Am J Physiol Endocrinol Metab 291: E952–E964, 2006.
First published June 6, 2006; doi:10.1152/ajpendo.00545.2005.
Mathematical model for the androgenic regulation of the prostate in intact and
castrated adult male rats
Laura K. Potter,1,2 Michael G. Zager,1,3 and Hugh A. Barton3
1
Curriculum in Toxicology, University of North Carolina, Chapel Hill; 2National Health and Environmental Effects
Research Laboratory, Experimental Toxicology Division, Office of Research and Development, United States
Environmental Protection Agency; and 3National Center for Computational Toxicology, Office of Research
and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina
Submitted 9 November 2005; accepted in final form 5 June 2006
Potter, Laura K., Michael G. Zager, and Hugh A. Barton.
Mathematical model for the androgenic regulation of the prostate
in intact and castrated adult male rats. Am J Physiol Endocrinol
Metab 291: E952–E964, 2006. First published June 6, 2006;
doi:10.1152/ajpendo.00545.2005.—The testicular-hypothalamic-
pituitary axis regulates male reproductive system functions. Un-
derstanding these regulatory mechanisms is important for assessing
the reproductive effects of environmental and pharmaceutical an-
drogenic and antiandrogenic compounds. A mathematical model
for the dynamics of androgenic synthesis, transport, metabolism,
and regulation of the adult rodent ventral prostate was developed
on the basis of a model by Barton and Anderson (1997). The model
describes the systemic and local kinetics of testosterone (T),
5␣-dihydrotestosterone (DHT), and luteinizing hormone (LH),
with metabolism of T to DHT by 5␣-reductase in liver and
prostate. Also included are feedback loops for the positive regu-
lation of T synthesis by LH and negative regulation of LH by T and
DHT. The model simulates maintenance of the prostate as a
function of hormone concentrations and androgen receptor (AR)-
mediated signal transduction. The regulatory processes involved in
prostate size and function include cell proliferation, apoptosis,
fluid production, and 5␣-reductase activity. Each process is con-
trolled through the occupancy of a representative gene by andro-
gen-AR dimers. The model simulates prostate dynamics for intact,
castrated, and intravenous T-injected rats. After calibration, the
model accurately captures the castration-induced regression of the
prostate compared with experimental data that show that the
prostate regresses to ⬃17 and 5% of its intact weight at 14 and 30
days postcastration, respectively. The model also accurately pre-
dicts serum T and AR levels following castration compared with
data. This model provides a framework for quantifying the kinetics
and effects of environmental and pharmaceutical endocrine active
compounds on the prostate.
rodent ventral prostate; androgen receptor; testosterone; 5␣-dihy-
drotestosterone; testicular-hypothalamic-pituitary axis
THE HYPOTHALAMUS, PITUITARY, AND TESTES produce endocrine
hormones responsible for regulation of the prostate and other
male sexual functions (12, 46). Exogenous endocrine active
compounds can disrupt these processes. Some pesticides (e.g.,
vinclozolin and linuron) are known to have antiandrogenic
activity (19, 20). Toxic effects of antiandrogens in male ro-
dents range from developmental effects such as reproductive
malformations, retained nipples, and undescended testes to
pubertal effects such as delayed puberty and reduced weights
Address for reprint requests and other correspondence: H. A. Barton, ORD
National Center for Computational Toxicology, US EPA, B205-01, Research
Triangle Park, NC 27711 (e-mail: habarton@alum.mit.edu).
E952
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of prostate and other reproductive organs. In the pharmaceuti-
cal setting, therapeutic drugs such as finasteride, dutasteride,
bicalutamide, and flutamide are used to treat benign prostatic
hyperplasia and/or prostate cancer by inhibiting androgen-
dependent growth processes.
The mechanisms of action of antiandrogens are generally of
two forms. The first is the androgen antagonist, which binds to
the androgen receptor (AR) but does not stimulate DNA
transcription, such as the pharmaceutical compounds flutamide
and bicalutamide or the environmental compound vinclozolin.
The second is the 5␣-reductase inhibitor, which blocks the
metabolism of testosterone (T) to 5␣-dihydrotestosterone
(DHT). The therapeutic drugs dutasteride and finasteride are
examples of 5␣-reductase inhibitors; no environmental exam-
ples are currently known. Both of these mechanisms effec-
tively inhibit AR-mediated DNA transcription, leading to re-
duction of prostate size and cell numbers and decreased pros-
tatic fluid production. Quantification of the male regulatory
processes and their disruptions would aid in the dose-response
assessment of environmental endocrine active compounds (4,
5). This requires biologically based quantitative methods de-
scribing not only the pharmacokinetics and mode of action of
the exogenous compound of interest but also the pharmacoki-
netics of the endogenous hormones and how they regulate the
male reproductive organs.
The objective in this research effort was to understand the
normal adult male hormonal regulation of the prostate to set a
foundation for quantitatively characterizing the effects of ex-
posure to antiandrogens in male rats. To quantitatively under-
stand the normal adult male hormonal regulation of the pros-
tate, mathematical descriptions of the kinetics of T, DHT, and
luteinizing hormone (LH) are required, along with several
pharmacodynamic components, such as prostatic AR concen-
trations, maintenance of prostate size, and regulation of pros-
tatic fluid production.
The regulation of T is crucial for prostate maintenance in
that the size and function of the prostate is gene regulated via
DNA binding by androgen-bound AR (21–23, 37, 42, 53). T is
produced mainly in the testicular Leydig cells in response to
LH released from the pituitary (12). It is metabolized to DHT
by 5␣-reductase in the liver and prostate (39, 50). The enzyme
5␣-reductase is upregulated by T and DHT via AR-mediated
gene expression (39, 50). LH upregulates the production of T
and, hence, DHT, which in turn downregulates LH, creating a
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION
negative feedback loop (12). In the blood, T and DHT bind to
serum albumin, which appears to play a role in regulating
transport and tissue uptake dynamics (15, 33, 49).
In this article, a model describing the endogenous hormone
kinetics of the testicular-pituitary axis and the dynamics of the
androgenic regulation of the prostate is presented. The model
includes the pharmacokinetics of T, DHT, and LH, as well as
the dynamics of AR binding and signaling as they relate to the
regulation of the prostate. Development of the model included
characterization of critical biological and physiological pro-
cesses inherent in the hormonal regulation of the male repro-
ductive system, including androgen-LH feedback loops and
AR-mediated regulation of the prostate.
The model structure for the hormonal transport, or pharma-
cokinetic component, is based on standard physiologically
based pharmacokinetic (PBPK) modeling (32), whereas the
dynamics of the AR-based regulation of the prostate are based
on mass action kinetics. These dynamics include binding of T
and DHT to the AR, dimerization of androgen-AR complexes,
and gene activation by these complexes via DNA binding. The
complexes regulate prostatic cellular mass, fluid production,
blood flow, AR concentrations, and 5␣-reductase activity.
Unknown physiological, kinetic, and binding parameters
were estimated using available experimental data from the
literature. The resulting calibrated model is capable of quanti-
tatively describing intact and castrated rats at steady state, as
well as the dynamics that occur following castration. This
model may be used for testing and generating hypotheses, data
interpretation, experimental design, and identifying key data
gaps in the study of the hormonal regulation of the prostate and
provides a framework for elaborations that address the effects
of exposure to exogenous, pharmaceutical, or environmental
androgens and antiandrogens (5).
METHODS
Model Structure: Pharmacokinetic Component
The transport and dispositional kinetics of T and DHT are de-
scribed using standard PBPK compartmental modeling (32), whereas
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E953
a single-compartment model is used for LH. Flow-limited compart-
ments are utilized in cases where the uptake rate of a compound into
a tissue is limited by the blood flow rate into the tissue rather than the
diffusion rate of the compound across cell membranes. Conversely,
diffusion-limited compartments are used when the diffusion across
cell membranes is slow compared with the blood flow rate into the
tissue (32). The pharmacokinetics of T and DHT are modeled with
compartments representing the systemic serum, liver, prostate, testes,
and rest of body (Fig. 1). LH is modeled with a single systemic
compartment that captures androgen-regulated synthesis and the ef-
fects of LH on T synthesis in the testes. All terms in the equations are
defined in Tables 1, 2, 3, and 4.
Systemic serum compartment. The compartment for systemic se-
rum includes exchange of T and DHT with the tissue compartments,
the binding dynamics of T and DHT to albumin, and a basal input rate
of T, due to limited synthesis of T outside the testes (29). A
simplifying assumption is made that all concentrations are rapidly
equilibrated between red blood cells and serum.
The rate equation for the kinetics of T in the systemic serum is
given as
dAT bl
⫽ Qb共CTbf ⫺ CTblf兲 ⫹ Qp共CTpf ⫺ CTbl兲 ⫹ Ql共CTlf ⫺ CTbl兲
dt
(1)
⫹ Qt共1 ⫺ ts兲共CTtv ⫺ CTblf兲 ⫹ k2T
The first four terms represent T exchange with the rest of body,
prostate, liver, and testes compartments, respectively, followed by the
basal synthesis of T. Free concentrations CTblf are affected by albu-
min binding in the blood as in Eq. 3 below. It is assumed that only free
T is available to enter the testes and rest-of-body compartments,
whereas both free and albumin-bound T are available for uptake into
the metabolically active prostate and liver (33).
The equation for the kinetics of DHT in systemic serum has a
similar form, except that basal DHT synthesis is not included, because
it is assumed that all significant amounts of DHT are produced in the
prostate and liver via metabolism (1). In addition, the rest-of-body
compartment for DHT incorporates the testes, which is modeled as a
separate compartment for T to capture the dynamics of T synthesis.
The equation for DHT transport in the systemic serum is given by
dAD bl
⫽ Qbt共CDbf ⫺ CDblf兲 ⫹ Qp共CDpf ⫺ CDblf兲 ⫹ Ql共CDlf ⫺ CDbl兲
dt
(2)
Fig. 1. Model schema for kinetics of testostwerone (T) and
5␣-dihydrotestosterone (DHT). Arrows depict blood flow to
and from tissue compartments, metabolism and clearance. Syn-
thesis of T occurs in blood and testicular Leydig cells (LC),
with androgen binding to albumin in the blood and to androgen
receptor (AR) in the prostate. The components of the testes
compartment for testosterone include the spermatic cord venous
blood (SV), testicular venous blood (TV), interstitial fluid (IF),
and seminiferous tubules (ST). Blood flow parameters are given
in Table 2.
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E954 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION

