Depression, Diabetes, Hypogonadism, Osteoporosis, Sarcopenia
Conditions
Keywords
Estrogen, Glucose Tolerance, Bone Density, Quality-of-Life, Sarcopenia
Brief summary
Background: Men≥65 years often produce lower levels of testosterone, meaning there is less testosterone circulating to the tissues of the body. This is associated with negative effects on muscle strength, bone density, sexual function, mood, and the ability to think to the best of one's ability. Testosterone replacement therapy often involves injections, patches, or gels that help to raise circulating testosterone levels, but these therapies often have side effects because they lead to imbalance of other hormones. Researchers have been studying the effectiveness of anastrozole, a drug that can lower estrogen levels while simultaneously increasing testosterone levels, as a treatment for the negative effects of decreased circulating testosterone levels that occur naturally with aging. Objectives: To evaluate whether anastrozole is as effective as testosterone gel in improving bone and muscle strength, hormone levels, and brain function in men over 65 years of age. Eligibility: Healthy men at least 65 years of age who have low levels of testosterone. Design: The study involves six study visits over a total of 12 months: screening, baseline, 6 weeks, 3 months, 6 months, and 12 months. All participants will receive calcium and vitamin D supplements to take daily, and will be randomized to one of three groups:Testosterone gel and placebo tablet, Anastrozole tablet and placebo gel, Placebo tablet and gel. Participants will have the following tests at each specified visit:Screening: Blood tests and rectal ultrasound to evaluate the prostate;Baseline: Blood and urine tests; growth hormone levels, muscle strength, bone density, and balance evaluation; imaging studies; cognitive testing; and questionnaires on quality of life, sexual function, depression, and urinary symptoms;Six weeks: Blood tests and dose adjustment of the gel or tablet;Three months: Blood and urine tests; growth hormone, muscle strength, bone density, and balance evaluation; and questionnaires on quality of life, sexual function, depression, and urinary symptoms;Six months: Blood and urine tests; muscle strength, bone density, and balance evaluation; cognitive testing; and questionnaires on quality of life, sexual function, depression, and urinary symptoms;Twelve months: Blood and urine tests; rectal ultrasound; muscle strength, bone density, and balance evaluation; imaging studies; cognitive testing; and questionnaires on quality of life, sexual function, depression, and urinary symptoms.
Detailed description
Approximately 20% of men over the age of 70 have low testosterone levels. In some studies, testosterone replacement has resulted in improvement in bone mass, muscle strength, quality of life and memory function. In the body, testosterone is converted into estrogen. Hence, it is unclear whether these beneficial effects are due to testosterone or estrogen. Research has shown that inhibition of estrogen production in men results in an increase in testosterone levels. In this study, patients will be assigned to one of three groups: one group will receive testosterone gel and a placebo tablet, one group will receive a 1mg Anastrozole tablet and a placebo gel, and one group will receive a placebo tablet and placebo gel. Each group will receive a daily dose of calcium with vitamin D. The study requires 6 visits over a 12-month period for testing and evaluation. Two of the 6 visits will require an overnight stay in the hospital so that an intravenous (IV) line can be placed in the arm to allow samples to be drawn throughout the night. Testing will include a cardiac stress test, a glucose tolerance test, bone and muscle tests, evaluation of memory function, etc. For the safety of the prostate, we will perform a prostate ultrasound at the start and end of the study and we will monitor urinary symptoms, prostate specific antigen (PSA) levels and the prostate exam throughout the study.
