Glucocorticoids
Glucocorticoids are steroid hormones produced by the adrenal cortex. The most important glucocorticoid is cortisol.
- effects
- mechanisms of action
- regulation of expression
- metabolism
- role of glucocorticoids in disease
- pharmacologic glucocorticoids
Effects on the Body
Regulation of Blood Glucose
Glucocorticoids act to increase and maintain normal blood glucose levels during periods of stress by:
- increasing glycogenolysis and gluconeogenesis in the liver
- increasing amino acid and fatty acid liberation from muscle and adipose tissue, respectively, to provide substrates for gluconeogenesis
- decreasing uptake and utilization of glucose in muscle and adipose tissue
Regluation of the immune response
Glucocorticoids are potent anti-inflammatory and immunosuppressant molecules, acting in part by:
- inhibiting IL-1β, phospholipase A2, COX-2, leading to decreased arachidonic acid and prostaglandin production
- decreased local production of histamine and bradykinin
Other Effects
Glucocorticoids also act on lymphoid, skin and connective, adipose, muscle, and hepatic tissue.
- GCs inhibit edema by potentiating vascocnstriction caused by NE and E
- inhibit fibroblast growth and reduces ECM deposition, reducing scarring
- decreases circulating lymphocyte levels, mainly by inducing redistribution to other compartments
Mechanisms of Action
Glucocorticoids are transported across the plasma membrane and signal through glucocorticoid receptor, which is present as two isoforms GRα and GRβ. GRα can both activate or inhibit gene transcription, while GRβ acts as a dominant-negative inhibitor of GRα.
GCs block transcription by NFkB, inhibiting the expression of IL-1β, IL-2, and TNF. This blocks IL-2 and IFNγ expression, leading to a decrease in leukocyte activity
Regulation of Glucocorticoid Expression
Cortisol is released by the zona fasciculata in the adrenal cortex in response to ACTH from the anterior pituitary, which in turn is stimulated by corticotropin releasing factor (CRF) from the hypothalamus.
Hypothalamic release of CRF is regulated by a number of factors, including:
- low cortisol
- hypoglycemia
- stress, anxiety, and depression
- trauma
- pyrogens
- various neurotransmitters
- Normally, cortisol expression is highest at night and is secreted in pulses. The unstressed adult produces 10-20 mg daily
- Ten percent of free cortisol is biologically active; 75% is bound to cortisol-binding globulin (CBG) and 15% is bound to albumin.
- TNF-alpha appears to increase GRβ expression, leading to decreased effects of GCs
Metabolism
Cortisol is metabolized in the liver by reduction and conjugated with sulfate or glucuronate, and excreted in the urine.
Cortisol-cortisone shunt
Because cortisol can bind mineralcorticoid receptor in the kidney and cause inappropriate activation of aldosterone-related pathways, a CP450 enzyme called 11βHSD2 converts cortisol to inactive cortisone in the kidney. Cortisone is then transmorted to sites of action, including the skin, liver, adipose tissue, and muscle, where 11βHSD1 reconverts cortisone into active cortisol.
Severe Cushing's disease results in levels of cortisol that override the capacity of 11βHSD2, leading to hypertension and hypokalemia.
Glycyrrhic acid in licorice inhibits 11βHSD2, leading to similar symptoms.
Role of Glucocorticoids in Disease
Glucocorticoid overproduction can occur due to various causes
Pharmacologic Glucocorticoids
Various glucocorticoids are used in clinical practice
- hydrocortisone is the name for exogenously administered cortisone
- prednisone
- dexamethasone