Model-projected mechanistic bases for sex differences in growth hormone regulation in humans
Catherine
Lloyd
Auckland Bioengineering Institute, The University of Auckland
Model Status
This model has been curated and is known to run in OpenCell and COR to recreate the published results. The units have been checked and they are consistent. Please note this particular version of the model is specific to females and also GHRH alone is being injected. To simulate the injection of GHS and L-arginine the CellML model will have to be adapted slightly - this is relatively simple to do and will require changing a few initial conditions and parameters according to the description in the original paper.
Model Structure
ABSTRACT: Models of physiological systems facilitate rational experimental design, inference, and prediction. A recent construct of regulated growth hormone (GH) secretion interlinks the actions of GH-releasing hormone (GHRH), somatostatin (SRIF), and GH secretagogues (GHS) with GH feedback in the rat (Farhy LS, Veldhuis JD. Am J Physiol Regul Integr Comp Physiol 288: R1649-R1663, 2005). In contrast, no comparable formalism exists to explicate GH dynamics in any other species. The present analyses explore whether a unifying model structure can represent species- and sex-defined distinctions in the human and rodent. The consensus principle that GHRH and GHS synergize in vivo but not in vitro was explicable by assuming that GHS 1) evokes GHRH release from the brain, 2) opposes inhibition by SRIF both in the hypothalamus and on the pituitary gland, and 3) stimulates pituitary GH release directly and additively with GHRH. The gender-selective principle that GH pulses are larger and more irregular in women than men was conferrable by way of 4) higher GHRH potency and 5) greater GHS efficacy. The overall construct predicts GHRH/GHS synergy in the human only in the presence of SRIF when the brain-pituitary nexus is intact, larger and more irregular GH pulses in women, and observed gender differences in feedback by GH and the single and paired actions of GHRH, GHS, and SRIF. The proposed model platform should enhance the framing and interpretation of novel clinical hypotheses and create a basis for interspecies generalization of GH-axis regulation.
The complete paper reference is cited below:
Model-projected mechanistic bases for sex differences in growth hormone regulation in humans, Leon S. Farhy, Cyril Y. Bowers and Johannes D. Veldhuis, 2006, American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, volume 17, 788-803. PubMed ID: 17185408
model diagram
A schematic diagram of the primary interconnections assumed among growth hormone (GH), growth hormone releasing hormone (GHRH), somatostatin (SRIF) in the periventricular nucleus (SRIF PeV) and arcuate nucleus (SRIF ArC), growth hormone secretagogues (GHS) and GH feedback in the human. The small green arrows denote greater potency (P) or efficacy (E) in women compared with men.
$\frac{d \mathrm{GH}}{d \mathrm{time}}=\mathrm{kr1}(\frac{\left(\frac{\mathrm{GHRH}+\mathrm{ghr\_GHRH}}{\mathrm{t1}}\right)^{\mathrm{n1}}}{\left(\frac{\mathrm{GHRH}+\mathrm{ghr\_GHRH}}{\mathrm{t1}}\right)^{\mathrm{n1}}+1.0}+\mathrm{g0}\frac{\left(\frac{\mathrm{GHS}}{\mathrm{tg0}}\right)^{\mathrm{ng0}}}{1.0+\left(\frac{\mathrm{GHS}}{\mathrm{tg0}}\right)^{\mathrm{ng0}}}+\frac{1.0+\mathrm{F1\_GHS}}{1.0+\left(\frac{\mathrm{SRIF\_PeV}}{\mathrm{t2}}\right)^{\mathrm{n2}}+\mathrm{F1\_GHS}})-\mathrm{k1}\mathrm{GH}$
