Developmental Research Pilot Project

Stephanie Page, MD, PhD, University of Washington

"Hormonal and Molecular Effects of Exogenous Dihydrotestosterone on the Prostate"

Abstract

Testosterone prescriptions have been growing exponentially recently, yet the effects of androgens on the prostate, and on prostate cancer risk, are poorly understood. Epidemiologic data correlating serum androgen levels with prostate cancer risk are conflicting and results from the only long-term intervention trial examining androgen manipulation and prostate cancer were mixed. Circulating and intraprostatic androgenic milieus differ and we have recently shown that manipulation of serum androgens does not result in equivalent intraprostatic hormonal changes. In the prostate, testosterone (T), is reduced to the more potent androgen, dihydrotestosterone (DHT), by prostatic 5a-reductase resulting in prostate DHT levels far exceeding serum levels. In contrast to T administration, exogenous DHT does not increase prostate size or prostate specific antigen in men. We hypothesize that by providing negative feedback at the pituitary and thus reducing circulating T, exogenous DHT may be a "prostate sparing androgen" which paradoxically decreases intraprostatic DHT and prostate epithelial cell proliferation.

We propose a randomized, double-blind, placebo-controlled trial of transdermal DHT gel in normal men. Blood samples and prostate biopsies will be taken on treatment Day 28 for determination of serum and prostate androgen concentrations and examination of prostate epithelial cell proliferation, apoptosis, and gene expression. Comparisons between treatment groups will allow us to determine 1) the relationship between serum and prostate androgens in response to exogenous DHT and 2) the impact of increases in serum DHT on the prostate epithelium. These results will inform future studies aimed to optimize therapies for prostate cancer prevention and androgen replacement in men.