libido from baseline (scale ranges from -2 to +2), with -2 being much less, -1 somewhat less, 0 same, +1 somewhat more, +2 much more
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: 0 g/Day | Change in Libido / Sexual Desire | -1.6 units on a scale | Standard Error 0.2 |
| Group 2: 1.25 g/Day | Change in Libido / Sexual Desire | -0.6 units on a scale | Standard Error 0.2 |
| Group 3: 2.5 g/Day | Change in Libido / Sexual Desire | -0.6 units on a scale | Standard Error 0.2 |
| Group 4: 5 g/Day | Change in Libido / Sexual Desire | -0.2 units on a scale | Standard Error 0.2 |
| Group 5: 10* g/Day | Change in Libido / Sexual Desire | 0 units on a scale | Standard Error 0.1 |
| Group 6: Placebo/Placebo (PBO/PBO) | Change in Libido / Sexual Desire | -0.3 units on a scale | Standard Error 0.1 |
Secondary
Percentage Change in Body Composition: Fat Mass
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: 0 g/Day | Percentage Change in Body Composition: Fat Mass | 9.8 Percentage change | Standard Error 2.4 |
| Group 2: 1.25 g/Day | Percentage Change in Body Composition: Fat Mass | 5.7 Percentage change | Standard Error 1.1 |
| Group 3: 2.5 g/Day | Percentage Change in Body Composition: Fat Mass | 1.9 Percentage change | Standard Error 1.5 |
| Group 4: 5 g/Day | Percentage Change in Body Composition: Fat Mass | 0.4 Percentage change | Standard Error 1.3 |
| Group 5: 10* g/Day | Percentage Change in Body Composition: Fat Mass | -1.6 Percentage change | Standard Error 1.6 |
| Group 6: Placebo/Placebo (PBO/PBO) | Percentage Change in Body Composition: Fat Mass | 2.3 Percentage change | Standard Error 1.9 |
Secondary
Percentage Change in Thigh Muscle Area
Assessed by quantitative computed tomography (QCT)
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: 0 g/Day | Percentage Change in Thigh Muscle Area | -1.5 percentage change | Standard Error 1.1 |
| Group 2: 1.25 g/Day | Percentage Change in Thigh Muscle Area | -1.6 percentage change | Standard Error 0.9 |
| Group 3: 2.5 g/Day | Percentage Change in Thigh Muscle Area | -0.4 percentage change | Standard Error 0.5 |
| Group 4: 5 g/Day | Percentage Change in Thigh Muscle Area | -0.5 percentage change | Standard Error 0.7 |
| Group 5: 10* g/Day | Percentage Change in Thigh Muscle Area | 0.5 percentage change | Standard Error 0.7 |
| Group 6: Placebo/Placebo (PBO/PBO) | Percentage Change in Thigh Muscle Area | -0.9 percentage change | Standard Error 0.6 |