$\frac{d \mathrm{SRIF\_PeV}}{d \mathrm{time}}=-(\mathrm{k4}\mathrm{SRIF\_PeV})+\mathrm{kr4}\frac{\left(\frac{\mathrm{GH}}{\mathrm{t5}}\right)^{\mathrm{n5}}}{\left(\frac{\mathrm{GH}}{\mathrm{t5}}\right)^{\mathrm{n5}}+1.0}+\mathrm{S\_basal}$
$\frac{d \mathrm{SRIF\_ArC}}{d \mathrm{time}}=\mathrm{kr2}\frac{\left(\frac{\mathrm{GHRH}+\mathrm{ghr\_GHRH}}{\mathrm{t3}}\right)^{\mathrm{n3}}}{1.0+\left(\frac{\mathrm{GHRH}+\mathrm{ghr\_GHRH}}{\mathrm{t3}}\right)^{\mathrm{n3}}}-\mathrm{k2}\mathrm{SRIF\_ArC}$
$\frac{d \mathrm{GHRH}}{d \mathrm{time}}=\mathrm{kr3}\frac{1.0+\mathrm{F2\_GHS}}{1.0+\left(\frac{\mathrm{SRIF\_PeV}+\mathrm{SRIF\_ArC}}{\mathrm{t4}}\right)^{\mathrm{n4}}+\mathrm{F2\_GHS}}+\mathrm{ghr\_GHRH}\times 1.0-\mathrm{k3}\mathrm{GHRH}$
$\mathrm{F1\_GHS}=\mathrm{g1}\frac{\left(\frac{\mathrm{GHS}}{\mathrm{tg1}}\right)^{\mathrm{ng1}}}{1.0+\left(\frac{\mathrm{GHS}}{\mathrm{tg1}}\right)^{\mathrm{ng1}}}\mathrm{F2\_GHS}=\mathrm{g2}\frac{\left(\frac{\mathrm{GHS}}{\mathrm{tg2}}\right)^{\mathrm{ng2}}}{1.0+\left(\frac{\mathrm{GHS}}{\mathrm{tg2}}\right)^{\mathrm{ng2}}}$
$\frac{d \mathrm{ghr\_GHRH}}{d \mathrm{time}}=\mathrm{inject}-\mathrm{kghr}\mathrm{ghr\_GHRH}\mathrm{dghr\_GHRH\_dt}=\mathrm{inject}-\mathrm{kghr}\mathrm{ghr\_GHRH}\mathrm{inject}=\begin{cases}0.0 & \text{if $\mathrm{time}< \mathrm{onset}$}\\ C & \text{if $(\mathrm{time}\ge \mathrm{onset})\land (\mathrm{time}\le \mathrm{onset}+\mathrm{duration})$}\\ 0.0 & \text{if $\mathrm{time}> \mathrm{onset}+\mathrm{duration}$}\end{cases}$
endocrine
somatostatin
hypothalamus
growth hormone releasing hormone
growth hormone
signal transduction
Farhy et al.'s 2007 model-projected mechanistic bases for sex differences in growth hormone regulation in humans.
hypothalamus
This is the CellML description of Farhy et al.'s 2007 model-projected mechanistic bases for sex differences in growth hormone regulation in humans.
Leon
Farhy
S
c.lloyd@auckland.ac.nz
Fixed a couple of equations, checked and corrected the units such that they are now correct and are consistent, and I added a stimulus to the model (in accordance with the stimulus described in the original publication). The model runs in PCEnv and COR to give the published results, but I can't get the model to oscillate because I haven't been able to include the time delays in the CellML code.
growth hormone
GH
simulation of GHRH infusion
ghr_GHRH
2007-09-02T15:10:58+12:00
Catherine Lloyd
Catherine Lloyd
2009-02-12T15:37:52+13:00
keyword
Model-projected mechanistic bases for sex differences in growth hormone regulation in humans.
292
R1577
R1593
Female-specific model and GHRH alone is being injected
The University of Auckland, Auckland Bioengineering Institute
somatostatin in the periventricular nucleus
SRIF_PeV
Added cmeta id's to several variables
somatostatin in the arcuate nucleus
SRIF_ArC
Jeelean
Lim
5
American Journal of Physiololgy. Regulatory, Integrative and Comparative Physiology
2007-04-00 00:00
Cyril
Bowers
Y
2007-06-21T00:00:00+00:00
growth hormone releasing hormone
GHRH
17185408
Catherine
Lloyd
May
Catherine
Lloyd
May
The University of Auckland
Auckland Bioengineering Institute
Fixed a couple of equations, checked and corrected the units such that they are now correct and are consistent, and I added a stimulus to the model (in accordance with the stimulus described in the original publication). The model runs in PCEnv and COR to give the published results, but I can't get the model to oscillate because I haven't been able to include the time delays in the CellML code.
Johannes
Veldhuis
D