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Abstract
Author SummaryGlucocorticoid steroid hormones, such as cortisol and corticosterone, provide a rapid response to both physical and psychological stress, and act on areas of the brain that influence learning, memory, and behaviour. Glucocorticoids are released from the adrenal glands in near-hourly pulses, which results in oscillating glucocorticoid levels in the blood and in target organs. These hormone oscillations can become disrupted during ageing and in stress-related disease (e.g., major depression), so it is important to identify the underlying mechanisms that govern their dynamics. Although the origin of the oscillations is not known, it is assumed that they are generated by a neuronal “pulse generator” within the brain. In this study, we present data that challenge this hypothesis. We characterize a peripheral hormonal system and show that constant levels of corticotrophin-releasing hormone can induce and regulate hormone oscillations independent of the brain. We also describe mechanisms that can disrupt these oscillations. These findings have important implications for our understanding of glucocorticoid signalling in both health and disease, and will be important for the design of novel treatment strategies that take into account timing of hormone administration to patients undergoing steroid therapy for inflammatory or malignant disease.
Highlights
A fundamental requisite for survival is the ability to respond and adapt to a changing environment
corticotrophin-releasing hormone (CRH) is synthesized by parvocellular neurons in the paraventricular nucleus (PVN) of the hypothalamus [9], and secreted into the hypothalamic-pituitary portal circulation from axons terminating in the external zone of the median eminence [10]
Since glucocorticoids rapidly inhibit CRH-induced adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary [29,30,31,32], we postulated that this fast inhibitory feedback process provides a potential mechanism within the pituitary-adrenal system for generating oscillatory dynamics. To explore this hypothesis further, and to determine qualitatively the dynamics that result from hormonal interactions between the anterior pituitary and adrenal cortex, we previously developed a mathematical model based on differential equations that incorporates rapid glucocorticoid inhibition of ACTH secretion [33]
Summary
A fundamental requisite for survival is the ability to respond and adapt to a changing environment This ability to respond to change or ‘‘stress’’ becomes more complex in multicellular organisms, and mammals have developed a well-integrated organization of hormonal, neural, and immunological systems that protect them from internal and external threats to their homeostatic state [1,2,3]. One of the most important of these systems, and one that is critical for life, is the hypothalamicpituitary-adrenal (HPA) axis. This neuroendocrine system regulates the secretion of vital adrenal glucocorticoid hormones (cortisol in humans and corticosterone in rodents), which have major effects on brain and metabolic function and are essential for successful recovery and adaptation to stress [4,5]. Activation of CRH receptors in corticotroph cells of the anterior pituitary results in adrenocorticotrophic hormone (ACTH) secretion into the general circulation, which in turn stimulates glucocorticoid-secreting cells within the adrenal cortex (Figure 1A)
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