The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal effectors of the stress system include corticotropin-releasing hormone (CRH); arginine vasopressin; the proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin, the glucocorticoids; and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors.

Adrenal insufficiency is the clinical manifestation of deficient production or action of glucocorticoids, with or without deficiency also in mineralocorticoids and adrenal androgens. It is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease due to impairment of the hypothalamic-pituitary axis. Prompt diagnosis and management are essential. The clinical manifestations of primary adrenal insufficiency result from deficiency of all adrenocortical hormones, but they can also include signs of other concurrent autoimmune conditions. In secondary or tertiary adrenal insufficiency, the clinical picture results from glucocorticoid deficiency only, but manifestations of the primary pathological disorder can also be present. The diagnostic investigation, although well established, can be challenging, especially in patients with secondary or tertiary adrenal insufficiency. We summarise knowledge at this time on the epidemiology, causal mechanisms, pathophysiology, clinical manifestations, diagnosis, and management of this disorder.

The characterization of the subfamily of steroid hormone receptors has enhanced our understanding of how a set of hormonally derived lipophilic ligands controls cellular and molecular functions to influence development and help achieve homeostasis. The glucocorticopid receptor (GR), the first member of this subfamily, is a ubiquitously expressed intracellular protein, which functions as a ligand-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes. The effector domains of the GR mediate transcriptional activation by recruiting coregulatory multi-subunit complexes that remodel chromatin, target initiation sites, and stabilize the RNA polymerase II machinery for repeated rounds of transcription of target genes. This review summarizes the basic aspects of the structure and of the human (h) GR, and the molecular basis of its biologic function.

Stress activates the central and peripheral components of the stress system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis and the arousal/sympathetic system. The principal effectors of the stress system are corticotropin-releasing hormone (CRH), arginine vasopressin, the proopiomelanocortin-derived peptides α-melanocyte-stimulating hormone and β-endorphin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development, and may account for a number of endocrine, metabolic, autoimmune and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors and the timing of the stressful event(s), given that prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors. The developing brain undergoes rapid growth and is characterized by high turnover of neuronal connections during the prenatal and early postnatal life. These processes and, hence, brain plasticity, slow down during childhood and puberty, and plateau in young adulthood. Hormonal actions in early life, and to a much lesser extent later, can be organizational, i.e., can have effects that last for long periods of time, often for the entire life of the individual. Hormones of the stress system and sex steroids have such effects, which influence the behavior and certain physiologic functions of individuals for life. Exposure of the developing brain to severe and/or prolonged stress may result in hyperactivity/hyperreactivity of the stress system, with resultant amygdala hyperfunction (fear reaction), decreased activity of the hippocampus (defective glucocorticoid-negative feedback, cognition), and the mesocorticolimbic dopaminergic system (dysthymia, novelty-seeking, addictive behaviors), hyperactivation of the HPA axis (hypercortisolism), suppression of reproductive, growth, thyroid and immune functions, and changes in pain perception. These changes may be accompanied by abnormal childhood, adolescent and adult behaviors, including excessive fear (‘inhibited child syndrome’) and addictive behaviors, dysthymia and/or depression, and gradual development of components of the metabolic syndrome X, including visceral obesity and essential hypertension. Prenatal stress exerted during the period of sexual differentiation may be accompanied by impairment of this process with behavioral and/or somatic sequelae. The vulnerability of individuals to develop varying degrees and/or components of the above life-long syndrome is defined by as yet unidentified genetic factors, which account for up to 60% of the variance. CRH has marked kindling and glucocorticoids have strong consolidating properties, hence ...

All living organisms have developed a highly conserved and regulatory system, the stress system, to cope with a broad spectrum of stressful stimuli that threaten, or are perceived as threatening, their dynamic equilibrium or homeostasis. This neuroendocrine system consists of the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-autonomic nervous system. In parallel with the evolution of the homeostasis and stress concepts from ancient Greek to modern medicine, significant advances in the field of neuroendocrinology have identified the physiologic biochemical effector molecules of the stress response. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome. This review describes the central and peripheral components of the stress system, provides a comprehensive overview of the stress response, and discusses the role of glucocorticoids in a broad spectrum of stress-related diseases.

The clinical spectrum of primary generalized glucocorticoid resistance is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess. The molecular basis of the condition has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction and reduce tissue sensitivity to glucocorticoids. A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology. The study of functional defects of natural hGR mutants enhances our understanding of the molecular mechanisms of hGR action and highlights the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.

No abstract

The stress system effectively restores the internal balance––or homeostasis––of living organisms in the face of random external or internal changes, the stressors. This highly complex system helps organisms to provide a series of neuroendocrine responses to stressors—the stress response—through coordinated activation of the hypothalamic–pituitary–adrenal (HPA) axis and the locus coeruleus/norepinephrine (LC/NE) autonomic nervous systems. In addition to stressors, life is influenced by daily light/dark changes due to the 24-h rotation of Earth. To adjust to these recurrent day/night cycles, the biological clock system employs the heterodimer of transcription factors CLOCK/BMAL1, along with a set of other transcription factors, to regulate the circadian pattern of gene expression. Interestingly, the stress system, through the HPA axis, communicates with the clock system; therefore, any uncoupling or dysregulation could potentially cause several disorders, such as metabolic, autoimmune, and mood disorders. In this review, we discuss the biological function of the two systems, their interactions, and the clinical implications of their dysregulation or uncoupling.