Short Note: Glucocorticoids

Definition and Principal Hormone

1. Regulation of Secretion

1. Corticotropin-Releasing Hormone (CRH): Secreted by the paraventricular nucleus of the hypothalamus (41-amino-acid peptide), transported via the hypophyseal portal system to the anterior pituitary. Inputs to the paraventricular nucleus arrive from the limbic system, brain stem, and arcuate nucleus.
2. ACTH (Corticotropin): A 39-amino-acid polypeptide released by the anterior pituitary in response to CRH. ACTH binds to adrenocortical cell receptors, activates adenylyl cyclase, raises intracellular cAMP, and activates protein kinase A. This activates the rate-limiting enzyme that converts cholesterol to pregnenolone, initiating steroid synthesis. Long-term ACTH stimulation causes hypertrophy and hyperplasia of the zona fasciculata and zona reticularis.
3. Negative feedback: Cortisol feeds back to inhibit both CRH (hypothalamus) and ACTH (anterior pituitary), maintaining normal plasma cortisol levels.
4. Stress response: Physical or mental stress (trauma, infection, surgery, intense heat/cold, debilitating disease) triggers a rapid, dramatic increase in CRH and ACTH secretion within minutes, raising cortisol secretion as much as 20-fold.
5. Circadian rhythm: Cortisol shows a diurnal pattern - highest levels in the early morning and lowest levels at night.

2. Mechanism of Action

• Cortisol enters the cytoplasm and binds to its specific glucocorticoid receptor (GR) protein
• The hormone-receptor complex translocates to the nucleus and binds glucocorticoid response elements (GREs) on DNA
• This induces or represses gene transcription, altering synthesis of mRNA and consequently the proteins that mediate glucocorticoid effects
• Additional nuclear transcription factors are required for proper GRE interaction
• Because new protein synthesis is needed, most effects are not immediate - requiring 45-60 minutes to begin, and several hours to days to fully develop
• At high concentrations, rapid non-genomic effects also occur (via plasma membrane receptors)
• Glucocorticoid receptors are also translocated to mitochondria, where they regulate mitochondrial gene transcription influencing oxidative phosphorylation and energy metabolism

3. Functions of Glucocorticoids

A. Effects on Carbohydrate Metabolism

• Stimulates gluconeogenesis in the liver by 6- to 10-fold - by increasing enzymes for amino acid-to-glucose conversion and by mobilizing amino acids from extrahepatic tissues (especially muscle)
• Antagonizes insulin (reduces GLUT4 translocation, decreases IRS-1 and PI3-kinase expression) causing insulin resistance
• Elevates blood glucose - can cause "adrenal diabetes"
• Promotes hepatic glycogen storage

B. Effects on Protein Metabolism

• Causes catabolism of proteins in most tissues (muscle, bone, skin, lymphoid tissue), releasing amino acids into blood
• Increases amino acid availability for gluconeogenesis in the liver
• In excess: muscle wasting, thin skin, poor wound healing, osteoporosis

C. Effects on Fat Metabolism

• Promotes mobilization of fatty acids from adipose tissue, increasing free fatty acids in plasma
• Activates cellular oxidation of fatty acids for energy
• In Cushing syndrome: characteristic redistribution of fat (central obesity, "buffalo hump," "moon face")

D. Anti-inflammatory and Stress Effects

• Blocks the five stages of inflammation by:
  • Stabilizing lysosomal membranes (prevents release of proteolytic enzymes)
  • Decreasing capillary permeability (blocks histamine effects)
  • Suppressing the immune system - decreases T-cell output and antibody formation
  • Reducing leukocyte migration and phagocytic activity
  • Inhibiting fibroblast proliferation (reducing fibrous scarring)
• Mobilizes amino acids and fats for energy, maintaining tissue viability during stress

E. Effects on Blood Cells and Immunity

• Decreases eosinophils and lymphocytes in blood (lymphocytopenia is a marker of cortisol excess)
• Causes atrophy of lymphoid tissue (thymus, lymph nodes)
• Stimulates erythropoietin synthesis, increasing red blood cell production
• Suppresses immune responses - useful clinically to prevent transplant rejection

F. Other Effects

• Blocks allergic reaction severity (prevents anaphylactic shock)
• Increases CNS excitability (excess causes euphoria or psychosis)
• Promotes fetal lung surfactant synthesis in late gestation

4. Effects of Deficiency (Addison's Disease / Adrenal Insufficiency)

Glucocorticoid Deficiency causes:

Mineralocorticoid Deficiency causes:

• Hyponatremia, hyperkalemia, mild acidosis (sodium/water lost in urine, potassium retained)
• Circulatory shock from plasma volume depletion - death within 4 days to 2 weeks if untreated

Melanin Pigmentation:

• Loss of cortisol removes negative feedback → elevated ACTH and MSH secretion → hyperpigmentation of skin and mucous membranes (characteristic bronze skin of Addison's disease)

Adrenal Crisis:

• Any physical stress (surgery, trauma, infection) provokes acute life-threatening glucocorticoid deficiency - requires immediate parenteral hydrocortisone