Interventions
1 mg tablet for 12 months
DRUGAnastrozole (Aromatase Inhibitor)
DRUGPlacebo tablet
Daily for 12 months
DRUGPlacebo gel
Daily for 12 months
DIETARY_SUPPLEMENTCalcium Cardone 500mg with vitamin D 400 IU
1 tablet three times a day
Sponsors
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
65 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* INCLUSION CRITERIA: 1. Men age 65 years or older 2. Serum testosterone level less than or equal to 350 ng/dl 3. Subject is able to complete an informed consent
Exclusion criteria
1. History of Stroke 2. History of Dementia 3. History of Diabetes 4. Blood pressure at rest of \> 155/90 mmHg. Elevated systolic or diastolic reading renders subject ineligible 5. Chronic medical condition, i.e. congestive heart failure 6. Arthritis, severe enough to prevent completion of the strength testing, history of joint replacement of knees or hip. 7. Inability to walk 50 meters 8. Known disease of the bone and/or taking medications to treat osteoporosis, i.e. Fosamax, Evista, Miacalcin 9. History of Gastric surgery 10. History of prostate cancer or any other cancers, including blood dyscrasias 11. History of severe benign prostatic hyperplasia (causing urinary problems) 12. History of heart attack or open-heart surgery within the past 6 months 13. Use of steroids within the past 3 months, including prednisone and/or cortisone injections, and inhaled steroids. Topical steroid cream is acceptable. 14. If you do not agree to refrain from taking the drugs Viagra, Cialis or Levitra for the duration of the study 15. Use of anabolic steroids, i.e. testosterone, (or any analog of testosterone) Dehydroepiandrosterone or any growth promoters i.e. growth hormone itself or analogs of growth hormone 16. Use of anti-androgen medications, i.e. Aldactone, Tagamet, Proscar, estrogens 17. Use of Dilantin or Phenobarbital 18. Alcohol intake \> 30 grams (drink more than 2 beers per day OR more than 1 glass of wine or cocktail daily) 19. Currently smokes any tobacco product 20. Having started a new medication during the past three months which may interfere with the outcome measures of the study 21. Polycythemia 22. Prostate specific antigen \> 4.0 ng/dl 23. Hematocrit \< 36 24. Liver function tests greater than 2 times upper normal limits or abnormal electrolytes, calcium or Parathyroid hormone , at the discretion of the investigator 25. Mini Mental Status Exam score less than or equal to 24
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Testosterone Gel vs. Anastrozole on Bone Mineral Density | 1 year | bone mineral density lumbar spine for all arms testosterone gel, anastrozole and placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Testosterone Gel vs. Anastrozole on Pulsatile Growth Hormone Release | 1 year | Overnight Growth hormone measures (total hormone secretion) for groups testosterone gel, anastrozole and placebo |
| Effect of Testosterone Gel vs. Anastrozole on Glucose Tolerance/Lipid Metabolism | 1 year | Primary outcome HOMA-IR for all groups testosterone gel, anastrozole and placebo Insulin resistance measure by HOMA-IR is a score if a person is insulin resistance the score should be between minimum 0.7- maximum 2 or more. Absolute changes in HOMAIR in all treatment arms, calculation time frame 1 year minus baseline point. |
| Effect of Testosterone Gel vs. Anastrozole on Prostate Volume/Prostate Specific Antigen Levels/Urinary Function | 1 year | rectal ultrasound prostate volume for all groups testosterone gel, anastrozole and placebo. Absolute changes in prostate volume in all treatment arms, calculation time frame 1 year minus baseline point. |
Countries
United States
Participant flow
Pre-assignment details
The study randomized 44 subjects, however 9 of them stop the study before having the second visit completed, so we started the analysis with 35 subjects. The participant flow module has 35 subjects, because these subjects have a baseline and 3 months endpoints.
