Cortisol

1. Overview

Cortisol is a vital steroid hormone that plays a central role in the regulation of metabolism, immune function, and the body's stress response. Often referred to as the "stress hormone," it is released in response to physical, emotional, and physiological stress. Cortisol belongs to the glucocorticoid class of hormones and is produced by the adrenal cortex as part of the hypothalamic-pituitary-adrenal (HPA) axis.

2. Location

Cortisol is synthesized and secreted by the zona fasciculata of the adrenal cortex, which is the middle layer of the adrenal gland. The adrenal glands are paired endocrine organs located on top of each kidney. Its secretion is regulated by adrenocorticotropic hormone (ACTH), which is released from the anterior pituitary in response to corticotropin-releasing hormone (CRH) from the hypothalamus.

3. Structure

Cortisol is a steroid hormone derived from cholesterol and consists of 21 carbon atoms, with the chemical formula C21H30O5. It has a cyclopentanoperhydrophenanthrene ring structure typical of steroid hormones and contains hydroxyl groups that contribute to its glucocorticoid activity. Cortisol is lipophilic and binds to intracellular glucocorticoid receptors to exert its effects.

4. Function

Cortisol exerts a wide array of physiological effects, particularly during stress, fasting, and inflammation:

• Regulates glucose metabolism by stimulating gluconeogenesis in the liver and inhibiting glucose uptake in peripheral tissues.

• Suppresses immune response by reducing the production of pro-inflammatory cytokines and immune cell activity.

• Promotes protein catabolism and lipolysis to provide substrates for energy production.

• Maintains vascular tone and responsiveness to catecholamines.

• Inhibits bone formation and calcium absorption in the gut.

5. Physiological role(s)

Cortisol is essential for homeostasis and impacts numerous body systems:

• Stress adaptation: Cortisol levels rise during stress to mobilize energy, maintain blood pressure, and modulate immune activity.

• Diurnal rhythm: Cortisol follows a circadian pattern, peaking in the early morning and declining at night. This rhythm supports wakefulness and energy metabolism.

• Metabolic regulation: Helps maintain blood glucose levels during fasting by promoting hepatic glucose production and inhibiting insulin sensitivity.

• Fetal development: Supports organ maturation, especially the lungs, during late gestation.

• Electrolyte balance: In high concentrations, cortisol can bind mineralocorticoid receptors and influence sodium retention and potassium excretion.

6. Clinical Significance

Abnormal cortisol production leads to a variety of endocrine disorders with significant health consequences:

• Cushing’s Syndrome:

  • Results from prolonged exposure to high cortisol levels.

  • Causes may include pituitary adenoma (Cushing's disease), adrenal tumors, or ectopic ACTH production.

  • Symptoms include central obesity, moon face, buffalo hump, hypertension, muscle wasting, hyperglycemia, and osteoporosis.

• Addison’s Disease (Primary Adrenal Insufficiency):

  • Characterized by low cortisol due to adrenal cortex destruction (e.g., autoimmune or infectious).

  • Symptoms include fatigue, weight loss, hypotension, hyperpigmentation, and electrolyte imbalances.

• Secondary Adrenal Insufficiency:

  • Caused by pituitary or hypothalamic dysfunction leading to decreased ACTH production.

  • Cortisol is low, but aldosterone may remain normal (since it is regulated more by the renin-angiotensin system).

• Congenital Adrenal Hyperplasia (CAH):

  • Genetic defects in enzymes (commonly 21-hydroxylase) disrupt cortisol synthesis.

  • Results in compensatory ACTH elevation, adrenal hyperplasia, and excess androgen production.

• Pharmacologic Use:

  • Synthetic glucocorticoids (e.g., prednisone, dexamethasone) are widely used to suppress inflammation, autoimmunity, and allergic reactions.

  • Chronic use can suppress the HPA axis and cause secondary adrenal insufficiency upon withdrawal.