Table 1. Model variables

Variable Symbol Initial Value Reference

Concentration of LH CLH 0.104 (6)

Concentration of T in testicular interstitial fluid CTif 307.29 (6)
Concentration of T in testicular seminiferous tubules CTst 307.29 (6)
Concentration of T in testicular venous blood CTtv 153.92 Steady state
Concentration of T in prostate CTp 11.38 (31)
Concentration of DHT in prostate CDp 52.46 (42)
Free concentration of AR in prostate CRf 0.95 Steady state
Concentration of T-bound AR in prostate CT:R 3.82 Steady state
Concentration of DHT-bound AR in prostate CD:R 15.76 Steady state
Concentration of dimerized complex T:AR-T:AR in prostate CTT 0.65 Steady state
Concentration of dimerized complex DHT:AR-T:AR in prostate CDT 2.69 Steady state
Concentration of dimerized complex DHT:AR-DHT:AR in prostate CDD 11.11 Steady state
Concentration of dimer T:AR-T:AR bound to cd DNA in prostate (cell death) CTTcd 3.35 ⫻ 10⫺4 Steady state
Concentration of dimer T:AR-T:AR bound to sec DNA in prostate (fluid secretion) CTTsec 3.16 ⫻ 10⫺4 Steady state
Concentration of dimer T:AR-T:AR bound to cp DNA in prostate (cell proliferation) CTTcp 2.48 ⫻ 10⫺4 Steady state
Concentration of dimer T:AR-T:AR bound to 5a DNA in prostate (5␣-reductase) CTT5a 3.41 ⫻ 10⫺4 Steady state
Concentration of dimer DHT:AR-DHT:AR bound to cd DNA in prostate CDDcd 0.068 Steady state
Concentration of dimer DHT:AR-DHT:AR bound to sec DNA in prostate CDDsec 0.065 Steady state
Concentration of dimer DHT:AR-DHT:AR bound to cp DNA in prostate CDDcp 0.051 Steady state
Concentration of dimer DHT:AR-DHT:AR bound to 5a DNA in prostate CDD5a 0.070 Steady state
Concentration of dimer T:AR-DHT:AR bound to cd DNA in prostate CDTcd 0.0021 Steady state
Concentration of dimer T:AR-DHT:AR bound to sec DNA in prostate CDTsec 0.0020 Steady state
Concentration of dimer T:AR-DHT:AR bound to cp DNA in prostate CDTcp 0.0015 Steady state
Concentration of dimer T:AR-DHT:AR bound to 5a DNA in prostate CDT5a 0.0021 Steady state
Free concentration of cd DNA binding site CDNAcdf 0.0044 Steady state
Free concentration of sec DNA binding site CDNAsecf 0.0083 Steady state
Free concentration of cp DNA binding site CDNAcpf 0.023 Steady state
Free concentration of 5a DNA binding site CDNA5af 0.0031 Steady state
Concentration of T in liver CTl 9.92 Steady state
Concentration of DHT in liver CDl 0.92 Steady state
Concentration of T in systemic serum CTbl 7.60 (6)
Concentration of DHT in systemic serum CDbl 0.59 (31)
Concentration of T-bound albumin in systemic serum CT:A 6.97 Steady state
Concentration of DHT-bound albumin in systemic serum CD:A 0.56 Steady state
Free concentration of albumin in systemic serum CAf 499992 Steady state
Occupancy of cd DNA binding site DNAocd 0.94 Steady state
Occupancy of sec DNA binding site DNAosec 0.90 Steady state
Occupancy of cp DNA binding site DNAocp 0.70 Steady state
Occupancy of 5a DNA binding site DNAo5a 0.96 Steady state
Volume of androgen-sensitive prostatic cell mass VPCl 1.00 ⫻ 10⫺4 (42)
Volume of androgen-sensitive prostatic ductal lumen mass VPLl 1.79 ⫻ 10⫺4 (42)
Total volume of prostate Vp 3.30 ⫻ 10⫺4 (52)
Concentrations are given in nM, volumes in liters, and occupancy is unitless. Equations in the text denote amounts with A (e.g., ATif is amount of T in testicular
interstitial fluid), and free tissue concentrations of T and DHT are denoted with f appended to the subscript (e.g., CTpf is free concentration of T in prostate).
Initial conditions for intact steady state are given in the 3rd column, with references in the 4th column. Initial values with the steady-state reference were
determined by matching intact and castrate steady states with experimental data when available (see Table 5) or by running the model to steady state after
calibration.

