Healthy
Conditions
Keywords
Dihydrotestosterone, Androgen, Prostate
Brief summary
The purpose of this research study is to understand the effects of a male hormone normally made in the body called Dihydrotestosterone (DHT) on the prostate gland that is located under the bladder. The knowledge gained from this study may be used to help in the future to develop a safe male hormonal contraceptive to prevent pregnancy, in the safe treatment of low male hormone levels in men, and in the treatment and prevention of diseases of the prostate. The investigators will be giving DHT in a gel form, to be applied to the skin, or a placebo gel (with no active drug in it). The investigators want to see the effects of DHT on levels of hormones in the blood and in the prostate gland itself. In addition, the investigators will be studying the effects of DHT on the cells and genes expressed within the prostate. The effect of DHT on the prostate is not known. Some studies suggest blocking production of DHT in the prostate helps growth of the gland with aging (a condition known as benign prostatic hyperplasia, or BPH for short) and may prevent prostate cancer. On the other hand, DHT administration may shrink the prostate, suggesting it may be beneficial for some men. Therefore, further studies looking at the effect of DHT on the prostate are needed.
Detailed description
In this study, we will examine the in vivo effects of DHT supplementation on the prostate and serum inflammatory markers at the molecular level. We hypothesize that increases in serum DHT will not increase intraprostatic DHT or prostate epithelial proliferation, and will be associated with decreases in markers of systemic inflammation. Normal, healthy, male study volunteers will be treated with either placebo gel (Group 1) or DHT gel (Group 2) for one month. Serum hormonal and inflammatory measurements will be assessed before, during, and after treatment, and the relationship between hormones and inflammatory markers associated with cardiovascular risk will be determined. Prostate biopsies will be taken after one month of treatment. Prostate tissue will be analyzed for changes in intraprostatic hormone levels as well as gene expression following treatment. SPECIFIC AIMS: 1. To determine the effect of increases in serum DHT, without concomitant increases in serum T or estrogen, on intraprostatic androgen levels. 2. To determine the effect of increases in serum DHT, without concomitant increases in serum T or estrogen, on prostate epithelial gene expression. 3. To determine the effect of increases in serum DHT, without concomitant increases in serum T or estrogen, on serum lipids and inflammatory markers including C-Reactive Protein \[CRP\], Tumor necrosis factor-alpha \[TNFα\], Interleukin-6 \[IL-6\], adiponectin, plasminogen activator inhibitor \[PAI-I\], and leptin. We will test the hypothesis in normal men (rather than hypogonadal men) as a proof of principle investigation. A normal hypothalamic-pituitary-testicular axis and regulation, circulating T and DHT levels and intraprostatic androgen concentrations in healthy, normal men will permit optimal testing of the hypothesis. Exogenous DHT administration in normal men is expected to suppress endogenous gonadotropin and testosterone secretion, compared to more variable effects in hypogonadal men that depend on the degree of hypogonadism in these men and whether they have primary (testicular) or secondary (hypothalamic-pituitary) hypogonadism. Furthermore, intraprostatic T and DHT concentrations and 5 alpha-reductase activity (that is androgen-dependent) is expected to be more variable in hypogonadal men, depending on the degree of androgen deficiency and circulating T and DHT levels. If results in normal men support the hypothesis, subsequent studies could be performed in hypogonadal men. Because of the larger variability in circulating and probably intraprostatic androgen concentrations in hypogonadal men, these studies will require much larger numbers of subjects.
