Healthy
Conditions
Keywords
Male Contraception, Testosterone, Testis, Contraception, Prostate
Brief summary
The investigators propose to examine the in vivo responses to hormonal manipulation at the molecular level directly in the tissue of interest (prostate). As in the investigators' previous, pilot study, the investigators will use the novel approach of procuring tissue specimens from normal, healthy men who might be chose to use a male hormonal contraceptive regimen were it available. The investigators will employ state of the art techniques such as laser capture microdissection (LCM) and cDNA microarrays to determine the tissue-specific consequences of male hormonal contraceptive regimens on the prostate. The results will help guide the design, safety monitoring, and selection of male hormonal contraceptive agents and provide valuable insights into prostate human prostate biology. The investigators will test the hypothesis that exogenous T administration that results in increased circulating T and dihydrotestosterone (DHT) levels will increase intraprostatic concentrations of T and its metabolite DHT. The investigators will test the hypothesis that the addition of a potent 5α-reductase inhibitor, dutasteride, or the progestin, Depomedoxyprogesterone (IM DMPA), to T administration in young and middle aged men will decrease intraprostatic DHT and increase intraprostatic T concentrations compared to T alone. The investigators will test the hypothesis that the addition of a 5α-reductase inhibitor dutasteride or the progestin IM DMPA to exogenous T, by reducing intraprostatic DHT, will decrease prostate epithelial proliferation, assessed by Ki-67 labeling index (Ki-67LI), and increase apoptosis, assessed by caspase-3 expression, and decrease androgen-regulated protein expression such as prostate specific antigen (PSA). The investigators will test the hypothesis that the addition of a 5α-reductase inhibitor or the progestin IM DMPA to exogenous T, by modifying the intraprostatic hormonal milieu, will alter prostate epithelial gene expression. Specifically, the investigators expect that the addition of the 5α-reductase inhibitor dutasteride or the progestin IM DMPA to exogenous T, will result in decreased expression of androgen-regulated genes such as PSA.
Detailed description
The purpose of this research study is to understand the effects of testosterone on the prostate. This knowledge will be used to help in the development of a safe male hormonal contraception. We will be administering three drugs in this study: Testim (testosterone (T) gel), dutasteride (which affects testosterone break down) and Depomedoxyprogesterone (DMPA, a progestin). We want to see their effects on levels of hormones in the blood and prostate. In addition, we will be examining the effects of these drugs on the expression of genes within the prostate. DMPA suppresses LH and FSH, which are hormones made by the pituitary gland, thus blocking the signal from the brain that causes the testes to make testosterone. Prolonged (\> 1 month) low levels of LH and FSH cause decreased sperm production in normal men. However, men may experience some side effects from the low levels of testosterone caused by DMPA; adding testosterone to DMPA eliminates these side effects while more effectively blocking LH and FSH release and sperm production. This combination of drugs is a promising male contraceptive regimen. However, the effect of these drugs on the prostate is not known. Some studies suggest that testosterone administration may promote prostate growth. Dutasteride blocks the conversion of testosterone to dihydrotestosterone and is used to treat men with enlarged prostates. Dutasteride shrinks the prostate. It is possible that combining testosterone and dutasteride may be an effective part of a male hormonal contraceptive regime. Therefore, further studies examining the effect of testosterone, DMPA and dutasteride on the prostate are needed.
Interventions
DRUGTestosterone gel
Testosterone gel 10 g
DRUGDutasteride
dutasteride 0.5 mg orally
DRUGDepo-Medroxyprogesterone (DMPA)
300 mg DMPA injection on Day 0 IM (into the muscle)
Place gel applied daily for 12 weeks
OTHERPlacebo dutasteride
placebo pill for 12 weeks
OTHERPlacebo DMPA
placebo DMPA injection Once
Sponsors
University of Washington
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
25 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Men in good health, and without a history of chronic androgen therapy or known history of gonadal or prostate abnormalities. * PSA ≤ 2. * Age 25-55 years * Ability to understand the study,study procedures and provide consent * Normal serum total T, LH, FSH, urine analyses, and sperm count \> or equal to 15million/ml * International Prostate Symptom Score (IPSS) \< 10 * Normal seminal fluid analysis (\>20 million sperm/ml) * Agree not to donate blood during the treatment and recovery periods
Exclusion criteria
* A history or evidence of prostate or breast cancer * History of invasive therapy for BPH * History of acute urinary retention * Current or past treatment with a 5α-reductase inhibitor * History of anti/androgenic drugs or drugs that interfere with steroid metabolism within past 3 months * Severe systemic illness (renal, liver, cardiac, lung disease, cancer, poorly controlled diabetes) * Known untreated obstructive sleep apnea * Hematocrit \> 52% * Skin disease that might interfere with T gel absorption * Hypersensitivity to any of the drugs used in the study * History of a bleeding disorder or anticoagulation * History of drug or alcohol abuse within 12 months * History of infertility or desire for fertility within 12 months, or current pregnant partner * A first-degree relative (i.e. father, brother) with a history of prostate cancer * Abnormal digital rectal examination or prostate ultrasound
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prostate-specific Antigen (PSA) | 10 weeks | PSA level week 10 end of treatment |
| Testosterone Concentration | 10 weeks | — |
| Dihydrotestosterone (DHT) Concentration | 10 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Androstenedione (AED) | 10 weeks |
| Dehydroepiandrosterone (DHEA) | 10 weeks |
Countries
United States
Participant flow
Recruitment details
Healthy male volunteers, 25-55 yr old, were recruited via advertisement: flyers on University campus and newspaper ads.