We assume standard binding kinetics for T and DHT binding to Michaelis-Menten term, and linear terms are included for the general
albumin: metabolic clearance of T and DHT in the liver (49). The rate equations
for T and DHT in the liver are given by
dCT:A
⫽ kTAonCTblfCAf ⫺ kTAoffCT:A (3)
dt dAT l VmaxlCTlf ATl
⫽ Ql共CTbl ⫺ CTlf兲 ⫺ ⫺ klT (8)
dCD:A dt km5␣ ⫹ CTlf PTl
⫽ kDAonCDblfCAf ⫺ kDAoffCD:A (4)
dt and
with free T, DHT, and albumin concentrations determined using mass dAD l VmaxlCTlf ADl
balance: ⫽ Ql共CDbl ⫺ CDlf兲 ⫹ ⫺ klD (9)
dt km5␣ ⫹ CTlf PDl
CT blf ⫽ CTbl ⫺ CT:A (5)
Free concentrations of T and DHT in the liver are given by the
CD blf ⫽ CDbl ⫺ CD:A (6) algebraic equations
CA f ⫽ CA ⫺ CT:A ⫺ CD:A (7)
CTl CDl
CT lf ⫽ , CDlf ⫽ (10)
Liver compartment. The kinetics of T and DHT in the liver are PTl PDl
described by using a flow-limited compartmental model. Metabolism
of T to DHT via 5␣-reductase in the liver is modeled with a so that free concentrations are proportional to total concentrations.

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 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION E955
Table 2. Model physiological parameters
Parameter Symbol Value Reference

Rat body mass bm 0.3 kg (6)

Rat body volume bv 0.3 liters Assuming density ⫽ 1
Volume of blood Vbl 0.021 liters (6)
Volume of liver Vl 0.012 liters (7)
Volume of rest-of-body (ROB) excluding testes Vb 0.24 liters (6)
Volume of ROB including testes Vbt 0.25 liters (6)
Volume of testes Vt 0.0033 liters (6)
Volume of interstitial tissue Vit 3.63 ⫻ 10⫺4 liters (6)
Volume of seminiferous tubules Vst 0.0029 liters (6)
Volume of interstitial fluid Vif 2.25 ⫻ 10⫺4 liters (6)
Basal prostatic ductal lumen volume VPL2 3.08 ⫻ 10⫺6 liters (42)
Basal prostate cell volume VPC2 5.08 ⫻ 10⫺5 liters (42)
Cardiac output Qc 6.08 l/h (6)
Steady state blood flow to prostate Qp0 0.024 l/h (16)
Proportional constant for Qp kQp 73.84 h⫺1 Steady state
Blood flow rate to testes (intact only) Qt 0.061 l/h (6)
Blood flow rate to liver Ql 1.06 l/h (7)
Blood flow rate to ROB excluding testes Qb Qc-Qp-Qt-Ql Flux balance
Blood flow rate to ROB including testes Qbt Qc-Qpt-Ql Flux balance
Fraction of testicular blood flow shunted to SV ts 0.56 (6)
Total DNA concentration per site (k ⫽ cp, cd, sec, 5a) CDNAk 0.075 nM Fitted
Total concentration of serum albumin CA 5.00 ⫻ 105 nM (10)
Parameters with steady state reference were determined by running the calibrated model to steady state.

Testes compartment. The testes compartment has a unique structure
based on the specific biology of the testes that is important for T since
the testicular Leydig cells are the major source for T synthesis (12).
Here, we give a brief outline of the model; for a comprehensive
development of the model structure and equations, the reader is
referred to Barton and Anderson (6). As previously mentioned, the
kinetics of DHT in the testes are incorporated in the rest-of-body
compartment, so that the testes compartment is utilized only for T.
The testes compartment is divided into two subcompartments,
representing the seminiferous tubules (ST) and the interstitial fluid
(IF). To account for the testicular shunt (30) that directs a portion of
the blood flow directly into the spermatic cord (bypassing the testes),
the blood flow rate to the testes compartment is split into two
components (Fig. 1). One component of the blood flow feeds into the
IF subcompartment, and the other component flows into the spermatic
cord and feeds directly into the systemic serum. The bias of the split
is controlled by the model parameter ts.
Circulating T reenters the IF via the blood and then diffuses
between the IF and ST as with a standard diffusion-limited compart-
ment (32). The ST compartment is present to facilitate future elabo-
rations to address spermatogenesis. The diffusion of T between the IF
and ST is controlled in the model by the parameter ␮. To account for

Table 3. Model hormone pharmacokinetic parameters

Parameter Symbol Value Reference

IF/blood partition coefficient for T PTif 1.96 Fitted

ST/IF partition coefficient for T PTst 1.00 (6)
Liver/blood partition coeff. for T PTl 2.75 Fitted
Liver/blood partition coeff. for DHT PDl 2.00 Fitted
ROB/blood partition coeff. for T PTb 1.00 (6)
ROB/blood partition coeff. for DHT PDb 0.62 Fitted
Testicular permeability coefficient ␮ 1000 l/h (6)
Coeff. for nonspecific T binding in prostate NTp 0.79 Fitted
Coeff. for nonspecific DHT binding in prostate NDp 1.00 Fitted
Relative potency of T for LH synthesis inhibition ␣T 0.25 (55)
Relative potency of DHT for LH synthesis inhibition ␣D 0.75 (55)
T synthesis rate in testes (intact only) k1t 40.32 l/h Fitted
Basal T synthesis rate k2t 0.17 nmol/h Fitted
Basal AR synthesis rate k1R 68.15 nmol/h Fitted
T elimination rate in liver k1T 87.93 h⫺1 Fitted
DHT elimination rate in liver klD 77.20 h⫺1 Fitted
AR elimination rate keR 71.90 l/h Fitted
T inhibition constant 1 for LH kLH1 0.13 l/h Fitted
T inhibition constant 2 for LH kLH2 0.026 nmol/h Fitted
Minimum LH synthesis rate kLH3 1.68 ⫻ 10⫺4 nmol/h Fitted
LH degradation rate constant kLH4 0.80 h⫺1 Fitted
Regulation constant for Vmax in prostate k5a 3.02 nmol/h Steady state
Vmax for T metabolism to DHT in liver Vmax1 3.65 nmol/h Fitted
Steady state Vmax for T metabolism to DHT in prostate Vmax0 2.89 nmol/h Fitted
km for T metabolism to DHT in prostate km5a 40.00 nM (35)
Initial values with the steady state reference were determined by running the calibrated model to steady state.

