Elsevier

European Urology

Volume 55, Issue 2, February 2009, Pages 310-321
European Urology

Review – Prostate Cancer
Shifting the Paradigm of Testosterone and Prostate Cancer: The Saturation Model and the Limits of Androgen-Dependent Growth

https://doi.org/10.1016/j.eururo.2008.09.024Get rights and content

Abstract

Context

The traditional belief that prostate cancer (PCa) growth is dependent on serum testosterone (T) level has been challenged by recent negative studies in noncastrated men.

Objective

To provide an improved framework for understanding the relationship of PCa to serum T level that is consistent with current evidence and is based on established biochemical principles of androgen action within the prostate.

Evidence acquisition

A literature search was performed of publications dating from 1941 to 2008 that addressed experimental and clinical effects of androgens on prostate growth. Review of studies investigating the prostatic effects of manipulation of androgen concentrations in human and animal studies, and in PCa cell lines.

Evidence synthesis

Prostate growth is exquisitely sensitive to variations in androgen concentrations at very low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels. This pattern is consistent with the observation that androgens exert their prostatic effects primarily via binding to the androgen receptor (AR), and that maximal androgen-AR binding is achieved at serum T concentrations well below the physiologic range. A Saturation Model is proposed that accounts for the seemingly contradictory results in human PCa studies. Changes in serum T concentrations below the point of maximal androgen-AR binding will elicit substantial changes in PCa growth, as seen with castration, or with T administration to previously castrated men. In contrast, once maximal androgen-AR binding is reached the presence of additional androgen produces little further effect.

Conclusions

The evidence clearly indicates that there is a limit to the ability of androgens to stimulate PCa growth. A Saturation Model based on androgen-AR binding provides a satisfactory conceptual framework to account for the dramatic effects seen with castration as well as the minor impact of T administration in noncastrated men.

Introduction

For >65 yr, it has been widely accepted that prostate cancer (PCa) growth is dependent on serum testosterone (T) concentrations, based on experiments by Huggins et al [1], [2] that castration caused PCa regression, whereas T administration caused more rapid PCa growth. Yet recent studies have shown little or no relationship between serum T concentrations and PCa [3], making the long-held belief in a T-dependent model of PCa problematic, if not untenable [4], [5]. We present here a simple yet critical refinement to the traditional view of T and PCa, namely, that there is a limit to the ability of T to stimulate PCa growth. The Saturation Model presented below is founded on basic biochemical principles of androgen action within the prostate, and it provides a robust framework for understanding the seemingly contradictory sets of results seen with T manipulation.

Defining the relationship between T and PCa is of considerable importance. Not only is androgen deprivation a mainstay of treatment for advanced PCa, but there is also growing interest in T therapy for hypogonadism. Although T therapy has been shown to improve sexual function, bone density, and body composition [6], none of these benefits might be worthwhile if T therapy increased the risk of PCa.

The Saturation Model has been introduced previously [7]; in this paper, we present the model in full, together with supporting evidence from human and laboratory studies. In brief, the Saturation Model accounts for the key observation that PCa growth is exquisitely sensitive to variation in serum T concentrations at or below the near-castrate range and is insensitive to T variations above this concentration. This model postulates that physiologic concentrations of T provide an excess of T and its intracellular prostatic metabolite, 5α-dihydrotestosterone (DHT), for optimal prostatic growth requirements. However, reducing T concentration below a critical concentration threshold (the Saturation Point) creates an intracellular milieu in which the availability of androgen becomes the rate-limiting step governing prostate tissue growth. This model is based on evidence that binding of androgen to the androgen receptor (AR) follows a similar saturation curve. We believe this simple model has important ramifications for clinical medicine and basic science research.

Section snippets

Androgen receptor binding

It is well-recognized that prostate tissue growth and function are modulated by androgens via specific interactions with the androgen receptor (AR). Metabolic transformation of T into DHT and subsequent interaction with AR initiates a cascade of signaling pathways, which involves recruitment of AR coactivators, leading to increased gene expression and regulation of cellular metabolism and cell growth.

The binding of DHT to AR is characterized by high degree of stereospecificity, high affinity,

The Saturation Model

We propose here a Saturation Model (Fig. 5a) to replace the traditional T-dependent model. This model posits that T and its intracellular metabolite 5α-DHT serve as critical factors for prostate tissue growth, but are present in excess at physiologic serum T concentrations. Below some critical serum T concentration, termed the Saturation Point, there is relative scarcity of T or DHT, causing androgen concentration to serve as the rate-limiting step in prostate tissue proliferation. Above this

Conclusions

The idea that there may be a limit to the ability of androgens to stimulate PCa growth represents a refinement of the traditional, T-dependent view of PCa first postulated in the 1940 s, at a time when there was no reliable serum marker for PCa and little experience with T therapy. Shifting the paradigm of T and PCa in this way unifies theory with a substantial body of evidence from human, animal, and cell lines that had been inconsistent with a T-dependent model of PCa growth. It may be time to

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