PROS-1-Male Hormonal Contraceptive Regimens on Prostate Tissue

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.

Timeline

Start

2009-01

Primary completion

2012-01

Completion

2012-03

Publications

• Background 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. doi: 10.1038/ncpendmet0069.
• Background 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. doi: 10.1093/humrep/dei300. Epub 2005 Sep 19.
• Background 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. doi: 10.1016/j.ajog.2004.01.061.
• Background Jacobsen SJ, Girman CJ, Lieber MM. Natural history of benign prostatic hyperplasia. Urology. 2001 Dec;58(6 Suppl 1):5-16; discussion 16. doi: 10.1016/s0090-4295(01)01298-5.
• Background 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. doi: 10.3322/canjclin.57.1.43.
• Background Wilson JD, George FW. The Physiology of Reproduction. Raven Press, 1994
• Background Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994;63:25-61. doi: 10.1146/annurev.bi.63.070194.000325. No abstract available.
• Background 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. doi: 10.1056/NEJMoa030660. Epub 2003 Jun 24.
• Background 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. doi: 10.1210/jcem-71-6-1552.
• Background 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. doi: 10.1007/BF00254427.
• Background 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. doi: 10.1158/1078-0432.ccr-1146-03.
• Background 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. doi: 10.1210/jcem-68-2-461.
• Background 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. doi: 10.1046/j.1365-2265.1997.950908.x.
• Background 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. doi: 10.1210/jc.2006-0968. Epub 2006 Aug 1.
• Background 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 Nov;91(11):4374-80. doi: 10.1210/jc.2006-1411. Epub 2006 Aug 29.

Drugs

Indications

No indication recorded.