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E956 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION

Table 4. Model biochemical and kinetic parameters for albumin, AR, DNA, and prostate
Parameter Symbol Value Reference

Association rate for T-AR kTRon 0.14 nM⫺1 h⫺1 (53)

Dissociation rate for T-AR kTRoff 0.069 h⫺1 Computed from (53)
Association rate for DHT-AR kDRon 0.053 nM⫺1 h⫺1 (53)
Dissociation rate for DHT-AR kDRoff 0.018 h⫺1 Computed from (53)
Equilibrium dissociation constant for T-albumin KTAd 4.50 ⫻ 104 nM (49)
Association rate for T-albumin kTAon 0.18 nM⫺1 h⫺1 Fitted
Dissociation rate for T-albumin kTAoff 8131 h⫺1 kTAoff ⫽ kTAon KTAd
Equilibrium dissociation constant for DHT-albumin KDAd 2.89 ⫻ 104 nM (49)
Association rate for DHT-albumin kDAon 0.15 nM⫺1 h⫺1 Fitted
Dissociation rate for DHT-albumin kDAoff 5407 h⫺1 kDAoff ⫽ kDAon KDAd
Association rates for androgen dimerization (I and J represent the 2
androgens in the dimer) kIJon 0.14 nM⫺1 h⫺1 Assumption
Dissociation rates for androgen dimerization kIJoff 3.13 h⫺1 Fitted
Association rates for DNA dimer formation (I and J represent the 2 dimers;
k denotes the representative genes (cd, cp, 5a, sec) kDNAonIJk 0.14 nM⫺1 h⫺1 Assumption
Dissociation rates for DNA dimer formation kDNAoffIJk See text Fitted
Steady state DNA occupancy for 5␣-reductase activity DNAo5a0 0.96 Steady state
Steady state DNA occupancy for cell proliferation DNAocp0 0.70 Steady state
Steady state DNA occupancy for cell death DNAocd0 0.94 Steady state
Steady state DNA occupancy for fluid production DNAosec0 0.89 Steady state
Fluid outflow rate constant kflo 0.043 h⫺1 Fitted
Fluid production rate constant ksec 8.44 ⫻ 10⫺6 kg/h Steady state
Prostate cell proliferation rate constant kcpl 1.17 ⫻ 10⫺7 kg/h Fitted
Prostate cell death rate constant kcdl 0.014 h⫺1 Steady state
Parameters with steady state reference were determined by running the calibrated model to steady state.

the synthesis of T in the Leydig cells, there is a source of T production dAD p VmaxCTpf
in the IF (12). Recalling that LH upregulates T synthesis in the Leydig ⫽ Qp共CDblf ⫺ CDpf兲 ⫹ (15)
cells (6), we assume a positive linear feedback mechanism in the dt km5␣ ⫹ CTpf
model with rate constant k1T. Once the testicular venous blood leaves Free prostatic T and DHT are available to bind to AR. The androgen-
the testes compartment, it immediately reenters the systemic serum bound AR complexes T:AR and DHT:AR then form homo- and het-
via the spermatic cord. The rate equation for T in the IF subcompart- erodimers. These dimers bind to DNA and stimulate the regulation of various
ment is given by processes. The equations for T and DHT binding to AR are given by
dAT if
dt
冉
⫽ Qt共1 ⫺ ts兲 CTblf ⫺
CTif
PTif
⫹␮冊 冉
CTst
PTst
冊
⫺ CTif ⫹ klTCLH (11)
dCT:R
dt
⫽ kTRonCTpfCRf ⫺ kTRoffCT:R (16)

With only diffusion occurring in the ST compartment, the correspond- and

ing rate equation is defined as dCD:R
⫽ kDRonCDpfCRf ⫺ kDRoffCD:R
冉 冊
(17)
dAT st CTst dt
⫽ ␮ CTif ⫺ (12)
dt PTst

The algebraic equation for the testicular venous blood describes the
concentration of T as proportional to the concentration in the inter-
stitial fluid due to nonspecific binding and is given by
CTif
CT tv ⫽ (13)
PTif
Prostate compartment. The prostate is a complex tissue with
multiple lobes and multiple cell types, which vary in their androgen
responsiveness (41). The model currently is parameterized to describe
the ventral lobe of the prostate, which represents 60 –70% of the rat
prostate (11). The prostate compartment includes transport to and
from the blood, the metabolism of T to DHT by 5␣-reductase, and the
dynamics of AR binding, dimerization, and DNA binding (Fig. 2).
The rate equations for the kinetics of T and DHT in the prostate are
given (respectively) by
dAT p VmaxCTpf Fig. 2. Schema of androgenic regulation in the prostate. T is converted to
⫽ Qp共CTbl ⫺ CTpf兲 ⫺ (14) DHT, either of which can bind to the AR and form homogeneous or hetero-
dt km5␣ ⫹ CTpf geneous dimers (T binding not shown here). AR-mediated DNA transcription
leads to upregulation of 5␣-reductase, cell proliferation, and fluid production
and as well as downregulation of apoptosis.

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 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION E957
The homo- and heterodimers (abbreviated as DT, DD, and TT) have Rest-of-body compartment. The rest-of-body compartment repre-
similar kinetics: sents all tissues and organs not included in the remaining compart-
ments and includes exchange with the systemic serum. Note that the
dCDT testes are included in the rest-of-body compartment for DHT but not
⫽ kDTon共CD:R兲共CT:R兲 ⫺ kDToffCDT (18)
dt for T since this tissue is modeled separately for T synthesis dynamics.
This results in two different blood flow rates, Qb and Qbt for the
dCDD
⫽ kDDon共CD:R兲2 ⫺ kDDoffCDD (19) rest-of-body compartments that exclude and include the testes. The
dt transport equations for T and DHT in the rest of body are given by
dCTT
dt
⫽ kTTon共CT:R兲2 ⫺ kTToffCTT (20)
dAT b
dt
冉
⫽ Qb CTblf ⫺
CTb
PTb
冊 (27)

