Glucocorticoids

Glucocorticoid structure

Lipid soluble, carbon ring steroid; easily crosses membranes; precursor to all steroid hormones

Adrenal cortex hormones

Cortisol (glucocorticoid) and Aldosterone (mineralocorticoid)

Cortisol synthesis

Produced in adrenal cortex from cholesterol; has 17-OH group

Cortisol function

Mediates stress response → increases glucose levels

Glucocorticoid secretion

Diurnal: peak in morning, lowest at night

HPA axis control

Serotonin → CRF → ACTH → cortisol; cortisol inhibits CRF & ACTH (negative feedback)

Main cortisol effects

Increases glucose, promotes gluconeogenesis, decreases peripheral glucose use, increases lipolysis and protein breakdown

Chronic cortisol excess

Muscle loss, fat gain, weak bones, hyperglycemia

Glucocorticoid receptor (GR)

Nuclear receptor acting as transcription factor; effects develop over hours to days

Anti-inflammatory action

Up-regulates anti-inflammatory proteins (M2 macrophages, Annexins); down-regulates pro-inflammatory proteins (M1 macrophages, IL-2)

NF-κB & AP-1 role

Pro-inflammatory transcription factors; glucocorticoids inhibit both

Therapeutic uses

Anti-inflammatory, immunosuppressive, antiproliferative

Cortisol vs Cortisone

Cortisol: active natural hormone; Cortisone: inactive until converted in liver

11β-Hydroxysteroid Dehydrogenase

Regulates local cortisol activity; protects tissues (e.g. kidney) from excess

Major adverse effects (chronic)

Cushing symptoms, infection risk, osteoporosis, hyperglycemia, psychosis

Withdrawal symptoms

Fever, fatigue, hypotension, nausea, myalgia, arthralgia

HPA axis suppression

Exogenous steroids decrease ACTH and CRH → decreased endogenous cortisol

Tapering importance

Avoid abrupt stop to prevent acute adrenal insufficiency

Hydrocortisone replacement

Mimics natural circadian rhythm; given 2-3 times daily