The Hypothalamo–Pituitary–Adrenocortical Axis—An Overview of the Role of Glucocorticoids in the Pathophysiology of Endocrine Disorders and Perspectives for the Future

Christopher D John, Julia C Buckingham
US Endocrinology, 2011;7(1):65-70

Abstract

Glucocorticoids (GCs) are the end products of the hypothalamo–pituitary–adrenocortical axis (HPA) and, via activation of the ubiquitously expressed GC receptor, influence numerous physiological processes. GCs are also involved in the regulation of basal homeostasis as well as mediating adaptive responses to stress that act to restore homeostasis. This article discusses the various factors that are important in regulating plasma and intracellular GC concentrations and describes the genomic and non-genomic mechanisms used by GCs to influence cellular processes. We describe the concept of allostatic overload associated with chronic HPA activation and the subsequent development of tissue dysfunction and disease. While allostasis is associated with acute stress and a restoration of homeostasis, chronic stress is likely to induce allostatic overload owing to the sustained activation of adaptive processes. Increased wear and tear in GC-sensitive tissues can eventually lead to tissue dysfunction and disease. Chronic elevations in GCs can also induce dysfunction or disease associated with decreased tissue function owing to the prolonged inhibitory effects of GCs or the redistribution of metabolic resource away from physiological systems not involved in restoring homeostasis. Numerous endocrine-related disorders are associated with aberrant GC levels and in terms of pathophysiology may be linked with chronic tissue-specific alterations in GC actions.
Keywords: Hypothalamo–pituitary–adrenocortical axis, glucocorticoids, allostasis, allostatic overload, endocrine disorders
Disclosure: The authors have no conflicts of interest to declare.
Received: October 05, 2010 Accepted February 02, 2011 Citation US Endocrinology, 2011;7(1):65-70
Correspondence: Christopher D John, PhD, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Commonwealth Building, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK. E: c.john@imperial.ac.uk
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The ability of an organism to respond to stressful stimuli is fundamentally important to that organism’s continuing survival. Recognition of a stressor elicits a range of physiological changes that enable the organism to cope and to facilitate the restoration of homeostasis. Many of these physiological changes are mediated via activation of the hypothalamo–pituitary–adrenocortical (HPA) axis and the consequent secretion of glucocorticoids (GCs) by the adrenal gland. Stimulation of the HPA axis is triggered by neural and humoral mechanisms that converge on the parvocellular neurones in the hypothalamic paraventricular nucleus (PVN) and cause release of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) into the hypothalamo–hypophyseal portal complex for transportation to the anterior pituitary gland. Here, these neurohormones bind to specific CRH and AVP receptors (CRH-R1 and V1b, respectively) on corticotroph cells to induce the release of corticotrophin (adrenocorticotrophic hormone [ACTH]) into the systemic circulation. ACTH acts within the adrenal glands to increase the synthesis and release of GCs, cortisol (in man and other primates) and corticosterone (in rodents). The secretion of these steroid hormones is further regulated by complex negative feedback effects of the GCs themselves on the pituitary gland, hypothalamus and extra-hypothalamic centers in the brain (e.g. hippocampus, brainstem). GCs were originally named on the basis of their influence on metabolic processes, specifically the generation of glucose from protein and lipids. However, GCs also exert a plethora of effects that together serve to maintain homeostasis. GCs thus prepare the organism to respond to stress and also protect the organism from the stress itself, in part by limiting the pathophysiological responses (e.g. inflammation) to the stress that, if left unchecked, may themselves threaten homeostasis.1

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