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.

Figure 1

Crosstalk between the immune system and the neuroendocrine axis. 11β-HSD, 11β-hydroxysteroid dehydrogenase; CBG, cortisol-binding globulin; HT, hypothalamus; IL, interleukin; PG, pituitary gland; TNF, tumour necrosis factor.

Figure 2

Molecular action of glucocorticoids. GR, glucocorticoid receptor; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; PI3 kinase, phosphatidylinositol 3-kinase.