Participants by arm
| Arm | Count |
|---|---|
| 1) Placebo Placebo Testosterone gel + Placebo Dutasteride pill + placebo DMPA | 8 |
| 2) Testosterone Gel Testosterone 1% transdermal gel 10g + placebo Dutasteride + placebo DMPA | 8 |
| 3) T Gel +Dutasteride Testosterone 1% transdermal gel 10g + dutasteride 0.5mg Orally + placebo DMPA | 9 |
| 4) T Gel+ DMPA Testosterone 1% transdermal gel 10g + placebo Dutasteride + DMPA 300mg injection (IM) | 7 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | noncompliant with drug administration | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | 1) Placebo | 2) Testosterone Gel | 3) T Gel +Dutasteride | 4) T Gel+ DMPA | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 8 Participants | 9 Participants | 7 Participants | 32 Participants |
| Age Continuous | 41 years STANDARD_DEVIATION 7.72 | 37 years STANDARD_DEVIATION 6.19 | 37 years STANDARD_DEVIATION 8.45 | 39 years STANDARD_DEVIATION 10.11 | 39 years STANDARD_DEVIATION 3.46 |
| Dihydrotestosterone (DHT) | 0.5 ng/mL | 0.6 ng/mL | 0.7 ng/mL | 0.6 ng/mL | 0.6 ng/mL |
| Follical-stimulating hormone (FSH) | 3.6 IU/liter | 3.3 IU/liter | 4.0 IU/liter | 2.8 IU/liter | 3.4 IU/liter |
| Luteinizing Hormone (LH) | 4.0 IU/liter | 3.9 IU/liter | 5.3 IU/liter | 3.2 IU/liter | 4.1 IU/liter |
| Prostate-Specific Antigen (PSA) | 0.7 ng/mL | 0.7 ng/mL | 0.9 ng/mL | 0.5 ng/mL | 0.7 ng/mL |
| Prostate volume | 25 ml | 15 ml | 15 ml | 19 ml | 18 ml |
| Region of Enrollment United States | 8 participants | 8 participants | 9 participants | 7 participants | 32 participants |
| Sex/Gender, Customized Female | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Sex/Gender, Customized Male | 8 participants | 8 participants | 9 participants | 7 participants | 32 participants |
| SHBG | 33 nmol/liter | 36 nmol/liter | 38 nmol/liter | 33 nmol/liter | 35 nmol/liter |
| Testosterone (T) concentration | 3.9 ng/mL | 3.9 ng/mL | 4.8 ng/mL | 4.0 ng/mL | 4.1 ng/mL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 2 / 7 | 1 / 9 | 1 / 7 |
| serious Total, serious adverse events | 0 / 8 | 0 / 7 | 0 / 9 | 0 / 7 |
Outcome results
Primary
Dihydrotestosterone (DHT) Concentration
Time frame: 10 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1) Placebo | Dihydrotestosterone (DHT) Concentration | 0.5 ng/mL |
| 2) Testosterone Gel | Dihydrotestosterone (DHT) Concentration | 1.8 ng/mL |
| 3) T Gel +Dutasteride | Dihydrotestosterone (DHT) Concentration | 0.5 ng/mL |
| 4) T Gel+ DMPA | Dihydrotestosterone (DHT) Concentration | 0.6 ng/mL |
Primary
Prostate-specific Antigen (PSA)
PSA level week 10 end of treatment
Time frame: 10 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1) Placebo | Prostate-specific Antigen (PSA) | 0.8 ng/mL |
| 2) Testosterone Gel | Prostate-specific Antigen (PSA) | 0.9 ng/mL |
| 3) T Gel +Dutasteride | Prostate-specific Antigen (PSA) | 0.7 ng/mL |
| 4) T Gel+ DMPA | Prostate-specific Antigen (PSA) | 0.4 ng/mL |
Primary
Testosterone Concentration
Time frame: 10 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1) Placebo | Testosterone Concentration | 4.0 ng/mL |
| 2) Testosterone Gel | Testosterone Concentration | 4.4 ng/mL |
| 3) T Gel +Dutasteride | Testosterone Concentration | 7.0 ng/mL |
| 4) T Gel+ DMPA | Testosterone Concentration | 1.8 ng/mL |
Secondary
Androstenedione (AED)
Time frame: 10 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1) Placebo | Androstenedione (AED) | 0.9 ng/mL |
| 2) Testosterone Gel | Androstenedione (AED) | 0.9 ng/mL |
| 3) T Gel +Dutasteride | Androstenedione (AED) | 1.8 ng/mL |
| 4) T Gel+ DMPA | Androstenedione (AED) | 0.7 ng/mL |
Secondary
Dehydroepiandrosterone (DHEA)
Time frame: 10 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1) Placebo | Dehydroepiandrosterone (DHEA) | 4.3 ng/mL |
| 2) Testosterone Gel | Dehydroepiandrosterone (DHEA) | 3.5 ng/mL |
| 3) T Gel +Dutasteride | Dehydroepiandrosterone (DHEA) | 3.8 ng/mL |
| 4) T Gel+ DMPA | Dehydroepiandrosterone (DHEA) | 3.2 ng/mL |