Modeling the male reproductive endocrine axis: Potential role for a delay mechanism in the inhibitory action of gonadal steroids on GnRH pulse frequency

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Abstract

Copyright © 2016 by the Endocrine Society. Wedevelopedacompartmentalmodelsowecould test mechanistic concepts in the control of themale reproductive endocrine axis. Using SAAM II computer software and a bank of experimental data from male sheep, we began by modeling GnRH-LH feed-forward and LH-T feedback.Akey assumption was that the primary control signal comes from a hypothetical neural network (the PULSAR) that emits a digital (pulsatile) signalofvariablefrequencythatdrivesGnRHsecretioninsquarewave-likepulses.This model produced endocrine profiles that matched experimental observations for the testis-intact animal and for changes in GnRH pulse frequency after castration and T replacement. In the second stage of the model development, we introduced a delay in the negative feedback caused by the aromatization of T to estradiol at the brain level, a concept supported by empirical observations. The simulations showed how changes in the process of aromatization could affect the response of the pulsatile signal to inhibition by steroid feedback. The sensitivity of the PULSAR to estradiol was a critical factor, but the most striking observation was the effect of time delays. With longer delays, there was a reduction in the rate of aromatization and therefore a decrease in local estradiol concentrations, and the outcome was multiple-pulse events in the secretion of GnRH/LH, reflecting experimental observations. In conclusion, our model successfully emulates the GnRH-LH-T-GnRH loop, accommodates a pivotal role for central aromatization in negative feedback, and suggests that time delays in negative feedback are an important aspect of the control of GnRH pulse frequency.
Original languageEnglish
Pages (from-to)2080-2092
Number of pages13
JournalEndocrinology
Volume157
Issue number5
DOIs
Publication statusPublished - 2016

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Gonadotropin-Releasing Hormone
Steroids
Estradiol
Castration
Testis
Sheep
Software
Observation
Databases
Brain

Cite this

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title = "Modeling the male reproductive endocrine axis: Potential role for a delay mechanism in the inhibitory action of gonadal steroids on GnRH pulse frequency",
abstract = "Copyright {\circledC} 2016 by the Endocrine Society. Wedevelopedacompartmentalmodelsowecould test mechanistic concepts in the control of themale reproductive endocrine axis. Using SAAM II computer software and a bank of experimental data from male sheep, we began by modeling GnRH-LH feed-forward and LH-T feedback.Akey assumption was that the primary control signal comes from a hypothetical neural network (the PULSAR) that emits a digital (pulsatile) signalofvariablefrequencythatdrivesGnRHsecretioninsquarewave-likepulses.This model produced endocrine profiles that matched experimental observations for the testis-intact animal and for changes in GnRH pulse frequency after castration and T replacement. In the second stage of the model development, we introduced a delay in the negative feedback caused by the aromatization of T to estradiol at the brain level, a concept supported by empirical observations. The simulations showed how changes in the process of aromatization could affect the response of the pulsatile signal to inhibition by steroid feedback. The sensitivity of the PULSAR to estradiol was a critical factor, but the most striking observation was the effect of time delays. With longer delays, there was a reduction in the rate of aromatization and therefore a decrease in local estradiol concentrations, and the outcome was multiple-pulse events in the secretion of GnRH/LH, reflecting experimental observations. In conclusion, our model successfully emulates the GnRH-LH-T-GnRH loop, accommodates a pivotal role for central aromatization in negative feedback, and suggests that time delays in negative feedback are an important aspect of the control of GnRH pulse frequency.",
author = "T.R. Ferasyi and Barrett, {Hugh H.} and Dominique Blache and Martin, {Graeme B.}",
year = "2016",
doi = "10.1210/en.2015-1913",
language = "English",
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T1 - Modeling the male reproductive endocrine axis: Potential role for a delay mechanism in the inhibitory action of gonadal steroids on GnRH pulse frequency

AU - Ferasyi, T.R.

AU - Barrett, Hugh H.

AU - Blache, Dominique

AU - Martin, Graeme B.

PY - 2016

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N2 - Copyright © 2016 by the Endocrine Society. Wedevelopedacompartmentalmodelsowecould test mechanistic concepts in the control of themale reproductive endocrine axis. Using SAAM II computer software and a bank of experimental data from male sheep, we began by modeling GnRH-LH feed-forward and LH-T feedback.Akey assumption was that the primary control signal comes from a hypothetical neural network (the PULSAR) that emits a digital (pulsatile) signalofvariablefrequencythatdrivesGnRHsecretioninsquarewave-likepulses.This model produced endocrine profiles that matched experimental observations for the testis-intact animal and for changes in GnRH pulse frequency after castration and T replacement. In the second stage of the model development, we introduced a delay in the negative feedback caused by the aromatization of T to estradiol at the brain level, a concept supported by empirical observations. The simulations showed how changes in the process of aromatization could affect the response of the pulsatile signal to inhibition by steroid feedback. The sensitivity of the PULSAR to estradiol was a critical factor, but the most striking observation was the effect of time delays. With longer delays, there was a reduction in the rate of aromatization and therefore a decrease in local estradiol concentrations, and the outcome was multiple-pulse events in the secretion of GnRH/LH, reflecting experimental observations. In conclusion, our model successfully emulates the GnRH-LH-T-GnRH loop, accommodates a pivotal role for central aromatization in negative feedback, and suggests that time delays in negative feedback are an important aspect of the control of GnRH pulse frequency.

AB - Copyright © 2016 by the Endocrine Society. Wedevelopedacompartmentalmodelsowecould test mechanistic concepts in the control of themale reproductive endocrine axis. Using SAAM II computer software and a bank of experimental data from male sheep, we began by modeling GnRH-LH feed-forward and LH-T feedback.Akey assumption was that the primary control signal comes from a hypothetical neural network (the PULSAR) that emits a digital (pulsatile) signalofvariablefrequencythatdrivesGnRHsecretioninsquarewave-likepulses.This model produced endocrine profiles that matched experimental observations for the testis-intact animal and for changes in GnRH pulse frequency after castration and T replacement. In the second stage of the model development, we introduced a delay in the negative feedback caused by the aromatization of T to estradiol at the brain level, a concept supported by empirical observations. The simulations showed how changes in the process of aromatization could affect the response of the pulsatile signal to inhibition by steroid feedback. The sensitivity of the PULSAR to estradiol was a critical factor, but the most striking observation was the effect of time delays. With longer delays, there was a reduction in the rate of aromatization and therefore a decrease in local estradiol concentrations, and the outcome was multiple-pulse events in the secretion of GnRH/LH, reflecting experimental observations. In conclusion, our model successfully emulates the GnRH-LH-T-GnRH loop, accommodates a pivotal role for central aromatization in negative feedback, and suggests that time delays in negative feedback are an important aspect of the control of GnRH pulse frequency.

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