Adrenocorticotropin (ACTH)- and Non-ACTH-Mediated Regulation of the Adrenal Cortex: Neural and Immune Inputs

Abstract

The maintenance of life depends on the capacity of the body to sustain its steady state or homeostasis; hence, the survival of the organism relies on its ability to react and adapt to the constant bombardment by physical and emotional threats or stressors (1, 2). To accomplish this, all living beings have developed an efficient but complex adaptive response system that allows the integration of the necessary defense mechanisms directed against both external and internal stressors. This coordinated response, the stress response, involves the nervous, endocrine, and immune systems. A qualitatively and quantitatively appropriate and time-limited stress response is a prerequisite for a healthy life. Inappropriate or inappropriately excessive and chronic hyperactivation of the stress system may lead to disease and, eventually, premature death.The two major peripheral limbs of the stress system are the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (1, 2). Their central components are, respectively, located in the hypothalamus and the brain stem. Stress-induced activation of the HPA axis is associated with release of hypothalamic CRH and vasopressin (AVP), the principal regulators of anterior pituitary corticotropin (ACTH) secretion, into the hypophyseal portal system. These hormones synergistically stimulate systemic ACTH secretion, which, in turn, stimulates the adrenal cortexes to secrete glucocorticoids. Central activation of the sympathetic neurons leads to activation of both the systemic sympathetic nervous system and, through the splanchnic nerves, the adrenal medullae (3). As the proper functioning of both the HPA axis and the sympathetic nervous system is crucial for survival and maintenance of health, it is not surprising that their regulation is developmentally plastic and complex, multilevel, and redundant. The regulation and central interaction of the HPA axis and the sympathetic nervous system and the immune system have been extensively studied and summarized in recent review articles (1, 3-5). The purpose of this brief review is to outline and discuss recent advances in the interactions and regulation of the adjacent peripheral limbs of the stress system, particularly the adrenal cortex and medulla, and to point out their implications for clinical endocrinology (Fig. 1).The adrenal gland has an astonishing capacity to adapt to various forms of acute and chronic stress (6 -8). After central activation of the HPA axis, ACTH triggers a physiologic, molecular, and morphological response of the adrenal cortex. This leads not only to glucocorticoid release, but also to up-regulation of steroidogenic cytochrome P 450 messenger ribonucleic acids (9, 10) and to conspicuous structural changes in the adrenal gland characterized by both hypervascularization and cellular hypertrophy and hyperplasia (11,12). These morphological changes are mirrored on the ultrastructural level; adrenocortical cells increase the number of their mitochondria, whereas their inner membranes form a dense vesi...

Cortisol response to ACTH stimulation correlates with blood interleukin 6 concentration in healthy humans

“…In addition to the endocrine system, the neural and immune systems are also involved in adrenal gland regulation (12). Dissociation between central activation of the HPA axis and the adrenal cortex can occur in a variety of situations (13).…”

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

“…12 While catecholamines and neuropeptides produced in the adrenal medulla regulate adrenocortical function, adrenocortical steroids influence the structure and function of the chromaffin cells in the adrenal medulla. 2,13,14 Glucocorticoids induce the enzyme responsible for catecholamine biosynthesis and glucocorticoid receptor-deficient mice have no adrenal epinephrine production. 15 Likewise, patients with adrenocortical insufficiency due to Addison's disease or 21-OH deficiency have low plasma epinephrine levels and adrenomedullary dysplasia.…”

La melatonina reduce la respuesta de cortisol al ACTH en humanos

“…Sin embargo, estudios realizados en mujeres y hombres, tratados con distintas dosis de melatonina, a distintas horas del día, en una o varias ocasiones, o estudiando el efecto de la administración de melatonina sobre la producción de cortisol estimulada por ACTH, tanto exógena como endógena, no han mostrado efectos claros sobre la concentración plasmática de cortisol [15][16][17][18][19] . Dada la compleja regulación de la corteza suprarrenal, es posible que en estos estudios un potencial efecto inhibidor de melatonina sobre la producción de cortisol haya sido enmascarado por los mecanismos de feedback entre cortisol y ACTH 20 .…”

“…Inmediatamente después los sujetos ingirieron 2 cápsulas de 3 mg de melatonina pura (Sigma, St. Louis, USA) o placebo (almidón), preparadas en la Farmacia Cruz Verde, Santiago, Chile. Treinta minutos después, previa extracción de otra muestra de sangre (tiempo 0), se les inyectó en el otro antebrazo una microdosis, recién preparada, de 1-24 ACTH [1 µg/1,73 m 2 de superficie corporal; Cortrosyn, Organon, Holanda 19,20 ], tomándose muestras de sangre 15, 30, 45 y 60 min después de la inyección. Los sueros o plasmas se separaron inmediatamente, guardándose en alícuotas a -20°C hasta su análisis.…”