Modeling the Male Reproductive Endocrine Axis: Potential Role for a Delay Mechanism in the Inhibitory Action of Gonadal Steroids on GnRH Pulse Frequency

Abstract

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-T feedback. 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 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.

Experimental Infection of Mid-Gestation Pregnant Female and Intact Male Sheep with Zika Virus

“…These animals become infected with ZIKV and high viral loads can be isolated from many organs including the testes [29,[33][34][35][36].Male sheep and humans share similar reproductive anatomy, including the presence of comparable accessory sex glands [37]. Thus, rams have been used as a model for the human male reproductive system, particularly with regards to endocrinology and embryology [38][39][40][41]. Recent work has shown that experimental infection of intact male sheep with bluetongue virus, a natural arbovirus of sheep, resulted in localization of the virus in the male reproductive tract and subsequent testicular degeneration, similar to pathology that can occur in ZIKV infection of male humans [42,43].…”

Systems of delay differential equations: Analysis of a model with feedback

“…This theory allowed to demonstrate the existence of positive periodic solutions when parameters are replaced by fixed periodic functions. It is observed that the results are also valid in the absence of delays; however, the study of delayed systems is of great interest because as shown in [7], in many cases delayed models fit experimental data better, particularly when feedback is present.…”

“…For example in [3], a model is proposed that establishes in relation to the hours of response between an increase in GnRH (Gonadotropin-releasing hormone) secretion and a pituitary FSH (Follicle-stimulating hormone) response under dietary treatment or minutes for responses to sociosexual signs as we can see in [7].…”

Increase and Redistribution of Sex Hormone Receptors in Premenopausal Women Are Associated with Varicose Vein Remodelling

“…This study suggests that part of the relaxing effect of E2 is independent of the Ca 2+ channel blockade. Under supraphysiological conditions, 17 β -oestradiol dilates the umbilical artery and vein [ 34 ]. 17 β -Oestradiol does not appear to decrease α -adrenergic system activity in SMCs in vivo [ 35 ].…”