<?xml version="1.0"?>
<!-- FILE : schlosser_model_2000.xml
CREATED : 20th June 2007
LAST MODIFIED : 20th June 2007
AUTHOR : Catherine Lloyd
Bioengineering Institute
The University of Auckland
MODEL STATUS : This model conforms to the CellML 1.1 Specification.
DESCRIPTION : This file contains a CellML description of Schlosser and Selgrade's 2000 mathematical model of gonadotropin regulation during the menstrual cycle in women.
CHANGES:
-->
<model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" cmeta:id="schlosser_model_2000" name="schlosser_model_2000">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Modelling Gonadotropin Regulation during the Menstrual Cycle in Women</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This CellML model runs in OpenCell to recreate the pubslihed results. The model also runs in COR but due to the time unit being days the model is not ideal for simulation in COR (where the default unit of time is ms). The units have been checked and they are consistent. The LH system (eq 1a-1e) and the FSH system (eq 2a-2e) are both described in this CellML model. Parameter values have been taken from tables 1 and 2 in the original published paper. We were unable to represent the time delays in equations 1c and 2c.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
Abstract: Increasing concerns that environmental contaminants may disrupt the endocrine system require development of mathematical tools to predict the potential for such compounds to significantly alter human endocrine function. The endocrine system is largely self-regulating, compensating for moderate changes in dietary phytoestrogens (e.g., in soy products) and normal variations in physiology. However, severe changes in dietary or oral exposures or in health status (e.g., anorexia) , can completely disrupt the menstrual cycle in women. Thus, risk assessment tools should account for normal regulation and its limits. We present a mathematical model for the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in women as a function of estrogen, progesterone, and inhibin blood levels. The model reproduces the time courses of LH and FSH during the menstrual cycle and correctly predicts observed effects of administered estrogen and progesterone on LH and FSH during clinical studies. The model should be useful for predicting effects of hormonally active substances, both in the pharmaceutical sciences and in toxicology and risk assessment.
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="schlosser_2000.png"/>
</imageobject>
</mediaobject>
<caption>Schematic diagram of the mathematical model of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and release. Solid arrows represent pathways of synthesis (syn), release into the blood (rel), and clearance from the blood (clear). Dashed arrows represent regulatory pathways, either positive (+) or negative (-), with feedback from estradiol (E2), progesterone (P4), and inhibin (Ih).</caption>
</informalfigure>
<para>
The original paper reference is cited below:
</para>
<para>
A model of gonadotropin regulation during the menstrual cycle in women: qualitative features Paul M. Schlosser and James F. Selgrade, 2000,
<emphasis>Environmental Health Perspectives</emphasis>, 108, 873-881. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11035997&query_hl=1&itool=pubmed_docsum">PubMed ID: 11035997</ulink>
</para>
</sect1>
</article>
</documentation>
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<unit multiplier="86400.0" units="second"/>
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<units base_units="yes" name="U"/>
<units name="U_L">
<unit units="U"/>
<unit exponent="-1" units="litre"/>
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<units name="U_L_day">
<unit units="U_L"/>
<unit exponent="-1" units="day"/>
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<units name="day2">
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<units name="ng_L">
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<units name="ng_L_day">
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<unit exponent="-1" units="day"/>
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<units name="L_ng">
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<units name="L_nmol">
<unit units="litre"/>
<unit exponent="-1" prefix="nano" units="mole"/>
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<units name="L_ng2">
<unit exponent="2" units="L_ng"/>
</units>
<units name="microg">
<unit prefix="micro" units="gram"/>
</units>
<units name="microg_l">
