Official Title: “The Effect of Male Hormonal Contraceptive Regimens on Prostate Tissue In Normal Men”

We propose here to examine the in vivo responses to hormonal manipulation at the molecular level directly in the tissue of interest (prostate). As in our previous, pilot study, we 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. We 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. Our results will help guide the design, safety monitoring, and selection of male hormonal contraceptive agents and provide valuable insights into prostate human prostate biology.

We 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.

We will test the hypothesis that the addition of a potent 5α-reductase inhibitor, dutasteride, or the progestin IM DMPA, to T administration in young and middle aged men will decrease intraprostatic DHT and increase intraprostatic T concentrations compared to T alone.

We 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 PSA.

We 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, we 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.

Study Type: Interventional

Study Design: Treatment, Randomized, Single Blind (Subject), Placebo Control, Parallel Assignment, Pharmacokinetics/Dynamics Study

Study Primary Completion Date: December 2009

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.

Intervention(s) in this Clinical Trial

• Drug: Testosterone gel
  • Testosterone gel 10 g
• Drug: Dutasteride
  • dutasteride 0.5 mg orally
• Drug: Depo-Medroxyprogesterone (DMPA)
  • 300 mg DMPA injection on Day 0 IM (into the muscle)
• Other: Placebo Testosterone gel
  • Place gel applied daily for 12 weeks
• Other: Placebo dutasteride
  • placebo pill for 12 weeks
• Other: Placebo DMPA
  • placebo DMPA injection Once

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: 1
  • Placebo gel + Placebo pill + placebo injection
• Active Comparator: 2
  • Testosterone 1% transdermal gel 10 g + placebo pill + placebo injection
• Active Comparator: 3
  • Testosterone 1% transdermal gel 10 g + dutasteride 0.5 mg Orally + placebo injection
• Active Comparator: 4
  • Testosterone 1% transdermal gel 10 g + placebo pill + DMPA 300 mg injection (IM)

Primary Measures

• Prostate tissue normal levels after treatment
  • Time Frame: 12-weeks
    Safety Issue?: Yes

Secondary Measures

• Prostate epithelial gene expression after treatment
  • Time Frame: 12-weeks
    Safety Issue?: 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 25-50 years
• Ability to understand the study,study procedures and provide consent
• Normal serum total T, LH, FSH, urine analyses, and sperm count
• 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 6 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

Gender Eligibility for this Clinical Trial: Male

Minimum Age for this Clinical Trial: 25 Years

Maximum Age for this Clinical Trial: 50 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: University of Washington

Overall Clinical Trial Officials and Contacts

William J Bremner, MD, PhD Principal Investigator University of Washington  

Overall Contact: Kymberley Anable 206-616-0482 kymmkatt@u.washington.edu

Information obtained from ClinicalTrials.gov on September 04, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00490555

Study ID Number: 06-4795-A

ClinicalTrials.gov Identifier: NCT00490555

Health Authority: United States: Food and Drug Administration

http://depts.washington.edu/popctr/is Dedicated to basic and clinical research focused primarily on the male reproductive system.