The dimers above are able to bind to DNA sites to form DNA-dimer and

complexes. In the model, there are four distinct DNA binding sites
that are involved in regulating 5␣-reductase synthesis, cell prolifera-
tion, apoptosis, and prostatic fluid production. Although numerous
genes are likely responsible for the regulation of the last three
processes, in the model the simplifying assumption was made to
represent each process by a single gene.
The four representative genes in the model are available to bind to
all three dimer types, yielding 12 equations for the concentrations of
the DNA-dimer complexes. One example is given here. The following
equation is for the concentration of the DHT:AR-DHT:AR dimer
bound to the 5␣-reductase synthesis-regulating gene:
dCDD 5a
⫽ kDNAonDD5aCDD 䡠 CDNA5af ⫺ kDNAoffDD5aCDD5a (21)
dt
where parameters and variables for the 12 DNA-dimer complexes are
given in Tables 1, 2, and 4. The dissociation rates for the DNA-dimer
complexes are determined to reflect relative potencies between T and
DHT as well as between the four representative DNA binding sites.
Specifically, we assume that the relative potencies for the dissociation
of DNA from the dimers T:AR-T:AR, D:AR-D:AR, and D:AR-T:AR
are 6, 0.5, and 4, respectively. These potencies account for the fact
that DHT is significantly more potent in mediating AR-based effects
than T is (55). Moreover, the four representative DNA binding sites
have relative potencies for dissociation with DNA-dimer complexes
that reflect the differential responses of the four regulatory events
(5␣-reductase activity, fluid production, cell proliferation, and apop-
tosis) to AR-mediated signaling. These potencies are 0.14, 0.4, 1.4,
and 0.2, respectively, and were estimated as part of the parameter
estimation process described below. The model is formulated so that
the occupancy of each gene can hold any value between 0 and 1,
representing the fraction of total possible occupancy.
Free concentrations of prostatic T, DHT, AR, and DNA sites are
given by
冉 冊
dAD b CDb
⫽ Qbt CDblf ⫺ (28)
dt PDb
LH pharmacokinetics. The kinetics of LH are described in the
model with a single equation that incorporates the synthesis and
elimination of LH in the serum. The synthesis of LH is negatively
regulated by T and DHT concentrations, with a small basal amount of
synthesis assumed. Similar to the upregulation of T by LH, we assume
a piecewise linear feedback mechanism to describe downregulation of
LH by T. Elimination of LH is proportional to the amount of LH in the
system. The transport equation is given by
dALH
⫽ max [⫺kLH1共␣TCTblf ⫹ ␣DCDblf兲 ⫹ kLH2,kLH3] ⫺ kLH4ALH
dt
(29)
where ␣T and ␣D represent the relative potency for inhibiting LH
production, kLH1 and kLH2 describe the decline in LH with increasing
androgen, kLH3 denotes the minimum LH synthesis rate, and kLH4
represents LH degradation. See Fig. 3 for a representative graph of the
LH synthesis rate function.
Model Structure: Pharmacodynamic Component
The model describes the dynamics of AR concentrations, prostatic
blood flow, 5␣-reductase activity, prostatic ductal lumen mass, and
prostate cellular mass. Prostatic blood flow is regulated by the size of
the prostatic cellular mass, whereas 5␣-reductase activity, cellular
mass, and ductal lumen mass are regulated via occupancy of DNA
binding sites.

CT pf ⫽
CTp ⫺ CT:R ⫺ 2CTT ⫺ CDT ⫺ 兺 共T兲 (22)
1 ⫹ NTp

CD pf ⫽
CDp ⫺ CD:R ⫺ 2CDD ⫺ CDT ⫺ 兺 共D兲 (23)
1 ⫹ NDp

CR f ⫽ CR ⫺ CT:R ⫺ CD:R ⫺ 2 兺 共dimer兲 ⫺ 2兺 共DNA兲 (24)

and
CDNA if ⫽ CDNAj ⫺ 共CTTj ⫹ CDDj ⫹ CDTj兲, j ⫽ cd,sec,cp,5a
(25)
where NTp and NDp are coefficients for nonspecific binding of T and
DHT, respectively, in the prostate, and ¥(T) and ¥(D) are all the
Fig. 3. LH synthesis rate function. LH synthesis is negatively regulated by
DNA-bound dimers containing T and D, respectively. The equations androgens and is modeled as a piecewise linear function with a minimal basal
for DNA occupancy are given by synthesis rate KLH LH LH
3 . Parameters K1 and K2 represent the slope and y-intercept
(respectively) of the leftmost linear piece. Weighted free androgen concentra-
CTTj ⫹ CDDj ⫹ CDTj
DNAo j ⫽ , j ⫽ cd,sec,cp,5a (26) tion reflects the stronger relative potency of DHT vs. T for LH synthesis
CDNAj inhibition. Parameters are detailed in Table 4.

