Synthesis and Location
Cortisol is produced in the zona fasciculata of the adrenal cortex. Its formation is a multi-step enzymatic biosynthesis pathway originating from cholesterol.
Key steps of synthesis: Cholesterol → Pregnenolone → Progesterone → 17-OH-progesterone → 11-Deoxycortisol → Cortisol.
During pregnancy, maternal blood cortisol levels increase 2–3 fold while maintaining diurnal rhythms. During this period, the hormone is additionally synthesized by the placenta together with the fetal adrenal glands. In the fetus, endogenous corticosteroid production begins around the 26th to 27th week of gestation.
Mechanism of Cellular Action
Being a steroid, cortisol readily passes through the plasma membrane. Its molecular mechanism is a chain reaction aimed at altering genome activity:
- Initial interaction: the hormone enters the cell and binds to a cytosolic receptor protein.
- Translocation: the resulting hormone-receptor complex migrates into the cell nucleus.
- Genome interaction: inside the nucleus, the complex binds to an enhancer—a DNA segment that enhances transcription (GRE — Glucocorticoid Response Element).
- Result: DNA conformation changes, gene transcription accelerates, and the number of mRNAs encoding specific enzymes increases, including gluconeogenesis enzymes such as phosphoenolpyruvate carboxykinase.
Physiological Effects
- Carbohydrate metabolism: stimulates gluconeogenesis—the synthesis of glucose from amino acids and pyruvate—in the liver and decreases glucose utilization by peripheral tissues. The net result is an increase in blood glucose.
- Protein metabolism: enhances proteolysis in skeletal muscle, supplying amino acids for gluconeogenesis.
- Lipid metabolism: normally stimulates lipolysis in the extremities. However, in excess, the hormone increases glucose transport into adipocytes, activates glycolysis in adipose tissue, and inhibits lipolysis, leading to triglyceride accumulation.
- Fetal development: cortisol is critically required for the synthesis of the surfactant system and lung maturation.
Regulation of Synthesis and Secretion
Cortisol production is controlled by the hypothalamic-pituitary-adrenal (HPA) axis via a negative feedback loop.
- Stimulators: decreased blood glucose, trauma, infection, stress, and morning hours (circadian rhythm).
- Regulatory cascade: hypothalamus releases corticotropin-releasing hormone (CRH) → CRH acts on the anterior pituitary, which secretes adrenocorticotropic hormone (ACTH) → ACTH stimulates the adrenal cortex to synthesize and secrete cortisol.
- Negative feedback: rising blood cortisol concentration inhibits the secretion of ACTH by the pituitary gland and CRH by the hypothalamus.
Clinical Significance and Pathologies
- Cushing's disease or syndrome: hypersecretion of glucocorticoids leading to hyperglycemia, triglyceride accumulation, and central obesity.
- Congenital adrenal hyperplasia (CAH): a genetic defect in enzymes, most commonly 21-hydroxylase. Blocking cortisol synthesis removes negative feedback → leads to excess ACTH → adrenal hyperplasia and shunting of precursors into the androgen synthesis pathway (virilization).
- Addison's disease: autoimmune or bilateral destruction of the adrenal cortex decreases cortisol levels. Due to the lack of negative feedback, ACTH synthesis increases; because ACTH shares structural homology with MSH, it causes skin hyperpigmentation.
- Pharmacology: synthetic fluorinated cortisol derivatives—dexamethasone and triamcinolone—have a high affinity for glucocorticoid receptors. They exert a potent anti-inflammatory effect with minimal mineralocorticoid activity; fluid retention is virtually absent.