CEP-1 Hormonal Regulation of Circulating Endothelial Progenitor Cells and HDL-C in Men

Study Overview
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Brief Summary
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The original purpose of this research study was to understand the effects of testosterone (T) and estrogen on stem cells in the blood. The knowledge would be used to help understand the effects of T and estrogen on cardiovascular (heart and blood vessel) disease, and to help in the development of a safe male hormonal contraceptive. The effect of androgens on the number of circulating endothelial progenitor (CEP) cells would best be observed in group 1 (placebo). Upon observation of group 1 under original protocol, changes in CEP cells were not significant but there were changes in markers of inflammation, lipids, and HDL protein composition. A modification to the protocol and title were made to reflect this for groups 2 and 3: Hormonal regulation of HDL-C in Men.

Detailed Description
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We will be administering three drugs: testosterone gel (T), anastrozole, and acyline. We want to see their effects on stem cells and hormone levels in the blood. Acyline suppress luteinizing hormone(LH) and follicle-stimulating hormone(FSH), which are hormones made by the pituitary gland, thus blocking the signal from the brain that causes the testes to make testosterone. Therefore acyline blocks testosterone production. Some men may experience side effects such as hot flashes or irritability from the low levels of T caused by acyline. We are studying whether adding T to acyline will reduce or eliminate these side effects. Since heart disease is a common problem in men we want to know about the effects of male hormonal contraception on the cardiovascular system. One way to evaluate these risks is to measure the number of progenitor cells and the types of cholesterol in the blood. Progenitor cells are cells that travel in the blood and go to areas of blood vessel injury to help repair the damage amd may help prevent heart attacks and stokes. Some studies suggest that T administration may increase the number of these cells in the blood but other studies have shown that estrogen may be responsible for this effect. In addition, T and estrogen may affect the amount and type of HDL cholesterol in the blood. This is the good cholesterol that is thought to protect people from heart attacks and strokes. Therefore, more studies to test the effects of T and estrogen on progenitor cells in the blood and to understand HDL cholesterol in men receiving testosterone are needed. Acyline is an experimental drug. The FDA allows its use only in research with a small number of volunteers. So far, over 125 men have received acyline. Anastrozole is a drug that blocks the production of estrogen from testosterone. Anastrozole has been given to men safely in the past. Anastrozole is not approved for use in men and is also an experimental drug. Testosterone gel will also be used in this study. It is FDA approved for use in men with low testosterone levels.

Official Title
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Hormonal Regulation of Circulating Endothelial Progenitor Cells and HDL-C in Men Title Changed With New Protocol (12/14/09): Hormonal Regulation of HDL-C in Men

Conditions
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Healthy

Intervention / Treatment
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* Drug: Acyline
* Drug: Acyline + Testosterone gel
* Drug: Acyline + testosterone gel + anastrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males age 18-55 years Normal serum total testosterone (300 ng/dl-1000 ng/dl) Normal LH and FSH levels Taking no regular medications Normal baseline serum hematology, chemistry and liver function tests Agrees not to donate blood during the study Agrees to use a form of contraception during the study Subject must be able to comply with all study procedures Exclusion Criteria: Clinically significant screening assessments or other relevant disease, allergy or surgery, as revealed by history, physical examination and/or laboratory assessments, which may limit participation or prevent completion of the study History of prostate cancer, breast cancer, or benign prostatic hypertrophy Prostate-specific antigen (PSA) > 3.0 History of regular, chronic testosterone or anabolic steroid use in the past year Chronic medical illness, prostate disease, or cardiovascular disease History of a bleeding disorder or need for anticoagulation Skin condition that might interfere with or be exacerbated by T gel use Sitting systolic blood pressure > 180mm Hg or <90 mm Hg or sitting diastolic blood pressure >110 mm Hg or < 60 mm Hg. History of clinically significant, untreated sleep apnea Participation in another drug-related research study within the past 2 months Participating in a regular physical relationship with a pregnant woman History of hypersensitivity to any of the study medications (T gel, anastrozole, acyline) History of medical or surgical therapy for benign prostatic hypertrophy Hematocrit > 55% History of drug or alcohol abuse within last 6 months Abnormal digital rectal exam at screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Acyline 300 µg/kg injections every two weeks (2 doses) + placebo (no active ingredients) gel daily for 28 days + oral placebo pill daily for 28 days | Drug: Acyline<br>* Acyline 300 μg/kg injections every two weeks (2 doses) for 28 days + placebo Testosterone gel daily for 28 days + placebo oral anastrozole pill daily for 28 days<br>* Other names: placebo pill;|
| Experimental: Group 2<br>Acyline 300 µg/kg injections every two weeks (2 doses) + Testosterone gel 100 mg daily for 28 days + oral placebo pill daily for 28 days | Drug: Acyline + Testosterone gel<br>* Acyline 300 μg/kg injections every two weeks (2 doses) for 28 days + Testosterone gel 100 mg daily for 28 days + placebo oral pill 1 mg daily for 28 days<br>* Other names: testosterone gel;|
| Experimental: Group 3<br>Acyline 300 μg/kg injections every two weeks (2 doses) for 28 days + Testosterone gel 100 mg daily for 28 days + oral anastrozole pill 1 mg daily for 28 days | Drug: Acyline + testosterone gel + anastrozole<br>* Acyline 300 μg/kg injections every two weeks (2 doses) for 28 days + Testosterone gel 100 mg daily for 28 days + oral anastrozole pill 1 mg daily for 28 days<br>* Other names: Anastrozole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endothelial Progenitor Cells | Number of CD33 + CD134+ cells as a percentage of all lymphocytes | Baseline, Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Follicle Stimulating Hormone (FSH) |  | Baseline, 28 days | 
| Luteinizing Hormone Concentration (LH) |  | Baseline, Day 28 | 
| Testosterone Concentration |  | Baseline, Day 28 | 
| Estradiol Concentration |  | Baseline, Day 28 | 
| Sex Hormone Binding Globulin (SHBG) |  | Baseline, Day 28 | 
| Quantitative Insulin Sensitivity Check Index (QUICKI) | QUICKI is a measure of insulin sensitivity calculated using fasting insulin and glucose concentration in a participants blood. Higher QUICKI are associated with decreased insulin resistance and increased insulin sensitivity. | Baseline, Day 28, Day 56 | 
| Homeostasis Model of Insulin Resistance (HOMA-IR) | HOMA IR is a measure of insulin sensitivity calculated using fasting insulin and glucose concentration in a participants blood. Higher HOMA IR numbers are associated with increased insulin resistance and decreased insulin sensitivity. | Baseline, Day 28, Day 56 | 
| Fasting Serum Insulin |  | Baseline, Day 28, Day 56 | 
| Fasting Lipid Levels |  | Baseline, Day 28, Day 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HDL, Insulin sensitivity, testosterone, estradiol, cholesterol