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 P450 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 vesicular pattern (13, 14). In addition, there is an increase in smooth endoplasmic reticulum and filopodia and a decrease in liposomes known to store cholesterol, the substrate for glucocorticoid biosynthesis (13–15). The adrenal gland, as the end organ of the human stress system, reacts with the above changes in many clinical situations that involve severe or chronic stress. Subacute or chronic stress, for example major surgery, or lingering affective disorders, chronic infections, and chronic autoimmune diseases are frequently associated with adrenal alterations (16). Only recently it became evident that in these states, dissociation between central activation of the HPA axis and the adrenal cortex may occur (7, 17). Thus, frequently, ACTH levels do not correspond to the chronically elevated concentrations of glucocorticoids and the hypertrophy/hyperplasia of the adrenal gland. This dissociation cannot be explained by the different half-lives of the pituitary and adrenal hormones and suggests a reset of the HPA axis and/or the presence of extrapituitary mechanisms of adrenal regulation. Mounting evidence in recent years suggests that the interaction of the two ontogenetically different parts of the adrenal gland, the cortex and the medulla, is not a one-way street but, rather, a bidirectional phenomenon that also receives input from the nervous and immune systems (Fig. 1) (17, 18). The influence of the adrenal cortex on the adrenal medulla and on the expression of catecholamine biosynthetic enzymes and synthesis has been well characterized in vitro (19) and in vivo (20). On the other hand, the influence of the sympatho-adrenomedullary system on adrenocortical functions includes the diurnal variation of adrenal steroidogenesis, which depends on the integrity of sympathetic innervation (for review, see Refs. 21, 22). Also, neural inputs seem to mediate compensatory growth in the remaining adrenal after