Interventions
DRUGDihydrotestosterone (DHT) gel (0.7%)
DHT gel, 70 mg/day for one month
DRUGPlacebo gel
Placebo gel for one month
Sponsors
National Institute on Aging (NIA)
ASCEND Therapeutics
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
35 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Males 35-55 years old * Normal serum total testosterone (300 ng/dl-1000 ng/dl) * Normal Luteinizing Hormone \[LH\] and Follicle Stimulating Hormone \[FSH\] levels * Informed consent * Taking no regular medications * Normal baseline prostate ultrasound, hematology, and liver function tests
Exclusion criteria
* History of prostate cancer * Prostate Specific Antigen \[PSA\] \> 2.0 * American Urological Association \[AUA\] prostate symptom score \> 10 * History of testosterone or anabolic steroid use in the past * Chronic medical illness or prostate disease * History of a bleeding disorder or need for anticoagulation * A first-degree relative (i.e. father, brother) with a history of prostate cancer * Abnormal digital rectal examination * Skin condition that might interfere with or be exacerbated by DHT gel use * History of untreated sleep apnea and/or psychiatric problems * Participation in another study in the past 2 months * Participating in a regular physical relationship with a pregnant woman
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prostate Tissue DHT and Testosterone Levels After 28 Days of Treatment With Dihydrotestosterone [DHT] Gel Versus Placebo Gel. | 28-days | After 4 weeks of either daily dihydrotestosterone transdermal gel or placebo gel, subjects underwent a prostate biopsy. Intraprostatic hormone concentrations, specifically DHT and Testosterone, were measured. Unit of measure is ng/g. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Prostate Epithelial Cell Proliferation | 28-days | Prostate epithelial cell proliferation in the prostate biopsy tissue was measured using Ki-67 immunohistochemical staining of prostate epithelium as a marker of cell proliferation (values are number of Ki-67 positive stained cells per 100 prostate epithelial cells). The placebo and treatment groups were compared. |
Countries
United States
Participant flow
Recruitment details
Up to 55 normal, healthy men between the ages of 35-55 will be recruited for this study. All subject activities will occur at the University of Washington in Seattle Washington.
Pre-assignment details
Subjects must meet all study protocol inclusion criteria such as informed consent, normal lab values, normal physical examination and normal prostate ultrasound, and not have exclusion criteria such as a first degree relative with or personal history of prostate cancer, PSA \>2.0 or a history of a bleeding disorder or need for anticoagulation.
Participants by arm
| Arm | Count |
|---|---|
| Placebo DHT Gel Placebo gel for one month | 16 |
| DHT Gel DHT gel (70 mg/day) for one month | 15 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Subject failed to disclose concommitant | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | DHT Gel | Placebo DHT Gel | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 16 Participants | 31 Participants |
| Age Continuous | 42.7 years STANDARD_DEVIATION 1.6 | 44.4 years STANDARD_DEVIATION 6.7 | 43.6 years STANDARD_DEVIATION 4.2 |
| Region of Enrollment United States | 15 participants | 16 participants | 31 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 15 Participants | 16 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 1 / 15 |
| serious Total, serious adverse events | 0 / 16 | 1 / 15 |
Outcome results
Primary
Prostate Tissue DHT and Testosterone Levels After 28 Days of Treatment With Dihydrotestosterone [DHT] Gel Versus Placebo Gel.
After 4 weeks of either daily dihydrotestosterone transdermal gel or placebo gel, subjects underwent a prostate biopsy. Intraprostatic hormone concentrations, specifically DHT and Testosterone, were measured. Unit of measure is ng/g.
Time frame: 28-days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo DHT Gel | Prostate Tissue DHT and Testosterone Levels After 28 Days of Treatment With Dihydrotestosterone [DHT] Gel Versus Placebo Gel. | DHT concentrations | 2.8 ng/g | Standard Deviation 0.2 |
| Placebo DHT Gel | Prostate Tissue DHT and Testosterone Levels After 28 Days of Treatment With Dihydrotestosterone [DHT] Gel Versus Placebo Gel. | Testosterone Concentrations | 0.6 ng/g | Standard Deviation 0.2 |
| DHT Gel | Prostate Tissue DHT and Testosterone Levels After 28 Days of Treatment With Dihydrotestosterone [DHT] Gel Versus Placebo Gel. | DHT concentrations | 3.1 ng/g | Standard Deviation 0.5 |
| DHT Gel | Prostate Tissue DHT and Testosterone Levels After 28 Days of Treatment With Dihydrotestosterone [DHT] Gel Versus Placebo Gel. | Testosterone Concentrations | 0.4 ng/g | Standard Deviation 0.1 |
Secondary
Prostate Epithelial Cell Proliferation
Prostate epithelial cell proliferation in the prostate biopsy tissue was measured using Ki-67 immunohistochemical staining of prostate epithelium as a marker of cell proliferation (values are number of Ki-67 positive stained cells per 100 prostate epithelial cells). The placebo and treatment groups were compared.
Time frame: 28-days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo DHT Gel | Prostate Epithelial Cell Proliferation | 1.3 #pos.Ki-67cells per100 prst. epth cells | Standard Deviation 0.5 |
| DHT Gel | Prostate Epithelial Cell Proliferation | 0.7 #pos.Ki-67cells per100 prst. epth cells | Standard Deviation 0.9 |