[Open Access PDF] Modeling The Male Reproductive Endocrine Axis - Potential Role for A Delay Mechanism in The Inhibitory Action of Gonadal Steroids on GnRH Pulse Frequency
We developed a compartmental model so we could test mechanistic concepts in the control of the male 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-testosterone feed-back.
A key assumption was that the primary control signal comes from a hypothetical neural network (the 'PULSAR') that emits a digital (pulsatile) signal of variable frequency that drives GnRH secretion in square-wave-like pulses.
This model produced endocrine profiles that matched experimental observations for the testis-intact animal, and for changes in GnRH pulse frequency following castration and testosterone replacement.
In the second stage of model development, we introduced a delay in negative feedback caused by aromatization of testosterone to estradiol at 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-testosterone-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.
Ferasyi TR, Barrett PH, Blache D, Martin GB. Modeling the male reproductive endocrine axis - potential role for a delay mechanism in the inhibitory action of gonadal steroids on GnRH pulse frequency. Endocrinology. http://press.endocrine.org/doi/abs/10.1210/en.2015-1913
We developed a compartmental model so we could test mechanistic concepts in the control of the male 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-testosterone feed-back.
A key assumption was that the primary control signal comes from a hypothetical neural network (the 'PULSAR') that emits a digital (pulsatile) signal of variable frequency that drives GnRH secretion in square-wave-like pulses.
This model produced endocrine profiles that matched experimental observations for the testis-intact animal, and for changes in GnRH pulse frequency following castration and testosterone replacement.
In the second stage of model development, we introduced a delay in negative feedback caused by aromatization of testosterone to estradiol at 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-testosterone-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.
Ferasyi TR, Barrett PH, Blache D, Martin GB. Modeling the male reproductive endocrine axis - potential role for a delay mechanism in the inhibitory action of gonadal steroids on GnRH pulse frequency. Endocrinology. http://press.endocrine.org/doi/abs/10.1210/en.2015-1913
