Science review: Mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids

Abstract

This review describes current knowledge on the mechanisms that underlie glucocorticoid insufficiency in sepsis and the molecular action of glucocorticoids. In patients with severe sepsis, numerous factors predispose to glucocorticoid insufficiency, including drugs, coagulation disorders and inflammatory mediators. These factors may compromise the hypothalamic–pituitary axis (i.e. secondary adrenal insufficiency) or the adrenal glands (i.e. primary adrenal failure), or may impair glucocorticoid access to target cells (i.e. peripheral tissue resistance). Irreversible anatomical damages to the hypothalamus, pituitary, or adrenal glands rarely occur. Conversely, transient functional impairment in hormone synthesis may be a common complication of severe sepsis. Glucocorticoids interact with a specific cytosolic glucocorticoid receptor, which undergoes conformational changes, sheds heat shock proteins and translocates to the nucleus. Glucocorticoids may also interact with membrane binding sites at the surface of the cells. The molecular action of glucocorticoids results in genomic and nongenomic effects. Direct and indirect transcriptional and post-transcriptional effects related to the cytosolic glucocorticoid receptor account for the genomic effects. Nongenomic effects are probably subsequent to cytosolic interaction between the glucocorticoid receptor and proteins, or to interaction between glucocorticoids and specific membrane binding sites.

Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate

“…Particularly in septic shock, elevated levels of cortisol may be too low for the high level of stress, as compared with those in nonseptic critical illness. This may be associated with a diminished adrenal responsiveness to additional stress, reflected by a diminished cortisol response to exogenous adrenocorticotropic hormone (ACTH) [2,5,6]. Adrenal dysfunction may thereby, together with tissue cortisol resistance, contribute to critical illness-related corticosteroid insufficiency (CIRCI) and subsequent attributable morbidity and mortality.…”

“…Adrenal dysfunction may thereby, together with tissue cortisol resistance, contribute to critical illness-related corticosteroid insufficiency (CIRCI) and subsequent attributable morbidity and mortality. The diagnosis of CIRCI and treatment with moderate doses of hydrocortisone, particularly in septic shock, remain highly controversial [2,5,6,8-11]. Mechanisms of adrenal dysfunction, particularly in the course of sepsis and shock, may include impaired availability or cleaving of the substrate (HDL-)cholesterol and impaired activity of steroidogenic enzymes, limiting an adequate adrenal stress (ACTH) response [2,6,12-15] (see Figure 1).…”

“…The diagnosis of CIRCI and treatment with moderate doses of hydrocortisone, particularly in septic shock, remain highly controversial [2,5,6,8-11]. Mechanisms of adrenal dysfunction, particularly in the course of sepsis and shock, may include impaired availability or cleaving of the substrate (HDL-)cholesterol and impaired activity of steroidogenic enzymes, limiting an adequate adrenal stress (ACTH) response [2,6,12-15] (see Figure 1). Impairment of cortisol secretion at baseline or with exogenous ACTH may also develop when (even a single dose of) etomidate, a known inhibitor of 11β-hydroxylase promoting conversion of 11β-deoxycortisol to cortisol, is used to facilitate intubation [2,4,6,16-29].…”

Critical Illness-Related Corticosteroid Insufficiency in Children

“…Many factors modulate CRH secretion during stress, including adrenergic agonists, opioids, and inflammation cytokines: interleukin (IL)-1, IL-2, IL-6, and tumor necrosis factor-α (TNF-α) [14]. Of note, cytokines, as well as catecholamines, angiotensin II, serotonin, and vasoactive intestinal peptide (VIP), also act directly on the pituitary to stimulate ACTH secretion [15]. In addition, reduction, during stress, of the negative feedback from cortisol to the hypothalamus-pituitary results in increased cortisol concentrations roughly proportional to the severity of the illness [16].…”

“…Different, and probably interacting, mechanisms account for the decreased activity of glucocorticoids. Two of them are a reduction of glucocorticoid receptors [31] and an increase in the conversion of cortisol to inactive cortisone by enhanced activity of 11-β-hydroxysteroid dehydrogenase stimulated by IL-2, IL-4, and IL-13 [15]. …”