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E958 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION
AR concentrations. Although the AR has been shown to be up-
regulated by androgens (48), here we make the simplifying assump-
tion that prostatic AR is produced at a constant rate and free AR is
eliminated at a linearly proportional rate. We further assume that
androgen-bound AR is not available for elimination. The equations for
total AR amount and concentration, respectively, are as follows:
dAR AR
⫽ k1R ⫺ keRCRf, CR ⫽ (30)
dt Vp
Recall that the concentration of free prostatic AR is given in Eq. 24.
Prostatic blood flow. Although it has been shown that prostatic
blood flow decreases almost immediately after castration (45), here
we make the simplifying assumption that the blood flow to the
prostate is proportional to the volume of the prostatic cell mass Vpc:
Q p ⫽ kQpVpc (31)
5␣-Reductase activity. The activity of 5␣-reductase and, hence, the
metabolism of T are regulated by AR binding and signaling (18, 43).
Here, we assume that Vmax is directly proportional to the occupancy,
DNAo5a, of the representative 5␣-reductase gene:
V max ⫽ k5aDNAo5a共t兲 (32)
Androgen-sensitive prostatic cellular mass. On the basis of exper-
imental data (11, 42), we assume that the prostate contains a basal
cellular mass, VPC2, that is not affected by androgens and an andro-
gen-sensitive cellular mass that is regulated via the occupancy of the
representative cell proliferation and apoptosis genes (Fig. 4). The
equation for the volume of the androgen-sensitive cellular mass is as
follows:
dVPC 1 VPC1共t兲
⫽ kcp1DNAocp ⫺ kcd1共1 ⫺ DNAocd兲VPC1共t兲 (33)
dt VPC1b
This is based on the assumption that the proliferation rate is propor-
tional to the occupancy DNAocp of the representative cell prolifera-
tion gene and that the rate of cell formation increases with prostate
cellular mass. Moreover, the death rate is negatively related to the
occupancy DNAocd of the representative apoptosis gene, since in this
case DNA occupancy results in protection from apoptosis (36).
Androgen-sensitive prostatic ductal lumen mass. As with the pros-
tate cellular mass, we assume that there is a basal amount VPL2 of the
ductal lumen that remains unaffected by androgen concentrations and
an androgen-sensitive amount that is regulated by the representative
Fig. 4. Prostate cell mass and duct lumen subcompartments. Basal cell mass
and duct lumen subcompartments have constant volumes, whereas androgen-
sensitive cell mass subcompartments are regulated by androgens and vary with
time. Model variables and parameters are detailed in Tables 1 and 2.
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fluid production gene in the model. The governing equation is given
by
dVPL 1 VPC1共t兲
⫽ ksecDNAosec ⫺ kfloVPL1 (34)
dt VPC1b
The growth rate of the ductal lumen is proportional to the occupancy
DNAosec of the representative fluid production gene and the size of
the androgen-sensitive prostate cellular mass relative to the intact,
steady-state cellular mass VPC1b. Specifically, when cellular mass
decreases following castration or antiandrogen exposure, the rate of
fluid production concurrently decreases, since there are fewer cells
present to secrete fluid. We also assume that there is linear degrada-
tion of ductal lumen as fluid exits the prostate.
The rate constants for cell proliferation and apoptosis in Eq. 33
were chosen so that both terms of the equation are equal when the
model reaches intact steady-state values, thus yielding equilibrium
and no change in prostate cellular mass. The rate constants for fluid
secretion and fluid flow in Eq. 34 were chosen similarly so that the
entire ventral prostate is at equilibrium when steady-state values are
reached.
Note that in Eqs. 33 and 34, the ratio VPC1(t)/VPC1b can become
unbounded under conditions of supernormal hormone levels and
prostate growth. However, in the scope of these modeling efforts,
supernormal hormone levels will not be simulated, and therefore
supernormal prostate volumes are not expected. If one were to use the
model under conditions of supernormal hormone levels, it would be
necessary to address this limitation, likely using experimental data
from androgen implant experiments in intact and castrated rats to
define an appropriate function.
Algebraic equation for prostate volume. Adding the basal and
androgen-sensitive volumes of the prostate cellular mass and ductal
lumen mass in the model, we are able to compute the total volume of
the prostate as a function of time:
V p共t兲 ⫽ VPC1共t兲 ⫹ VPC2 ⫹ VPL1共t兲 ⫹ VPL2 (35)
Model Implementation and Calibration
The model was implemented computationally in Matlab (The
Mathworks, Natick, MA). Parameters for the model were chosen on
the basis of values from the literature where possible. Other parameter
values were estimated by comparison with experimental data, and a
selected set was reestimated using standard least squares parameter
estimation techniques (51).
One parameter estimation problem was formulated to estimate
pharmacokinetic parameters such as tissue/blood partition coefficients
and the feedback parameters for LH and T synthesis. These parame-
ters were estimated using a submodel that contains only the pharma-
cokinetics of T, DHT, and LH without any of the pharmacodynamic
phenomena. The estimation problem involved comparing submodel
simulations to intact and castrate steady-state values and data as in (6).
A second parameter estimation problem was formulated with the
full model to estimate pharmacodynamic parameters, such as binding
constants, prostatic fluid production rate, 5␣-reductase Vmax, and
prostatic cell proliferation and death rates. These parameters were
estimated in comparison with intact and castrate steady-state behav-
iors and the dynamics of prostate regression following castration.
The third and final estimation problem was formulated with the full
model and included all parameters estimated in the first two estima-
tion problems, where the initial value for each unknown parameter
was the optimal value obtained from the respective previous estima-
tion problem. This allowed for a more accurate fit to the overall
model, since a submodel was used in the first problem to estimate
reasonable starting points for the pharmacokinetic parameters. Model
fits using the final parameter values are presented in RESULTS. A
complete list of model parameters with values and references is given
in Tables 2– 4.
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 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION E959
Table 5. Comparison of model-simulated intact and castrate
steady-state values with experimental data
Intact Steady State Castrate Steady State

Hormone Model Experimental data Model Experimental data

Serum T, nM 7.6 7.6 (6) 0.31 See RESULTS

Free serum T, % 8.3 22.0 (49) 8.3 NA
Prostatic T, nM 11.4 12.1 (31) 1.13 NA
Free prostatic T, % 17.4 6.7 (55) 26.2 NA
T in IF, nM 307.3 307.0 (6)
Serum DHT, nM 0.59 0.6 (31) 0.01 0.07 (17)
Free serum DHT, % 5.5 18.0 (49) 5.46 NA
Prostatic DHT, nM 52.5 53 (42) 0.09 NA
Free prostatic DHT, % 10.8 NA 19.2 NA
Serum LH, nM 0.104 0.104 (6) 1.49 NA

RESULTS
The model was used to predict the dynamics of androgen
levels and prostate regulation under various conditions, includ-
ing the intact steady state, exogenous dosing of T via intrave-
nous injections, and castration. The simulations reported in this
section vary in time duration from 8 h to 30 days. Although rats
grow significantly in the time span of 30 days and the prostate
grows at a similar rate to the whole body (8, 37), we assume a
constant body mass in the model and report all simulations and
experimental data as fractions of intact values.
Predicting Steady-State Concentrations
Table 5 reports steady-state concentrations of T, LH, and
DHT in serum and various tissues for intact and castrate
conditions. These concentrations were obtained by simulating
an unperturbed intact or castrate state until equilibrium was
obtained for all model species. The results given in Table 5
suggest that the model is capable of predicting both intact and
castrate steady-state concentrations of T, DHT, and LH com-
pared with the data.
Simulating an Intravenous Dose of T
Results of a simulated intravenous injection of 0.02 nmol T
are shown in Fig. 5, which depicts time courses for T and LH
concentrations in blood and T concentrations in the testes. The
plots illustrate the ability of the model to simulate T and LH
regulation in serum and the testes after a perturbation of the
intact steady-state system. Note the immediate spike in serum
T concentrations from the steady-state concentration of 7.6
nM, and the resulting acute decrease in serum LH concentra-
Fig. 6. Effects of castration on serum T. Model simulations (solid line) are
compared with experimental data as a fraction of intact values.
tions, followed by decaying oscillatory effects due to the
stabilizing ability of the feedback system. After ⬃4 h from the
time of injection, the system is essentially stable.
Simulating Serum T Levels After Castration
Systemic T concentrations drop rapidly following castration
(9, 26). Data show that, within the first 30 min, serum T levels
drop to ⬃15% of intact values. After 6 h, serum T levels are
reported to be less than 5% of intact values. Figure 6 depicts
these data and the corresponding model prediction. Serum T in
castrated rats is often close to assay detection limits and is quite
variable, as evidenced by values ranging from 0.4 to 5% of
intact values in Kyprianou and Isaacs (26). Therefore, an
extratesticular synthesis rate of T included in the systemic
serum compartmental model was calibrated to give 5% of
intact levels, which yielded a good overall fit with all of the
experimental data used to calibrate the model.
Simulating Regression of the Prostate Postcastration
Suzuki et al. (48) report substantial decreases in prostatic
AR levels in response to castration. Figure 7 depicts the model
prediction vs. the experimental data. As can be seen, the
predicted AR levels at each time point are within the given
error bars for the data.
Several studies have demonstrated a sigmoidal decrease in
prostate weight in time after castration (27, 28, 40, 42). Figure

Fig. 5. Simulated T and LH concentrations following iv

injection with 0.02 nmol T. After initial perturbation of
the steady-state system (serum T 7.6 nM, serum LH
0.10 nM), feedback between T and LH forces the
system back to near-equilibrium within 4 h. The imme-
diate spike in serum T due to the injection causes an
immediate drop in LH levels, resulting in an acute
decrease in T production in the testes, demonstrated by
the drop in concentration depicted. Resulting waves in
plots are due to feedback mechanisms forcing the sys-
tem to equilibrium.

