The Origin of Glucocorticoid Hormone Oscillations

Walker, Jamie J.; Spiga, Francesca; Waite, Eleanor; Zhao, Zidong; Kershaw, Yvonne M.; Terry, John R.; Lightman, Stafford L.

doi:10.1371/journal.pbio.1001341

Cited by 165 publications

(136 citation statements)

References 55 publications

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“…Although there is some evidence for pulsatility of CRH (1,2), our recent work suggests that ACTH and CORT pulsatility is predominantly generated by a subhypothalamic oscillator within the pituitary-adrenal system (3,4). The amplitude of these pulses varies in a circadian manner with larger pulses occurring at the start of the active phase (morning in humans, evening in rodents).…”

mentioning

confidence: 95%

Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The hypothalamic-pituitary-adrenal axis is a dynamic system regulating glucocorticoid hormone synthesis in the adrenal glands. Many key factors within the adrenal steroidogenic pathway have been identified and studied, but little is known about how these factors function collectively as a dynamic network of interacting components. To investigate this, we developed a mathematical model of the adrenal steroidogenic regulatory network that accounts for key regulatory processes occurring at different timescales. We used our model to predict the time evolution of steroidogenesis in response to physiological adrenocorticotropic hormone (ACTH) perturbations, ranging from basal pulses to larger stress-like stimulations (e.g., inflammatory stress). Testing these predictions experimentally in the rat, our results show that the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, but coupling this regulatory network with the immune pathway is necessary to explain the dissociated dynamics between ACTH and glucocorticoids observed under conditions of inflammatory stress. T he hypothalamic-pituitary-adrenal (HPA) axis is a stressresponsive neuroendocrine system that controls circulating levels of the vital glucocorticoid (CORT) hormones corticosterone (in rodents) and cortisol (in humans). These are steroids synthesized by the adrenal gland in response to stimulation by adrenocorticotropic hormone (ACTH), which is secreted by the anterior pituitary in response to corticotrophin-releasing hormone (CRH) and arginine vasopressin released from hypothalamic paraventricular neurons. These neurons receive circadian inputs from the suprachiasmatic nucleus and are activated in response to stress. Via the bloodstream, CORT accesses target tissues where it mediates metabolic, cognitive, and immune responses. CORT also regulates its own production through negative feedback inhibition of ACTH and CRH secretion from the pituitary and hypothalamus, respectively. To mount an effective response to stress, CORT must be secreted rapidly by the adrenal glands. However, because of its lipophilic nature, CORT cannot be prestored in vesicles and must therefore be rapidly synthesized de novo in response to ACTH stimulation.Under basal, unstressed conditions, ACTH and CORT exhibit ultradian oscillations. Although there is some evidence for pulsatility of CRH (1, 2), our recent work suggests that ACTH and CORT pulsatility is predominantly generated by a subhypothalamic oscillator within the pituitary-adrenal system (3, 4). The amplitude of these pulses varies in a circadian manner with larger pulses occurring at the start of the active phase (morning in humans, evening in rodents). Under normal physiological conditions, CORT secretion is tightly correlated with ACTH (5). However, there are a number of conditions where a dynamic dissociation between these hormones occurs (reviewed in ref. 6). For example, there is evidence that proinflammatory cytokines released during inflammation can poten...

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confidence: 95%

Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…The secreted ACTH is moved by the bloodstream to the adrenal among others, where it affects the adrenal to release cortisol. Cortisol feeds back on hypothalamus and inhibits the release of CRH and ACTH, leading to a down-regulation of the cortisol synthesis (Beishuizen and Thijs 2003;Walker et al 2012;Webster and Sternberg 2004). The secretion of cortisol has been studied extensively revealing both circadian and ultradian oscillations in the concentration (Rankin et al 2012).…”

Section: Physiological Backgroundmentioning

confidence: 99%

“…The auto-up-regulation of CRH is inhibited by cortisol (Beishuizen and Thijs 2003;Walker et al 2012;Webster and Sternberg 2004). A basic level of secretion of CRH is included in the model, to ensure a positive production rate.…”

Section: Equation For Crh (C)mentioning

confidence: 99%

“…The stimulation of ACTH by CRH is inhibited by cortisol (Beishuizen and Thijs 2003;Walker et al 2012;Webster and Sternberg 2004). The HPA activation caused by endotoxin is modulated partly by a stimulation of ACTH by TNF-α (Beishuizen and Thijs 2003;John and Buckingham 2003).…”

Section: Equation For Acth (A)mentioning

confidence: 99%

“…The secretion of cortisol is stimulated by ACTH (Beishuizen and Thijs 2003;Walker et al 2012;Webster and Sternberg 2004). The ACTH stimulation is inhibited by TGF-β (Liakos et al 2003).…”

Section: Equation For Cortisol (F)mentioning

confidence: 99%

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Integrated Inflammatory Stress (ITIS) Model

et al. 2017

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Integrated Inflammatory Stress (ITIS) ModelBangsgaard, Elisabeth O.; Hjorth, Poul G.; Olufsen, Mette S.; Mehlsen, Jesper; Ottesen, Johnny T. Published in: Bulletin of Mathematical BiologyLink to article, DOI: 10.1007/s11538-017-0293-2 Publication date: 2017 Document VersionPublisher's PDF, also known as Version of record Abstract During the last decade, there has been an increasing interest in the coupling between the acute inflammatory response and the Hypothalamic-Pituitary-Adrenal (HPA) axis. The inflammatory response is activated acutely by pathogen-or damagerelated molecular patterns, whereas the HPA axis maintains a long-term level of the stress hormone cortisol which is also anti-inflammatory. A new integrated model of the interaction between these two subsystems of the inflammatory system is proposed and coined the integrated inflammatory stress (ITIS) model. The coupling mechanisms describing the interactions between the subsystems in the ITIS model are formulated based on biological reasoning and its ability to describe clinical data. The ITIS model is calibrated and validated by simulating various scenarios related to endotoxin (LPS) exposure. The model is capable of reproducing human data of tumor necrosis factor alpha, adrenocorticotropic hormone (ACTH) and cortisol and suggests that repeated LPS injections lead to a deficient response. The ITIS model predicts that the most extensive response to an LPS injection in ACTH and cortisol concentrations is observed in the early hours of the day. A constant activation results in elevated levels of the variables in the model while a prolonged change of the oscillations in ACTH and

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To Stress or Not to Stress: A Question of Models

2015

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Stress research is a rapidly evolving field that encompasses numerous disciplines ranging from neuroscience to metabolism. With many new researchers migrating into the field, navigating the hows and whys of specific research questions can sometimes be enigmatic given the availability of so many models in the stress field. Additionally, as with every field, there are many seemingly minor experimental details that can have dramatic influences on data interpretation, although many of these are unknown to those not familiar with the field. The aim of this overview is to provide some suggestions and points to guide researchers moving into the stress field and highlight relevant methodological points that they should consider when choosing a model for stress and deciding how to structure a study. We briefly provide a primer on the basics of endpoint measurements in the stress field, factors to consider when choosing a model for acute stress, the difference between repeated and chronic stress, and importantly, influencing variables that modulate endpoints of analysis in stress work.

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The Origin of Glucocorticoid Hormone Oscillations

Abstract: Characterization of a peripheral hormonal system identifies the origin and mechanisms of regulation of glucocorticoid hormone oscillations in rats.

Cited by 165 publications

References 55 publications

Dynamic responses of the adrenal steroidogenic regulatory network

Dynamic responses of the adrenal steroidogenic regulatory network

Integrated Inflammatory Stress (ITIS) Model

To Stress or Not to Stress: A Question of Models

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