Participants by arm
| Arm | Count |
|---|---|
| Transdermal Testosterone participants will receive testosterone gel (5 gm) plus placebo tablet daily for 12 months
Androgel (Testosterone Gel): 1 mg tablet for 12 months
Placebo tablet: Daily for 12 months
Calcium Cardone 500mg with vitamin D 400 IU: 1 tablet three times a day | 13 |
| Aromatase Inhibitor participants will receive anastrozole 1 mg tablet plus placebo gel daily for 12 months
Anastrozole (Aromatase Inhibitor)
Placebo gel: Daily for 12 months
Calcium Cardone 500mg with vitamin D 400 IU: 1 tablet three times a day | 13 |
| Placebo participants will receive a placebo tablet and placebo gel daily for 12 months
Placebo tablet: Daily for 12 months
Placebo gel: Daily for 12 months
Calcium Cardone 500mg with vitamin D 400 IU: 1 tablet three times a day | 9 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 3 | 0 |
Baseline characteristics
| Characteristic | Transdermal Testosterone | Aromatase Inhibitor | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 72 years STANDARD_DEVIATION 5.1 | 70 years STANDARD_DEVIATION 3 | 72 years STANDARD_DEVIATION 3.4 | 71 years STANDARD_DEVIATION 1.2 |
| Bioavailable Testosterone | 114.4 ng/dL STANDARD_DEVIATION 37.2 | 114.8 ng/dL STANDARD_DEVIATION 36.3 | 91.2 ng/dL STANDARD_DEVIATION 31.7 | 106.8 ng/dL STANDARD_DEVIATION 13.5 |
| Body mass index | 30.1 kg/m2 STANDARD_DEVIATION 4 | 27.8 kg/m2 STANDARD_DEVIATION 4.1 | 27.6 kg/m2 STANDARD_DEVIATION 3.5 | 28.5 kg/m2 STANDARD_DEVIATION 1.4 |
| Bone mineral density | 1.4 g/cm2 STANDARD_DEVIATION 0.2 | 1.3 g/cm2 STANDARD_DEVIATION 0.2 | 1.2 g/cm2 STANDARD_DEVIATION 0.1 | 1.3 g/cm2 STANDARD_DEVIATION 0.1 |
| Diastolic blood pressure | 73.3 mmHg STANDARD_DEVIATION 5.3 | 72.4 mmHg STANDARD_DEVIATION 9.4 | 73.1 mmHg STANDARD_DEVIATION 10.4 | 72.9 mmHg STANDARD_DEVIATION 0.5 |
| Estradiol | 2.0 ng/dL STANDARD_DEVIATION 0.7 | 1.5 ng/dL STANDARD_DEVIATION 0.6 | 1.6 ng/dL STANDARD_DEVIATION 0.5 | 1.700 ng/dL STANDARD_DEVIATION 0.3 |
| Fat mass | 31.6 kg STANDARD_DEVIATION 10.4 | 26.9 kg STANDARD_DEVIATION 9.6 | 28.5 kg STANDARD_DEVIATION 7.6 | 29.0 kg STANDARD_DEVIATION 2.4 |
| follicle-stimulating hormone | 8.0 mlU/ml STANDARD_DEVIATION 6.4 | 6.5 mlU/ml STANDARD_DEVIATION 5.3 | 8.2 mlU/ml STANDARD_DEVIATION 10.9 | 7.567 mlU/ml STANDARD_DEVIATION 0.9 |
| hand grip | 41.1 kg STANDARD_DEVIATION 6.9 | 39.2 kg STANDARD_DEVIATION 9.9 | 39.3 kg STANDARD_DEVIATION 7.2 | 39.9 kg STANDARD_DEVIATION 1.1 |
| knee strength | 133.8 Nm STANDARD_DEVIATION 44.3 | 138.7 Nm STANDARD_DEVIATION 48.6 | 155.4 Nm STANDARD_DEVIATION 41.9 | 142.6 Nm STANDARD_DEVIATION 11.3 |
| lean body mass | 56.0 kg STANDARD_DEVIATION 12 | 54.7 kg STANDARD_DEVIATION 11 | 56.0 kg STANDARD_DEVIATION 7.2 | 55.6 kg STANDARD_DEVIATION 0.8 |
| luteinizing hormone | 11.4 mlU/ml STANDARD_DEVIATION 8.2 | 6.4 mlU/ml STANDARD_DEVIATION 2.7 | 12.2 mlU/ml STANDARD_DEVIATION 10.1 | 10.00 mlU/ml STANDARD_DEVIATION 3.1 |
| Region of Enrollment United States | 13 participants | 13 participants | 9 participants | 35 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 9 Participants | 35 Participants |
| Sex hormone-binding globulin | 43.4 nmol/L STANDARD_DEVIATION 22.2 | 39.9 nmol/L STANDARD_DEVIATION 19.4 | 58.6 nmol/L STANDARD_DEVIATION 21.3 | 47.30 nmol/L STANDARD_DEVIATION 10 |
| Systolic blood pressure | 137.8 mmHg STANDARD_DEVIATION 9.4 | 134.5 mmHg STANDARD_DEVIATION 14.5 | 133.7 mmHg STANDARD_DEVIATION 11.2 | 135.3 mmHg STANDARD_DEVIATION 2.2 |