<unit prefix="micro" units="gram"/>
<unit exponent="-1" units="litre"/>
</units>
<units name="microg_day">
<unit prefix="micro" units="gram"/>
<unit exponent="-1" units="day"/>
</units>
<units name="microg_l_day">
<unit prefix="micro" units="gram"/>
<unit exponent="-1" units="litre"/>
<unit exponent="-1" units="day"/>
</units>
<units name="first_order_rate_constant">
<unit exponent="-1" units="day"/>
</units>
<component name="environment">
<variable cmeta:id="environment_time" name="time" public_interface="out" units="day"/>
</component>
<component cmeta:id="RP_LH" name="RP_LH">
<variable cmeta:id="RP_LH_rel_LH_E2_P4_RP_LH" name="rel_LH_E2_P4_RP_LH" public_interface="out" units="microg_day"/>
<variable cmeta:id="RP_LH_RP_LH" initial_value="467.0" name="RP_LH" units="microg"/>
<variable cmeta:id="RP_LH_syn_LH_E2_P4" name="syn_LH_E2_P4" units="microg_day"/>
<variable initial_value="1400.0" name="V0_LH" units="microg_day"/>
<variable initial_value="95900.0" name="V1_LH" units="microg_day"/>
<variable initial_value="8.0" name="h" units="dimensionless"/>
<variable initial_value="360.0" name="Km_LH" units="ng_L"/>
<variable initial_value="26.0" name="Ki_LHP" units="nmol_L"/>
<variable initial_value="3.0" name="kLH_rel" units="first_order_rate_constant"/>
<variable initial_value="0.024" name="CLH_P" units="L_nmol"/>
<variable initial_value="0.008" name="CLH_E" units="L_ng"/>
<variable name="E2" public_interface="in" units="ng_L"/>
<variable name="E2_dE" public_interface="in" units="ng_L"/>
<variable name="P4" public_interface="in" units="nmol_L"/>
<variable name="P4_dP" public_interface="in" units="nmol_L"/>
<variable name="time" public_interface="in" units="day"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> RP_LH </ci>
</apply>
<apply>
<minus/>
<ci> syn_LH_E2_P4 </ci>
<ci> rel_LH_E2_P4_RP_LH </ci>
</apply>
</apply>
<apply id="syn_LH_E2_P4_calculation">
<eq/>
<ci> syn_LH_E2_P4 </ci>
<apply>
<divide/>
<apply>
<plus/>
<ci> V0_LH </ci>
<apply>
<divide/>
<apply>
<times/>
<ci> V1_LH </ci>
<apply>
<power/>
<ci> E2_dE </ci>
<ci> h </ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<power/>
<ci> Km_LH </ci>
<ci> h </ci>
</apply>
<apply>
<power/>
<ci> E2_dE </ci>
<ci> h </ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<divide/>
<ci> P4_dP </ci>
<ci> Ki_LHP </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="rel_LH_E2_P4_RP_LH_calculation">
<eq/>
<ci> rel_LH_E2_P4_RP_LH </ci>
<apply>
<divide/>
<apply>
<times/>
<ci> kLH_rel </ci>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<times/>
<ci> CLH_P </ci>
<ci> P4 </ci>
</apply>
</apply>
<ci> RP_LH </ci>
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<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<times/>
<ci> CLH_E </ci>
<ci> E2 </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="LH" name="LH">
<variable cmeta:id="LH_LH" initial_value="40.0" name="LH" units="microg_l"/>
<variable initial_value="2.5" name="v_dis" units="litre"/>
<variable name="clear_LH" units="microg_l_day"/>
<variable initial_value="14.0" name="kLH_cl" units="first_order_rate_constant"/>
<variable name="rel_LH_E2_P4_RP_LH" public_interface="in" units="microg_day"/>
<variable name="time" public_interface="in" units="day"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci> LH </ci>
</apply>
<apply>
<minus/>
<apply>
<divide/>
<ci> rel_LH_E2_P4_RP_LH </ci>
<ci> v_dis </ci>
</apply>
<ci> clear_LH </ci>
</apply>
</apply>
<apply id="clear_LH_calculation">
<eq/>
<ci> clear_LH </ci>
<apply>
<times/>
<ci> kLH_cl </ci>
<ci> LH </ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="RP_FSH" name="RP_FSH">
<variable cmeta:id="RP_FSH_rel_FSH_E2_P4_RP_FSH" name="rel_FSH_E2_P4_RP_FSH" public_interface="out" units="microg_day"/>
<variable cmeta:id="RP_FSH_RP_FSH" initial_value="0.0" name="RP_FSH" units="microg"/>
<variable cmeta:id="RP_FSH_syn_FSH_Ih" name="syn_FSH_Ih" units="microg_day"/>
<variable initial_value="4400.0" name="V_FSH" units="microg_day"/>
<variable initial_value="1176.5" name="Ki_FSH_Ih" units="U_L"/>
<variable initial_value="45.0" name="kFSH_rel" units="first_order_rate_constant"/>
<variable initial_value="3.0" name="CFSH_P" units="L_nmol"/>
<variable initial_value="0.005" name="CFSH_E" units="L_ng2"/>
<variable name="Ih_dIh" public_interface="in" units="U_L"/>
<variable name="E2" public_interface="in" units="ng_L"/>
<variable name="P4" public_interface="in" units="nmol_L"/>
<variable name="time" public_interface="in" units="day"/>
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<ci> syn_FSH_Ih </ci>
<ci> rel_FSH_E2_P4_RP_FSH </ci>
</apply>
</apply>
