Dynamic responses of the adrenal steroidogenic regulatory network

Abstract

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...

Corticosteroids and the brain

“…This cyclic pattern is caused by the delay between the activation and negative feedback of the hypothalamus-pituitary-adrenal axis, as was first predicted in a mathematical model and later demonstrated experimentally (Walker et al 2012). The kinetic and dynamic properties of ultradian pulses are not static but are liable to changes for example in association with activation of the immune system and specific diseases (Spiga et al 2017). It was shown that ultradian patterns in the circulation, at least in rodents, are maintained in the brain (Qian et al 2012).…”

The human stress response

“…Despite this fall in ACTH levels, small changes in these basal levels of ACTH initiate large pulses of cortisol, indicating a rapidly induced increased sensitivity of the adrenal cortex to ACTH. This effect has now been investigated in reverse translation studies in rats and complemented with mathematical modelling, which enabled the importance of the dynamic adrenal steroidogenic regulatory network to be characterised 47 .…”

“…As CORT is highly lipophilic it is not prestored in vesicles and is synthesised de novo in response to ACTH. During long-term stress a dissociation between ACTH and CORT secretion develops 93,94 , predominantly via increased adrenal sensitivity to ACTH 47 or non-ACTH mediated mechanisms 94 . This effect is seen in patients undergoing cardiac surgery, who show a marked shift in adrenal responsiveness (figure 1) 46 , reverse translation animal studies suggest this shift arises secondary to changes in the regulation of both stimulatory and inhibitory intra-adrenal signalling pathways 46 .…”

Molecular Mechanisms of Glucocorticoid Resistance in Corticotropinomas: New Developments and Drug Targets

“…In turn, ACTH stimulates the steroidogenesis in adrenocortical cells by binding the melanocortin 2 receptor (MC2R) (21), whereas cortisol and other glucocorticoids exert a negative feedback at hypothalamic and pituitary level, allowing therefore to keep a balance between cortisol requirement and cortisol secretion (22,23) (Figure 1). Furthermore, cortisol synthesis might be also regulated by itself in an auto-feedback loop within the adrenal gland (24,25). The physiological glucocorticoid negative feedback on the HPA axis is exerted upon binding to the glucocorticoid receptor (GR), encoded by NR3C1 gene.…”