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Model informed quantification of the feed‐forward stimulation of growth hormone by growth hormone‐releasing hormone

AIMS: Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This st...

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Autores principales: van Esdonk, Michiel J., Burggraaf, Jacobus, van der Graaf, Piet H., Stevens, Jasper
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373696/
https://www.ncbi.nlm.nih.gov/pubmed/32087619
http://dx.doi.org/10.1111/bcp.14265
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author van Esdonk, Michiel J.
Burggraaf, Jacobus
van der Graaf, Piet H.
Stevens, Jasper
author_facet van Esdonk, Michiel J.
Burggraaf, Jacobus
van der Graaf, Piet H.
Stevens, Jasper
author_sort van Esdonk, Michiel J.
collection PubMed
description AIMS: Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This study reports on the development of a population nonlinear mixed effects model for GH stimulation, incorporating individual GH kinetics and the stimulation of GH by GH‐releasing hormone (GHRH). METHODS: Literature data on the systemic circulation, the median eminence, and the anterior pituitary were included as system parameters in the model. Population parameters were estimated on data from 8 healthy normal weight and 16 obese women who received a 33 μg recombinant human GH dose. The next day, a bolus injection of 100 μg GHRH was given to stimulate GH secretion. RESULTS: The GH kinetics were best described with the addition of 2 distribution compartments with a bodyweight dependent clearance (increasing linearly from 24.7 L/h for a 60‐kg subject to 32.1 L/h for a 100‐kg subject). The model described the data adequately with high parameter precision and significant interindividual variability on the GH clearance and distribution volume. Additionally, high variability in the amount of secreted GH, driven by GHRH receptor activation, was identified (coefficient of variation = 90%). CONCLUSION: The stimulation of GH by GHRH was quantified and significant interindividual variability was identified on multiple parameters. This model sets the stage for further development of by inclusion of additional physiological components to quantify GH secretion in humans.
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spelling pubmed-73736962020-07-22 Model informed quantification of the feed‐forward stimulation of growth hormone by growth hormone‐releasing hormone van Esdonk, Michiel J. Burggraaf, Jacobus van der Graaf, Piet H. Stevens, Jasper Br J Clin Pharmacol Original Articles AIMS: Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This study reports on the development of a population nonlinear mixed effects model for GH stimulation, incorporating individual GH kinetics and the stimulation of GH by GH‐releasing hormone (GHRH). METHODS: Literature data on the systemic circulation, the median eminence, and the anterior pituitary were included as system parameters in the model. Population parameters were estimated on data from 8 healthy normal weight and 16 obese women who received a 33 μg recombinant human GH dose. The next day, a bolus injection of 100 μg GHRH was given to stimulate GH secretion. RESULTS: The GH kinetics were best described with the addition of 2 distribution compartments with a bodyweight dependent clearance (increasing linearly from 24.7 L/h for a 60‐kg subject to 32.1 L/h for a 100‐kg subject). The model described the data adequately with high parameter precision and significant interindividual variability on the GH clearance and distribution volume. Additionally, high variability in the amount of secreted GH, driven by GHRH receptor activation, was identified (coefficient of variation = 90%). CONCLUSION: The stimulation of GH by GHRH was quantified and significant interindividual variability was identified on multiple parameters. This model sets the stage for further development of by inclusion of additional physiological components to quantify GH secretion in humans. John Wiley and Sons Inc. 2020-03-09 2020-08 /pmc/articles/PMC7373696/ /pubmed/32087619 http://dx.doi.org/10.1111/bcp.14265 Text en © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
van Esdonk, Michiel J.
Burggraaf, Jacobus
van der Graaf, Piet H.
Stevens, Jasper
Model informed quantification of the feed‐forward stimulation of growth hormone by growth hormone‐releasing hormone
title Model informed quantification of the feed‐forward stimulation of growth hormone by growth hormone‐releasing hormone
title_full Model informed quantification of the feed‐forward stimulation of growth hormone by growth hormone‐releasing hormone
title_fullStr Model informed quantification of the feed‐forward stimulation of growth hormone by growth hormone‐releasing hormone
title_full_unstemmed Model informed quantification of the feed‐forward stimulation of growth hormone by growth hormone‐releasing hormone
title_short Model informed quantification of the feed‐forward stimulation of growth hormone by growth hormone‐releasing hormone
title_sort model informed quantification of the feed‐forward stimulation of growth hormone by growth hormone‐releasing hormone
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373696/
https://www.ncbi.nlm.nih.gov/pubmed/32087619
http://dx.doi.org/10.1111/bcp.14265
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