Glucocorticoid Secretion and Mechanism

• Glucocorticoids are steroid hormones secreted by the adrenal glands, which sit atop each kidney.
• The adrenal gland consists of two layers: the inner medulla and the outer cortex.
• The adrenal cortex secretes corticosteroid hormones, including glucocorticoids, under the control of adrenocorticotropic hormone (ACTH).

Regulation of Glucocorticoid Secretion

• The hypothalamus secretes corticotropin releasing hormone (CRH), which stimulates the anterior pituitary gland to secrete ACTH.
• ACTH travels to the adrenal glands and binds to ACTH receptors on adrenocortical cells.
• This binding causes adrenocortical cells to release glucocorticoids from the zona fasciculata.
• Glucocorticoids have anti-inflammatory and metabolic effects.
• Excess glucocorticoids exert a negative feedback effect on the hypothalamic-pituitary-adrenal axis, suppressing the release of CRH and ACTH.

Mechanism of Action

• Glucocorticoids enter the circulation and travel to target cells.
• As lipophilic molecules, they cross the cell membrane and bind with cytoplasmic glucocorticoid receptors.
• The glucocorticoid-receptor complex undergoes structural changes, allowing it to enter the nucleus and bind to glucocorticoid response elements (GRE) on chromatin.
• This binding induces transcription of specific mRNA, leading to the synthesis of proteins that modify cell functions and metabolic effects.

Cortisol

• Cortisol is the most important glucocorticoid in humans and is released during times of stress, such as illness or starvation.
• Cortisol regulates the immune response and cellular metabolism, including gluconeogenesis.
• It promotes an anti-inflammatory state by inhibiting prostaglandins, leukotrienes, and interleukin-2 production.
• Cortisol has catabolic effects on the body, triggering lipolysis in adipose tissue and proteolysis in muscles.
• The resulting free fatty acids and amino acids are substrates for gluconeogenesis in the liver.
• Cortisol increases insulin resistance in tissues, leading to elevated blood glucose levels, a diabetogenic effect.
• Cortisol maintains blood pressure by up-regulating alpha1 adrenergic receptors, causing vasoconstriction.

Synthetic Glucocorticoids

• Synthetic glucocorticoids produce similar effects to endogenous cortisol but also increase the number of neutrophils in the blood through demargination.
• Demargination is when neutrophils detach from the endothelial lining of blood vessels and enter the circulation.
• Synthetic glucocorticoids decrease lymphocyte, monocyte, basophil, and eosinophil counts.

Classification Based on Duration of Action

• Short-acting glucocorticoids: Duration of 8-12 hours; includes cortisone and hydrocortisone.
• Cortisone is taken orally and converted to hydrocortisone in the liver; inactive topically.
• Hydrocortisone is chemically identical to cortisol and can be taken orally, intravenously, or intramuscularly; drug of choice for acute adrenal insufficiency; also available topically.
• Intermediate-acting glucocorticoids: Duration of 12-36 hours; includes prednisone, prednisolone, methylprednisolone, and triamcinolone.
• Prednisone is taken orally.
• Prednisolone can be administered perorally, intravenously, and topically.
• Methylprednisolone can be administered orally, intravenously, intramuscularly, or intra-articularly.
• Triamcinolone can be administered orally, intramuscularly, topically, and intra-articularly.
• They are 4-5 times more potent than short-acting glucocorticoids.
• Long-acting glucocorticoids: Duration of 36-72 hours; includes betamethasone and dexamethasone.
• Can be taken orally or injected intravenously, intramuscularly, or intra-articularly.
• Dexamethasone can be used topically.
• These medications are 25 times more potent than short-acting glucocorticoids.

Clinical Uses of Glucocorticoids

• Treatment of adrenal conditions: Used in primary adrenal insufficiency (Addison disease) and congenital adrenal hyperplasia.
• Short-acting glucocorticoids are used as physiologic replacement therapy to mimic the normal diurnal pattern, with the largest dose in the morning and a smaller dose in the afternoon.
• Hydrocortisone is used to treat life-threatening adrenal crises due to its rapid effect.
• Anti-inflammatory/immunosuppressive therapy: Used in asthma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, acute multiple sclerosis exacerbation, idiopathic thrombocytopenic purpura, eczema, allergic conjunctivitis, and rhinitis.
• Treatment of hypersensitivity states: Used in severe allergic reactions and to prevent graft-versus-host disease.
• Miscellaneous conditions: Used in chemotherapy-induced vomiting, hypercalcemia, and mountain sickness.
• Betamethasone can be given to pregnant women to speed up fetal lung maturation.
• Neoplastic conditions: Used as adjuvant therapy in hematopoietic cancers (acute lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphomas) due to their anti-lymphocytic effect.
• Dexamethasone is used to relieve cerebral edema in individuals with metastatic or primary brain tumors.

Dexamethasone Suppression Test

• Dexamethasone is a potent medication that can suppress the hypothalamic-pituitary-adrenal axis, even at low doses.
• Used in the overnight dexamethasone suppression test to diagnose Cushing syndrome.
• Cushing syndrome is caused by excessive cortisol production, either due to Cushing disease (pituitary adenoma overproducing ACTH) or other factors.
• Symptoms of Cushing's syndrome include obesity (buffalo hump, truncal obesity, moon facies), hyperglycemia, diabetes, muscle weakness, skin stretch marks, hypertension, osteoporosis, and increased risk of infections.
• In the test, a low dose of dexamethasone is administered to suppress ACTH production.
• Failure to suppress cortisol levels indicates Cushing syndrome.

Side Effects of Synthetic Glucocorticoids

• Rare when administered for physiologic replacement therapy but more common with high doses for prolonged periods.
• Iatrogenic Cushing syndrome: Side effects mimic those of Cushing syndrome and are more common than regular Cushing syndrome.
• Fluid and electrolyte disturbances: Fluid retention, hypertension, and hypokalemia.
• Endocrine side effects: Hyperglycemia, diabetes, and suppression of the hypothalamic-pituitary-adrenal axis, leading to adrenocortical atrophy.
• Immunosuppression: Increased risk of infection and impaired wound healing.
• Musculoskeletal side effects: Myopathy, avascular necrosis of femoral and humeral heads, osteoporosis, and pathological fractures.
• Psychiatric disturbances: Depression, insomnia, psychosis, and mood swings.
• Other side effects: Peptic ulcers and cataracts.
• Growth inhibition in children.
• Patients on long-term glucocorticoid therapy may require "stress doses" before or after surgery or during severe illness to prevent adrenal crisis.
• Alternate-day therapy (ADT) involves taking a doubled daily dose every other day to prevent suppression of the HPA axis and adrenocortical atrophy.