<apply id="syn_FSH_Ih_calculation">
<eq/>
<ci> syn_FSH_Ih </ci>
<apply>
<divide/>
<ci> V_FSH </ci>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<divide/>
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<ci> Ki_FSH_Ih </ci>
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</apply>
</apply>
</apply>
<apply id="rel_FSH_E2_P4_RP_FSH_calculation">
<eq/>
<ci> rel_FSH_E2_P4_RP_FSH </ci>
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<divide/>
<apply>
<times/>
<ci> kFSH_rel </ci>
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<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<times/>
<ci> CFSH_P </ci>
<ci> P4 </ci>
</apply>
</apply>
<ci> RP_FSH </ci>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 1.0 </cn>
<apply>
<times/>
<ci> CFSH_E </ci>
<apply>
<power/>
<ci> E2 </ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 2.0 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="FSH" name="FSH">
<variable cmeta:id="FSH_FSH" initial_value="150.0" name="FSH" units="microg_l"/>
<variable initial_value="2.5" name="v_dis" units="litre"/>
<variable name="clear_FSH" units="microg_l_day"/>
<variable initial_value="8.21" name="kFSH_cl" units="first_order_rate_constant"/>
<variable name="rel_FSH_E2_P4_RP_FSH" public_interface="in" units="microg_day"/>
<variable name="time" public_interface="in" units="day"/>
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<ci> v_dis </ci>
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<ci> clear_FSH </ci>
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</apply>
<apply id="clear_FSH_calculation">
<eq/>
<ci> clear_FSH </ci>
<apply>
<times/>
<ci> kFSH_cl </ci>
<ci> FSH </ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="E2" name="E2">
<variable cmeta:id="E2_E2" name="E2" public_interface="out" units="ng_L"/>
<variable name="time" public_interface="in" units="day"/>
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<eq/>
<ci> E2 </ci>
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<variable name="time" public_interface="in" units="day"/>
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<variable name="time" public_interface="in" units="day"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
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<variable name="time" public_interface="in" units="day"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
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<ci> P4_dP </ci>
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<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="nmol_L"> 52.0 </cn>
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<ci> time </ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="day"> 7.0 </cn>
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Schlosser and Selgrade's 2000 mathematical model of gonadotropin regulation during the menstrual cycle in women.
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<dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">estradiol concentration at a time with a delay</dcterms:alternative>
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<vCard:FN xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">Catherine Lloyd</vCard:FN>
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<dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">inhibin concentration at a time with a delay</dcterms:alternative>
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<dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">blood concentration of follicle-stimulating hormone</dcterms:alternative>
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<dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">A model of gonadotropin regulation during the menstrual cycle in women: qualitative features</dc:title>
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<rdf:value>The units are consistent and the model runs in PCEnv to give the published results - one note: to recreate all the published results will require different variants of the model (or CellML1.1 to import different initial conditions and parameter values) because the conditions for each result were different.</rdf:value>
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<rdf:value>I've run the model in COR and in the process corrected all the units such that they are now consistent. I also altered a couple of the equations - in this case CellML could handle the time delays because they were fixed - and the model now runs in PCEnv to give the published results.</rdf:value>
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