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E960 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION
Fig. 7. Effects of castration on prostatic AR levels. Model simulations (solid
line) are compared with experimental data as a fraction of intact values.
8 includes model predictions of postcastration prostate weight
vs. experimental data. The model predictions match well with
a majority of the data across the different experiments. More-
over, the simulations suggest that the prostate has lost all
androgen-sensitive cellular mass and ductal lumen mass by
about the 11th day after castration. The remaining androgen-
insensitive prostate mass is ⬃16.4% of the total intact mass.
In addition to predicting the time course of the entire
prostate volume after castration, model simulations capture the
regression of the ductal lumen component. Figure 9 depicts
model predictions of the ductal lumen mass after castration
compared with experimental data (42), showing a good match
between the data and the model.
As illustrated by the experimental data presented in Figs.
6 –9, there is a clear sequence of regulatory events that occurs
after castration, leading to decreased prostate weight. Within
1 h, there is a sharp decrease in serum androgen concentrations
followed by a drop in prostatic AR levels over a couple of
days. As AR concentrations decrease, the prostate responds
more slowly with decreased fluid production, so that the ductal
lumen mass shrinks to less than 10% of the intact mass within
a week. Finally, the prostatic cellular mass regresses at a
Fig. 8. Effects of castration on prostate weight. Model simulations (solid line)
are compared with experimental data as a fraction of intact values.
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Fig. 9. Effects of castration on prostatic ductal lumen mass. Model simulations
(solid line) are compared with experimental data.
slower pace, reaching its minimum ⬃2 wk after castration.
These dynamics, which are shown together with corresponding
model simulations in Fig. 10, are consistent with a gene-
regulatory delay in the prostatic response to androgen removal.
Model Validation
The predictive accuracy of the model was tested by com-
paring simulations with experimental data that were not used in
the calibration process. These include prostatic blood flow rate
measurements after castration as well as additional data for
postcastration regression of the prostate. Figure 11 depicts
model simulations compared with the additional prostate
weight and blood flow data. The model accurately predicts the
prostate weight data, although it overpredicts the weight at 72 h
postcastration. The data from these two studies at this partic-
ular time point happen to be significantly lower than data at the
same point from the studies used to calibrate the model (see
Fig. 8), which explains why the model is overpredicting the
new data.
Moreover, the model predictions for prostatic blood flow
rate after castration are reasonably accurate compared with the
data (Fig. 11). Note that no prostatic blood flow data were used
in the model calibration process, so the accurate prediction of
prostatic blood flow helps to further validate the model as a
plausible representation of the biology. Because the current
state of the model approximates the relationship between blood
flow and tissue volume without describing the complex causal
relationship (24, 36a), these results may further suggest that the
simplified description provides a reasonable approximation of
prostatic blood flow behavior.
DISCUSSION
The objective of this research effort was to understand the
normal adult male hormonal regulation of the prostate as a
foundation for quantitatively characterizing the effects of en-
vironmental or pharmaceutical antiandrogen exposure in male
rats. Because it is impossible to capture all physiological and
biological details in a mathematical model, a typical approach
is to describe the critical determinants of biological behavior
while reasonably simplifying many other details. The result is
a model that is a mix of mechanistic and empirical elements.
The goal is then to obtain a parameter set that produces
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 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION E961

Fig. 10. Timing of postcastration events. Model simu-

lations (solid lines) are compared with experimental
data for serum T, DHT, prostatic AR, prostate weight,
and weight of prostate cell mass and ductal lumen mass
as a fraction of intact values.

biologically plausible behavior and that matches well with
available experimental data.
The model captures the kinetics of the endogenous andro-
gens and their regulatory effects on the size and function of the
prostate in the adult male rat. It also is capable of simulating
intact steady-state conditions and accurately predicting the
experimentally observed sequence of events that occurs after
castration, including the immediate drop in serum androgen
concentrations.
The model also captures the cascade of events that occur
following castration and rapid elimination of circulating T
(except for continuing low levels of adrenal production). The
hypothesis is incorporated that the binding affinities of T and
DHT for AR are similar to what is reported in Ref. 53, with
equilibrium dissociation constants of 0.49 and 0.34 nM, re-
spectively, but rapid degradation of free AR is prevented by the
two androgens to different extents due to the approximately
threefold faster on and off rates for T than for DHT (53, 54).
Thus the greater potency of DHT for gene activation in this
model in part reflects greater stability of the receptor ligand
complex. This stability initially mitigates the rapid decline in
serum T (occurring in hours), so that prostatic AR declines
over days. The consequences of declining AR show up first in
diminished gene occupancy related to 5␣-reductase activity,
production of prostatic fluid, and finally in decreased cell
proliferation and increased apoptosis (40). This sequence of
events is accurately captured by the model simulations of
postcastration dynamics.
Although cell proliferation, apoptosis, and fluid secretion are
each regulated by multiple genes, characterizing each process
with a single gene proved to be a reasonable simplification.
These simplified empirical descriptions of known complex
biological processes can be augmented if necessary to include
greater mechanistic details. Such details may then be incorpo-
rated into the model as needed, based on the particular problem
to be solved.
This model has a description of the central axis feedback
between LH and T that revises that used in Barton and
Andersen (6). The new description returns to the same steady
state for serum concentrations of T in intact animals after
perturbations such as an intravenous dose of T or an implant
releasing constant levels of T at physiological or lower con-
centrations (simulations not shown). The previous model
would establish a new different steady state for serum T
concentrations. Experimental data are not entirely consistent
on this issue, although return to control steady-state T levels in
intact animals with implants giving physiological or lower
serum T concentrations is reported by Darras et al. (11),
Perheentupa et al. (38), and Zirkin et al. (56), supporting the
new empirical description of the feedback mechanism.
In a case where limited data are available to qualitatively or
quantitatively capture the underlying biology of the central axis

Fig. 11. Model validation. Model simulations (solid lines) are compared with experimental data for prostate weight (left) and prostatic blood flow (right)
following castration as a fraction of intact values. Data shown here were not included in the parameter estimation process.

