The Hypothalamus-Pituitary-Adrenocortical response to critical illness: a concept in need of revision

Endocr Rev. 2023 Jul 6:bnad021. doi: 10.1210/endrev/bnad021. Online ahead of print.ABSTRACTBased on insights obtained during the last decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical (HPA) axis in response to critical illness is in need of revision. After a brief central HPA axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally-activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11βHSD1, GRα and FKBP51 that appear to titrate increased GRα-action in vital organs and tissues while reducing GRα-action in neutrophils possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of POMC into ACTH, thereby reducing ACTH-driven cortisol secretion, while ongoing central activation results in increased circulating POMC. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require inten...
Source: ENDOCR REV - Category: Endocrinology Authors: Source Type: research