| Total Testosterone | 300.1 ng/dL STANDARD_DEVIATION 81.9 | 271.6 ng/dL STANDARD_DEVIATION 85.6 | 303.8 ng/dL STANDARD_DEVIATION 94.7 | 291.8 ng/dL STANDARD_DEVIATION 17.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 17 | 0 / 14 | 0 / 13 |
| serious Total, serious adverse events | 3 / 17 | 6 / 14 | 3 / 13 |
Outcome results
Primary
Effect of Testosterone Gel vs. Anastrozole on Bone Mineral Density
bone mineral density lumbar spine for all arms testosterone gel, anastrozole and placebo
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone | Effect of Testosterone Gel vs. Anastrozole on Bone Mineral Density | 0.042 g/cm2 | Standard Deviation 0.008 |
| Aromatase Inhibitor | Effect of Testosterone Gel vs. Anastrozole on Bone Mineral Density | 0.008 g/cm2 | Standard Deviation 0.012 |
| Placebo | Effect of Testosterone Gel vs. Anastrozole on Bone Mineral Density | 0.047 g/cm2 | Standard Deviation 0.013 |
Secondary
Effect of Testosterone Gel vs. Anastrozole on Glucose Tolerance/Lipid Metabolism
Primary outcome HOMA-IR for all groups testosterone gel, anastrozole and placebo Insulin resistance measure by HOMA-IR is a score if a person is insulin resistance the score should be between minimum 0.7- maximum 2 or more. Absolute changes in HOMAIR in all treatment arms, calculation time frame 1 year minus baseline point.
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone | Effect of Testosterone Gel vs. Anastrozole on Glucose Tolerance/Lipid Metabolism | -0.05 score on a scale | Standard Error 0.21 |
| Aromatase Inhibitor | Effect of Testosterone Gel vs. Anastrozole on Glucose Tolerance/Lipid Metabolism | 0.15 score on a scale | Standard Error 0.1 |
| Placebo | Effect of Testosterone Gel vs. Anastrozole on Glucose Tolerance/Lipid Metabolism | -0.11 score on a scale | Standard Error 0.26 |
Secondary
Effect of Testosterone Gel vs. Anastrozole on Prostate Volume/Prostate Specific Antigen Levels/Urinary Function
rectal ultrasound prostate volume for all groups testosterone gel, anastrozole and placebo. Absolute changes in prostate volume in all treatment arms, calculation time frame 1 year minus baseline point.
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone | Effect of Testosterone Gel vs. Anastrozole on Prostate Volume/Prostate Specific Antigen Levels/Urinary Function | 4.5 cc | Standard Error 1.76 |
| Aromatase Inhibitor | Effect of Testosterone Gel vs. Anastrozole on Prostate Volume/Prostate Specific Antigen Levels/Urinary Function | -1.66 cc | Standard Error 3.54 |
| Placebo | Effect of Testosterone Gel vs. Anastrozole on Prostate Volume/Prostate Specific Antigen Levels/Urinary Function | -1.05 cc | Standard Error 1.52 |
Secondary
Effect of Testosterone Gel vs. Anastrozole on Pulsatile Growth Hormone Release
Overnight Growth hormone measures (total hormone secretion) for groups testosterone gel, anastrozole and placebo
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transdermal Testosterone | Effect of Testosterone Gel vs. Anastrozole on Pulsatile Growth Hormone Release | 5.8 ng/ml/8h | Standard Error 1.4 |
| Aromatase Inhibitor | Effect of Testosterone Gel vs. Anastrozole on Pulsatile Growth Hormone Release | 10 ng/ml/8h | Standard Error 2.2 |
| Placebo | Effect of Testosterone Gel vs. Anastrozole on Pulsatile Growth Hormone Release | 7.7 ng/ml/8h | Standard Error 2.2 |