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E962 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION
feedback, the model can serve as a tool to test different
hypotheses about biological mechanisms. Current efforts are
underway to explore the dynamics of androgens and prostate
mass in response to external androgen implants. Model simu-
lations may be able to motivate new experiments to help
elucidate the regulatory mechanisms of androgen levels and
AR-mediated prostate maintenance under different hormonal
conditions.
This model has 25 unknown parameters that needed to be
estimated compared with experimental data. This must be
addressed carefully to minimize problems of mathematical
ill-posedness and to maximize the biological plausibility of the
model. Parameter estimation problems often are subject to
ill-posedness, which means that there may not be a solution to
the problem, there may be more than one solution, or the
problem may be highly sensitive to perturbations in data or
parameters (25).
In this case, the unknown parameters first were separated
into two subsets based on function and estimated using two
separate estimation problems. As described in METHODS, the
pharmacokinetic parameters were estimated by comparing a
pharmacokinetic submodel to measurements of steady-state
androgen concentrations as in Ref. 6, while the pharmacody-
namic parameters were estimated using the full model com-
pared with steady-state concentrations and measurements of
postcastration dynamics.
This approach helped address ill-posedness by splitting the
estimation into two problems, effectively reducing the size of
the unknown parameter space for each problem. Moreover, the
parameters to be estimated were grouped with experimental
data that were more directly related to the relevant biology for
each parameter subset (pharmacokinetic vs. pharmacody-
namic). Incorporating a variety of experimental data also can
help reduce ill-posedness by requiring the model to reproduce
multiple behaviors. In particular, the postcastration dynamics
data represent measurements of several different model vari-
ables in time, so that the resulting model simulations capture
the biology over several time scales and complexity scales
ranging from the receptor level up to the tissue and systemic
levels.
The final step involved solving a third estimation problem
for all parameters from the first two problems using the full
model. Because the pharmacokinetic parameters were esti-
mated using a submodel, it was important to reestimate all
parameters together. The pharmacokinetic submodel did not
contain androgen binding to AR, which can significantly alter
tissue concentrations by sequestering T and DHT in the pros-
tate, for example. The third estimation problem allowed for
recalibration of the pharmacokinetic (as well as pharmacody-
namic) parameters by taking the full model into account. The
resulting final parameter values did not significantly change the
model fits to the data for postcastration dynamics but did
improve the predictions of steady-state androgen tissue con-
centrations. The parameters that changed the most after the
third estimation problem were related to LH synthesis, albu-
min-androgen binding rates, tissue partition coefficients, and
the Vmax for 5␣-reductase in the liver. Overall, the final
parameter set provides a good fit to the wide variety of data
used in the calibration process.
The results presented here show the ability of the model to
reproduce a variety of different biological behaviors, including
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the intact and castrate steady-state conditions, as well as the
dynamics of androgens and the regression of the prostate
following castration. Model simulations match well with mul-
tiple types of experimental measurements on both the systemic
and tissue-specific levels, including hormone and AR concen-
trations, prostatic blood flow, enzymatic activity of 5␣-reduc-
tase, and AR-mediated regulation of prostate size and function.
Based on these results, the model and the estimated param-
eter set seem to provide a plausible representation of the
biology. This is further supported by simulations showing that
the model matches well with postcastration prostatic blood
flow data that were not used in the model calibration process.
This model validation can be further enhanced as additional
experimental data become available.
By using a systems approach to the gene-regulated processes
involved in prostate maintenance, this model may be used as a
tool for data analysis, generating and testing hypotheses, and
experimental design in the research of the prostate. Moreover,
the design of this model can serve as a template for developing
models for many other gene-regulated biological processes.
The PBPK backbone efficiently describes the transport of
relevant compounds through the tissues, while the tissue-
specific pharmacodynamic submodel captures key biological
activity related to protein synthesis and signal transduction.
The versatility of the model and its capability of capturing
the dynamics of prostate behavior under varying conditions
make it useful in both toxicological and pharmaceutical set-
tings. Because some pesticides have androgen-antagonistic
properties (5), augmentation of the model to simulate the
kinetics and effects of androgen antagonist exposure would
make it a suitable tool for risk assessment. Furthermore, with
enhancements, the model is a potential drug development tool
to predict a response to administration of 5␣-reductase inhib-
itors and androgen antagonists. Both classes of antiandrogens
are frequently used in therapies to treat diseases such as benign
prostatic hyperplasia and prostate cancer. By calibrating the
model with experimental data for a given antiandrogen, the
model then can be used to predict the aggregate effect on the
prostate of similar compounds by adjusting compound-specific
parameters such as binding constants. This type of analysis can
yield crucial decision-making estimates of EC50, Emax, and
efficacious dose ranges and frequencies, as well as the ability
to quantitatively link biomarker data to clinical drug efficacy.
The ability of the model to be expanded allows for the
potential to address a broad range of issues associated with
male reproductive function, especially prostate function and
maintenance. One major objective is to characterize the effects
of prepubertal exposure to antiandrogens, such as vinclozolin,
in male rats, because this has been proposed as a bioassay for
detecting compounds with endocrine disrupting activity (47).
This will involve adapting the model to describe the normal
pubertal maturation process as well as the effects on that
process that result from prepubertal vinclozolin exposure. Such
an elaboration will require modeling prepubertal regulation
dominated by androstanediol and the transition to adult andro-
gen regulation dominated by T and DHT. These modeling
efforts will provide a quantitative means for understanding the
dynamic changes in the male reproductive endocrine system
that occur during pubertal development, such as tissue growth,
androgen production in the testes, and concentrations of an-
drogens and binding proteins (2, 3, 13, 14, 34, 44, 47). The
291 • NOVEMBER 2006 • www.ajpendo.org
 MATHEMATICAL MODEL FOR ANDROGENIC PROSTATE REGULATION
pubertal model will also aid in quantitatively describing how
antiandrogens interfere with these pubertal changes, enhance
understanding of the dose-response relationships, and improve
accuracy in the risk assessment of these chemicals (5).
ACKNOWLEDGMENTS
We thank Dr. Roger Rittmaster (GlaxoSmithKline, Research Triangle Park,
NC) and colleagues at Dalhousie University (Halifax, NS, Canada) for pro-
viding us with experimental data.
L. K. Potter’s current address: Scientific Computing & Mathematical
Modeling, GlaxoSmithKline, Research Triangle Park, NC 27709.
M. G. Zager’s current address: Pharmacokinetics, Dynamics and Metabo-
lism, La Jolla Laboratories, Pfizer, Inc., San Diego, CA 92121.
GRANTS
L. K. Potter and M. G. Zager were funded by the Environmental Protection
Agency (EPA)/University of North Carolina Toxicology Research Program,
Training Agreement TA-829472, with the Curriculum in Toxicology, Univer-
sity of North Carolina, Chapel Hill, NC. This work was reviewed by the EPA
and approved for publication but does not necessarily reflect official Agency
policy. Mention of trade names or commercial products does not constitute
endorsement or recommendation by the EPA for use.
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