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

Phase 2

Completed

Conditions: Healthy

Interventions: Drug: Acyline + testosterone gel + anastrozole
Drug: Acyline
Drug: Acyline + Testosterone gel

Registration Number: NCT00729859

Lead Sponsor: University of Washington

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 31

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 3	Acyline + testosterone gel + anastrozole	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
Group 1	Acyline	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
Group 2	Acyline + Testosterone gel	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

Primary Outcome Measures

Name	Time	Method
Endothelial Progenitor Cells	Baseline, Day 28	Number of CD33 + CD134+ cells as a percentage of all lymphocytes

Secondary Outcome Measures

Name	Time	Method
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)	Baseline, Day 28, Day 56	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.
Homeostasis Model of Insulin Resistance (HOMA-IR)	Baseline, Day 28, Day 56	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.
Fasting Serum Insulin	Baseline, Day 28, Day 56
Fasting Lipid Levels	Baseline, Day 28, Day 56