PROS-1-Male Hormonal Contraceptive Regimens on Prostate Tissue - Full Text View

Sponsor:	University of Washington
Collaborator:	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by:	University of Washington
ClinicalTrials.gov Identifier:	NCT00490555

Purpose

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.

Condition	Intervention	Phase
Healthy	Drug: Testosterone gel Drug: Dutasteride Drug: Depo-Medroxyprogesterone (DMPA) Other: Placebo Testosterone gel Other: Placebo dutasteride Other: Placebo DMPA	Phase II Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Single Blind (Subject), Placebo Control, Parallel Assignment, Pharmacokinetics/Dynamics Study
Official Title:	The Effect of Male Hormonal Contraceptive Regimens on Prostate Tissue In Normal Men

Resource links provided by NLM:

Drug Information available for: Testosterone Propionate Methyltestosterone Testosterone Medroxyprogesterone 17-acetate Dutasteride Oxymesterone Testosterone enanthate Medroxyprogesterone Testosterone undecanoate

U.S. FDA Resources

Further study details as provided by University of Washington:

Primary Outcome Measures:

Prostate tissue normal levels after treatment [ Time Frame: 12-weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Prostate epithelial gene expression after treatment [ Time Frame: 12-weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	48
Study Start Date:	January 2009
Estimated Study Completion Date:	January 2012
Estimated Primary Completion Date:	January 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Placebo Comparator Placebo gel + Placebo pill + placebo injection	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
2: Active Comparator Testosterone 1% transdermal gel 10 g + placebo pill + placebo injection	Drug: Testosterone gel Testosterone gel 10 g
3: Active Comparator Testosterone 1% transdermal gel 10 g + dutasteride 0.5 mg Orally + placebo injection	Drug: Testosterone gel Testosterone gel 10 g Drug: Dutasteride dutasteride 0.5 mg orally
4: Active Comparator Testosterone 1% transdermal gel 10 g + placebo pill + DMPA 300 mg injection (IM)	Drug: Testosterone gel Testosterone gel 10 g Drug: Depo-Medroxyprogesterone (DMPA) 300 mg DMPA injection on Day 0 IM (into the muscle) Other: Placebo dutasteride placebo pill for 12 weeks

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.

Eligibility

Ages Eligible for Study:	25 Years to 55 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00490555

Contacts

Contact: Kathryn Duncan	206-616-0482	kymmkatt@u.washington.edu
Contact: Kathy Winter	206-616-0484	klwinter@u.washington.edu

Locations

United States, Washington
University of Washington	Recruiting
Seattle, Washington, United States, 98195
Contact: Kymberley Anable 206-616-0482 kymmkatt@u.washington.edu
Contact: Kathy Winter 206-616-0484 klwinter@u.washington.edu
Principal Investigator: Stephanie T Page, MD, MPH
Sub-Investigator: John K Amory, MD, MPH
Sub-Investigator: Peter Nelson, MD
Sub-Investigator: Daniel Lin, MD
Sub-Investigator: Lawrence True, MD
Sub-Investigator: Elahe M Mostaghel, MD, PhD
Sub-Investigator: Bradley D Anawalt, MD
Sub-Investigator: Alvin M Matsumoto, MD
Sub-Investigator: David Hess, MD
Sub-Investigator: Christine Snyder, MD
Sub-Investigator: Mara Y Roth, MD
Sub-Investigator: Jonathan Wright, MD

Sponsors and Collaborators

University of Washington

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Principal Investigator:

Stephanie T Page, MD, PhD

University of Washington

More Information

Additional Information:

http://depts.washington.edu/popctr/is Dedicated to basic and clinical research focused primarily on the male reproductive system. This link exits the ClinicalTrials.gov site

This link exits the ClinicalTrials.gov site

Publications:

Amory JK, Page ST, Bremner WJ. Drug insight: Recent advances in male hormonal contraception. Nat Clin Pract Endocrinol Metab. 2006 Jan;2(1):32-41. Review.

