Potter, Zager, Barton, 2006

Model Status

This CellML version of the model has been checked in COR and PCEnv. The units have been checked and are correct and are consistent. The model runs in PCEnv and may recreate the published results. Equation 29 has been fixed with the help of the model author.

Model Structure

Endocrine hormones, responsible for the regulation of the prostate and other male sexual functions, are produced by the hypothalamus, pituitary and testes. Some environmental compounds can have endocrine functions and can disrupt these processes. For example, some pesticides mimic estrogen and in doing so have an anti-androgenic activity. These can affect the development of male sex organs, and can result in delayed puberty and possibly reduced sperm counts and fertility. Anti-androgens generally function via one of two mechanisms:

  • 1) Androgen agonists bind to the androgen receptor (AR) but do not stimulate DNA transcription, therefore inhibiting the signalling pathway highlighted in the figure below; and

  • 2) 5-alpha-reductase inhibitors block the metabolism of testosterone (T) to 5alpha-dihydrotestosterone (DHT).

An improved understanding of the male regulatory processes and their disruptions would aid in the dose-response assessment of the environmental chemicals that act as anti-androgens. Mathematical models for the androgenic regulation of the prostate, based on biological data, would hopefully facilitate this. The aim of Potter et al's mathematical model described here is to understand normal adult male hormonal regulation of the prostate, forming a foundation for characterising the effects of environmental anti-androgens in male rats.

Model schema for testosterone (T) and 5alpha-dihydrotestosterone (DHT) kinetics. Arrows represent blood flow between tissue compartments, substrate metabolism, and clearance (as labelled). T synthesis occurs in the blood and in testicular Leydig cells (LC), with androgen binding to albumin in the blood and to androgen receptor (AR) in the prostate. The testes compartment can be further broken down into spermatic cord venous blood (SV), testicular venous blood (TV), interstitial fluid (IF), and seminiferous tubules (ST). Androgenic regulation in the prostate is highlighted. T is converted to DHT, and either T or DHT can bind to the AR and form homogeneous or heterogeneous dimers (this diagram is only showing DHT binding, not T binding). AR-mediated DNA transcription leads to enhanced cell proliferation and conversion of T to DHT, and inhibition of cell apoptosis.

T is mainly produced in the testicular Leydig cells in response to luteinising hormone (LH) secreted from the pituitary. T is metabolised to DHT by 5-alpha-reductase in the liver and prostate. Enzyme activity is upregulated by T and DHT via AR-mediated gene expression (highlighted in the figure above). The conversion of T to DHT down-regulates LH, creating a negative feedback loop. In the blood, T and DHT bind to serum albumin which regulates hormone transport and tissue uptake kinetics. The mathematical model described here in CellML contains equations to describe these processes. The model structure for hormonal transport is based on pharmacokinetic modelling, while the equations for AR-regulation in the prostate are based on mass-action kinetics. Many model parameters were based on experimental measurements.

The complete original paper reference is cited below:

Mathematical model for the androgenic regulation of the prostate in intact and castrated adult male rats, Laura K. Potter, Michael G. Zager, and Hugh A. Barton, 2006, American Journal of Physiology: Endocrinology and Metabolism , volume 291, E952-E964. (Full text (HTML) and PDF versions of the article are available to subscribers on the American Journal of Physiology: Endocrinology and Metabolism website.) PubMed ID: 16757547