/* * Model-projected mechanistic bases for sex differences in growth * hormone regulation in humans * * 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 males 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 * * [[Image file: farhy_model_2007.gif]] * * 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. */ import nsrunit; unit conversion on; unit ng_ml=1E-6 kilogram^1*meter^(-3); unit pg_ml=1E-9 kilogram^1*meter^(-3); unit hour=3600 second^1; unit first_order_rate_constant=2.7777778E-4 second^(-1); unit ng_ml_hr=2.7777778E-10 kilogram^1*meter^(-3)*second^(-1); unit pg_ml_hr=2.7777778E-13 kilogram^1*meter^(-3)*second^(-1); math main { realDomain time hour; time.min=0; extern time.max; extern time.delta; real GH(time) ng_ml; when(time=time.min) GH=0.0; real GHS dimensionless; GHS=20.0; real k1 first_order_rate_constant; k1=3.0; real kr1 ng_ml_hr; kr1=600.0; real t1 pg_ml; t1=400.0; real n1 dimensionless; n1=5.0; real n2 dimensionless; n2=2.0; real g0 dimensionless; g0=1.0; real ng0 dimensionless; ng0=2.9; real tg0 dimensionless; tg0=200.0; real t2 pg_ml; t2=10.0; real SRIF_PeV(time) pg_ml; when(time=time.min) SRIF_PeV=0.0; real F1_GHS dimensionless; real GHRH(time) pg_ml; when(time=time.min) GHRH=0.0; real ghr_GHRH(time) pg_ml; when(time=time.min) ghr_GHRH=0.0; real k4 first_order_rate_constant; k4=25.0; real kr4 pg_ml_hr; kr4=20400.0; real t5 ng_ml; t5=10.0; real n5 dimensionless; n5=2.0; real S_basal pg_ml_hr; S_basal=900.0; real SRIF_ArC(time) pg_ml; when(time=time.min) SRIF_ArC=0.0; real k2 first_order_rate_constant; k2=25.0; real kr2 pg_ml_hr; kr2=2200.0; real t3 pg_ml; t3=400.0; real n3 dimensionless; n3=2.0; real k3 first_order_rate_constant; k3=40.0; real kr3 pg_ml_hr; kr3=63000.0; real t4 pg_ml; t4=28.0; real n4 dimensionless; n4=5.0; real F2_GHS dimensionless; real g1 dimensionless; g1=45000.0; real g2 dimensionless; g2=100.0; real tg1 dimensionless; tg1=390.0; real tg2 dimensionless; tg2=10000.0; real ng1 dimensionless; ng1=3.0; real ng2 dimensionless; ng2=2.0; real dghr_GHRH_dt(time) pg_ml_hr; real inject(time) pg_ml_hr; real kghr first_order_rate_constant; kghr=15.0; real C pg_ml_hr; C=10000.0; real onset hour; onset=2.0; real duration hour; duration=0.2; // // GH:time=(kr1*(((GHRH+ghr_GHRH)/t1)^n1/(((GHRH+ghr_GHRH)/t1)^n1+1)+g0*((GHS/tg0)^ng0/(1+(GHS/tg0)^ng0))+(1+F1_GHS)/(1+(SRIF_PeV/t2)^n2+F1_GHS))-k1*GH); // SRIF_PeV:time=((-1)*(k4*SRIF_PeV)+kr4*((GH/t5)^n5/((GH/t5)^n5+1))+S_basal); // SRIF_ArC:time=(kr2*(((GHRH+ghr_GHRH)/t3)^n3/(1+((GHRH+ghr_GHRH)/t3)^n3))-k2*SRIF_ArC); // GHRH:time=(kr3*((1+F2_GHS)/(1+((SRIF_PeV+SRIF_ArC)/t4)^n4+F2_GHS))+ghr_GHRH*(1 first_order_rate_constant)-k3*GHRH); // F1_GHS=(g1*((GHS/tg1)^ng1/(1+(GHS/tg1)^ng1))); F2_GHS=(g2*((GHS/tg2)^ng2/(1+(GHS/tg2)^ng2))); // ghr_GHRH:time=(inject-kghr*ghr_GHRH); dghr_GHRH_dt=(inject-kghr*ghr_GHRH); inject=(if (time=onset) and (time<=(onset+duration))) C else if (time>(onset+duration)) (0 pg_ml_hr) else 0); }