Cortisol

Where is it produced and how is it synthesized?

Cortisol is produced in the zona fasciculata of the adrenal cortex. The process of its formation is a multistep matrix biosynthesis using cholesterol as a precursor.

Key stages of synthesis: Cholesterol → Pregnenolone → Progesterone → 17-OH-progesterone → 11-Deoxycortisol → Cortisol.

During pregnancy, maternal blood cortisol levels increase 2-to-3-fold while maintaining daily fluctuations. During this period, the hormone is additionally synthesized by the placenta together with the fetal adrenal glands. In the fetus, the production of its own corticosteroids begins at 26–27 weeks of intrauterine development.

Mechanism of cellular action

Being a steroid, cortisol easily crosses the plasma membrane. Its molecular mechanism represents a chain reaction aimed at altering genome function:

1. Primary interaction: the hormone enters the cell and binds to a cytosolic receptor protein.
2. Translocation: the resulting hormone-receptor complex moves into the cell nucleus.
3. Interaction with the genome: in the nucleus, the complex binds to an enhancer—a DNA region that enhances transcription (GRE — Glucocorticoid Response Element).
4. Result: DNA conformation changes, gene transcription is accelerated, and the amount of mRNA 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 reduces glucose utilization by peripheral tissues. The end result is an increase in blood glucose levels.
• Protein metabolism: enhances proteolysis in muscles, supplying amino acids for gluconeogenesis.
• Lipid metabolism: normally stimulates lipolysis in the limbs. However, in the presence of hormone excess, glucose transport into adipocytes increases, glycolysis in adipose tissue is activated, and lipolytic reactions are inhibited, leading to triglyceride accumulation.
• Fetal development: cortisol is critically necessary for the synthesis of the surfactant system and the maturation of lung tissue.

Regulation of synthesis and secretion

Cortisol production is controlled by the hypothalamic-pituitary-adrenal axis via negative feedback.

• Stimulators: decreased glucose levels, trauma, infections, stress, and morning hours (circadian rhythm).
• Regulatory cascade: hypothalamus releases corticotropin-releasing hormone (CRH) → CRH acts on the pituitary gland, which secretes adrenocorticotropic hormone (ACTH) → ACTH stimulates the adrenal cortex to synthesize and secrete cortisol.
• Feedback: an increase in blood cortisol concentration inhibits the secretion of ACTH in the pituitary gland and corticotropin-releasing hormone in the hypothalamus.

Clinical significance and pathologies

• Cushing's disease or syndrome: hyperproduction of glucocorticoids leading to hyperglycemia, triglyceride accumulation, and obesity.
• Adrenogenital syndrome (AGS): a genetic defect in enzymes, most commonly 21-hydroxylase. The blockade of cortisol synthesis removes negative feedback → leads to ACTH excess → adrenal hyperplasia and the shunting of precursors into the androgen synthesis pathway (virilization).
• Addison's (bronze) disease: bilateral destruction of the adrenal glands reduces cortisol levels. Due to the lack of feedback, ACTH synthesis increases, which has melanocyte-stimulating activity, causing skin hyperpigmentation.
• Pharmacology: synthetic fluorinated derivatives of cortisol—dexamethasone and triamcinolone—have a high affinity for glucocorticoid receptors. They exert a powerful anti-inflammatory effect and have minimal impact on mineral metabolism; fluid retention is virtually absent.

Class and exam questions

What else to study on this topic

• Adrenocorticotropic hormone (ACTH)
• Gluconeogenesis
• Hypothalamo-pituitary system
• Adrenogenital syndrome

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.