Dose-Response of Gonadal Steroids and Bone Turnover in Older Men

Study Overview
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Brief Summary
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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
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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

Official Title
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Dose-Response of Gonadal Steroids and Bone Turnover in Older Men

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Testosterone
* Drug: Goserelin acetate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 75 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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 0 g/day<br>Zoladex plus Placebo Testosterone (T) gel | Drug: Testosterone<br>* Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day<br>* Other names: Androgel;Drug: Goserelin acetate<br>* 3.6 gms sc every 4 weeks<br>* Other names: Zoladex;|
| Experimental: Group 2: 1.25 g/day<br>Zoladex plus 1.25 g/day T gel | Drug: Testosterone<br>* Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day<br>* Other names: Androgel;Drug: Goserelin acetate<br>* 3.6 gms sc every 4 weeks<br>* Other names: Zoladex;|
| Experimental: Group 3: 2.5 g/day<br>Zoladex plus 2.5 g/day T gel | Drug: Testosterone<br>* Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day<br>* Other names: Androgel;Drug: Goserelin acetate<br>* 3.6 gms sc every 4 weeks<br>* Other names: Zoladex;|
| Experimental: Group 4: 5 g/day<br>Zoladex plus 5 g/day T gel | Drug: Testosterone<br>* Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day<br>* Other names: Androgel;Drug: Goserelin acetate<br>* 3.6 gms sc every 4 weeks<br>* Other names: Zoladex;|
| Experimental: Group 5: 10* g/day<br>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 | Drug: Testosterone<br>* Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day<br>* Other names: Androgel;Drug: Goserelin acetate<br>* 3.6 gms sc every 4 weeks<br>* Other names: Zoladex;|
| Experimental: Group 6: Placebo/Placebo (PBO/PBO)<br>Placebo Zoladex plus Placebo T gel (controls) | Drug: Testosterone<br>* Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day<br>* Other names: Androgel;Drug: Goserelin acetate<br>* 3.6 gms sc every 4 weeks<br>* Other names: Zoladex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX) |  | Baseline and 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Body Composition: Fat Mass |  | Baseline and 16 weeks | 
| Percentage Change in Thigh Muscle Area | Assessed by quantitative computed tomography (QCT) | Baseline and 16 weeks | 
| 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. | Baseline and 16 weeks | 
| 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 | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Testosterone, Bone turnover, Aging, Body composition, Hypogonadism, Sexual function