What is the mechanism of action and function of cortisol?

Cortisol Mechanism of Action and Function

Cortisol is the dominant glucocorticoid hormone in humans, produced in the zona fasciculata of the adrenal cortex, functioning through lipophilic cellular penetration and genomic receptor binding to regulate metabolism, stress responses, inflammation, and immune function. 1

Production and Regulation

• Cortisol synthesis occurs in the zona fasciculata of the adrenal cortex under control of the hypothalamic-pituitary-adrenal (HPA) axis 1
• The HPA axis operates through a hierarchical cascade: corticotropin-releasing hormone (CRH) from the hypothalamus stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary, which in turn drives cortisol production 1
• Baseline cortisol production is approximately 5-10 mg per m² of body surface area daily, equivalent to 15-25 mg total per day in adults, or up to 20 mg daily 1
• Cortisol secretion follows both pulsatile (ultradian) and circadian patterns, with peak levels in the morning (140-700 nmol/L at 0900h) and nadir at midnight (80-350 nmol/L) 1

Mechanism of Action

• Cortisol is highly lipophilic, allowing passive diffusion across cell membranes to reach intracellular glucocorticoid receptors 1
• In plasma, cortisol is extensively protein-bound: 60-80% binds to cortisol-binding globulin (CBG), 15-35% to albumin, with only approximately 5-10% remaining as free, biologically active hormone 1, 2
• The free cortisol fraction represents the biologically active component that exerts physiologic effects on target tissues 2, 3
• Cortisol acts through genomic mechanisms by binding intracellular receptors that regulate gene transcription, though the specific molecular pathways are detailed in the metabolic syndrome literature 4

Physiologic Functions

Stress Response

• During major physiologic stress (such as surgery), cortisol secretion increases five-fold to approximately 100 mg per day, returning to baseline within 24-48 hours after uncomplicated procedures 1
• Cortisol mediates the fight-or-flight response through adrenal release that enables threat management with short-term physiological changes including increased heart rate and blood pressure 1
• Chronic or excessive cortisol activation can lead to HPA axis dysregulation with consequent neuroendocrine stress response abnormalities 1

Metabolic Regulation

• Cortisol regulates energy metabolism and promotes lipolysis as part of its glucocorticoid activity 1
• The hormone plays a central role in glucose homeostasis and insulin sensitivity, with chronic excess associated with insulin resistance and visceral obesity 1, 4
• Hypercortisolemia leads to visceral obesity and the severe cardiovascular complications seen in Cushing's syndrome 1

Anti-inflammatory and Immune Effects

• Cortisol exerts potent anti-inflammatory and immunosuppressive actions on the immune system 1
• The hormone can alter immune function by up-regulating the inflammatory system while diminishing humoral immunity, potentially inducing cytokine-mediated "sickness behavior" 1

Developmental and Behavioral Effects

• Cortisol in breast milk may influence infant neurodevelopment and behavior, with evidence suggesting sex-specific effects on temperament and fear reactivity 1
• Milk glucocorticoids are absorbed through the infant gut into systemic circulation and may impact programming of the neuroendocrine stress axis 1
• Cortisol dysregulation is implicated in various psychiatric disorders, with fluctuations in secretion accompanying mental illness severity 5

Clinical Measurement Considerations

• Serum cortisol assays measure total cortisol and can be misleading in patients with altered protein concentrations affecting CBG or albumin levels 2
• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) offers superior specificity and sensitivity compared to traditional immunoassays for cortisol measurement 2, 3
• Unbound cortisol is excreted unchanged in urine, with 24-hour urine free cortisol correlating well with mean serum-free cortisol in conditions of cortisol excess 2, 3
• Salivary cortisol reflects unbound serum cortisol and provides a reliable alternative for measuring free cortisol 2, 3

Critical Clinical Pitfall

A common error is interpreting total serum cortisol without considering protein-binding status—in patients with altered CBG or albumin levels (critical illness, liver disease, nephrotic syndrome, pregnancy), total cortisol may be misleading as it does not reflect the biologically active free fraction 2. In these situations, measurement of free cortisol (salivary or urine) or use of LC-MS/MS methods provides more accurate assessment of true cortisol bioavailability.