Brady BM, Amory JK, Perheentupa A, Zitzmann M, Hay CJ, Apter D, Anderson RA, Bremner WJ, Pollanen P, Nieschlag E, Wu FC, Kersemaekers WM. A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive. Hum Reprod. 2006 Jan;21(1):285-94. Epub 2005 Sep 19.

Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol. 2004 Apr;190(4 Suppl):S5-22. Review.

Jacobsen SJ, Girman CJ, Lieber MM. Natural history of benign prostatic hyperplasia. Urology. 2001 Dec;58(6 Suppl 1):5-16; discussion 16. Review.

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66.

Wilson JD, George FW. The Physiology of Reproduction. Raven Press, 1994

Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994;63:25-61. Review. No abstract available.

Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003 Jul 17;349(3):215-24. Epub 2003 Jun 24.

Geller J. Effect of finasteride, a 5 alpha-reductase inhibitor on prostate tissue androgens and prostate-specific antigen. J Clin Endocrinol Metab. 1990 Dec;71(6):1552-5.

Geller J, Albert J. Effects of castration compared with total androgen blockade on tissue dihydrotestosterone (DHT) concentration in benign prostatic hyperplasia (BPH). Urol Res. 1987;15(3):151-3.

Mohler JL, Gregory CW, Ford OH 3rd, Kim D, Weaver CM, Petrusz P, Wilson EM, French FS. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004 Jan 15;10(2):440-8.

Forti G, Salerno R, Moneti G, Zoppi S, Fiorelli G, Marinoni T, Natali A, Costantini A, Serio M, Martini L, et al. Three-month treatment with a long-acting gonadotropin-releasing hormone agonist of patients with benign prostatic hyperplasia: effects on tissue androgen concentration, 5 alpha-reductase activity and androgen receptor content. J Clin Endocrinol Metab. 1989 Feb;68(2):461-8.

Habib FK, Ross M, Tate R, Chisholm GD. Differential effect of finasteride on the tissue androgen concentrations in benign prostatic hyperplasia. Clin Endocrinol (Oxf). 1997 Feb;46(2):137-44.

Page ST, Lin DW, Mostaghel EA, Hess DL, True LD, Amory JK, Nelson PS, Matsumoto AM, Bremner WJ. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab. 2006 Oct;91(10):3850-6. Epub 2006 Aug 1.

Page ST, Amory JK, Anawalt BD, Irwig MS, Brockenbrough AT, Matsumoto AM, Bremner WJ. TESTOSTERONE GEL COMBINED WITH DEPOMEDROXYPROGESTERONE ACETATE IS AN EFFECTIVE MALE HORMONAL CONTRACEPTIVE REGIMEN AND IS NOT ENHANCED BY THE ADDITION OF A GnRH ANTAGONIST. J Clin Endocrinol Metab. 2006 Aug 29; [Epub ahead of print]

Responsible Party:	University of Washington ( Stephanie T Page, MD, PhD )
Study ID Numbers:	31434-A, RFA-HD-06-014;, 06-4795-A 01
Study First Received:	June 20, 2007
Last Updated:	January 27, 2010
ClinicalTrials.gov Identifier:	NCT00490555 History of Changes
Health Authority:	United States: Food and Drug Administration; United States: Institutional Review Board

Keywords provided by University of Washington:

Male Contraception
Testosterone
Testis
Contraception
Prostate

Additional relevant MeSH terms:

Medroxyprogesterone 17-Acetate
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Contraceptive Agents
Contraceptives, Oral
Physiological Effects of Drugs
Contraceptive Agents, Female
Hormones, Hormone Substitutes, and Hormone Antagonists
Enzyme Inhibitors
Reproductive Control Agents
Methyltestosterone

Contraceptive Agents, Male
Hormones
Pharmacologic Actions
Testosterone 17 beta-cypionate
Dutasteride
Anabolic Agents
Testosterone
Therapeutic Uses
Contraceptives, Oral, Synthetic
Medroxyprogesterone
Androgens

ClinicalTrials.gov processed this record on February 04, 2010