Effects of Aromatase Inhibition Versus Testosterone in Older Men With Low Testosterone: Randomized-Controlled Trial.

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Effects of Aromatase Inhibition and Testosterone Replacement in Sex Steroids, Pituitary Hormones, Markers of Bone Turnover, Muscle Strength, and Cognition in Older Men

Conditions
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Hypogonadism, Diabetes, Sarcopenia, Osteoporosis, Depression

Intervention / Treatment
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* Drug: Androgel (Testosterone Gel)
* Drug: Anastrozole (Aromatase Inhibitor)
* Drug: Placebo tablet
* Drug: Placebo gel
* Dietary Supplement: Calcium Cardone 500mg with vitamin D 400 IU


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Men age 65 years or older Serum testosterone level less than or equal to 350 ng/dl Subject is able to complete an informed consent EXCLUSION CRITERIA: History of Stroke History of Dementia History of Diabetes Blood pressure at rest of > 155/90 mmHg. Elevated systolic or diastolic reading renders subject ineligible Chronic medical condition, i.e. congestive heart failure Arthritis, severe enough to prevent completion of the strength testing, history of joint replacement of knees or hip. Inability to walk 50 meters Known disease of the bone and/or taking medications to treat osteoporosis, i.e. Fosamax, Evista, Miacalcin History of Gastric surgery History of prostate cancer or any other cancers, including blood dyscrasias History of severe benign prostatic hyperplasia (causing urinary problems) History of heart attack or open-heart surgery within the past 6 months Use of steroids within the past 3 months, including prednisone and/or cortisone injections, and inhaled steroids. Topical steroid cream is acceptable. If you do not agree to refrain from taking the drugs Viagra, Cialis or Levitra for the duration of the study 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 Use of anti-androgen medications, i.e. Aldactone, Tagamet, Proscar, estrogens Use of Dilantin or Phenobarbital Alcohol intake > 30 grams (drink more than 2 beers per day OR more than 1 glass of wine or cocktail daily) Currently smokes any tobacco product Having started a new medication during the past three months which may interfere with the outcome measures of the study Polycythemia Prostate specific antigen > 4.0 ng/dl Hematocrit < 36 Liver function tests greater than 2 times upper normal limits or abnormal electrolytes, calcium or Parathyroid hormone , at the discretion of the investigator Mini Mental Status Exam score less than or equal to 24

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (Androgel) testosterone gel<br>17 participants will receive testosterone gel (5 gm) plus placebo tablet daily for 12 months and 'Calcium Cardone 500mg with vitamin D 400 IU' | Drug: Androgel (Testosterone Gel)<br>* 1 mg tablet for 12 months<br>Drug: Placebo tablet<br>* Daily for 12 months<br>Dietary Supplement: Calcium Cardone 500mg with vitamin D 400 IU<br>* 1 tablet three times a day<br>|
| Experimental: anastrozole (Aromatase inhibitor)<br>14 participants will receive anastrozole 1 mg tablet plus placebo gel daily for 12 months and 'Calcium Cardone 500mg with vitamin D 400 IU' | Drug: Anastrozole (Aromatase Inhibitor)<br> <br> Drug: Placebo gel<br>* Daily for 12 months<br>Dietary Supplement: Calcium Cardone 500mg with vitamin D 400 IU<br>* 1 tablet three times a day<br>|
| Placebo Comparator: placebo<br>13 participants will receive a placebo tablet and placebo gel daily for 12 months and 'Calcium Cardone 500mg with vitamin D 400 IU' | Drug: Placebo tablet<br>* Daily for 12 months<br>Drug: Placebo gel<br>* Daily for 12 months<br>Dietary Supplement: Calcium Cardone 500mg with vitamin D 400 IU<br>* 1 tablet three times a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Testosterone Gel vs. Anastrozole on Bone Mineral Density | bone mineral density lumbar spine for all arms testosterone gel, anastrozole and placebo | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 1 year | 
| 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. | 1 year | 
| 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. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Estrogen, Glucose Tolerance, Bone Density, Quality-of-Life, Sarcopenia