What is cortisol involved in?

Cortisol Involvement in Human Physiology

Cortisol is fundamentally involved in stress response, metabolic regulation, immune function, cardiovascular homeostasis, and neuroendocrine control through the hypothalamic-pituitary-adrenal (HPA) axis. 1

Primary Physiological Roles

Stress Response and HPA Axis Regulation

• The HPA axis controls cortisol synthesis in the zona fasciculata of the adrenal cortex, with corticotropin-releasing hormone (CRH) stimulating adrenocorticotropic hormone (ACTH) release, which drives cortisol production. 1

• Baseline cortisol production is approximately 15-25 mg total per day in adults, with secretion following both pulsatile (ultradian) and circadian patterns, peaking in the morning and reaching nadir at midnight. 1

• During major physiologic stress, 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 of epinephrine and cortisol, enabling threat management with short-term physiological changes including increased heart rate and blood pressure. 2

Metabolic Functions

• Cortisol regulates energy metabolism and promotes lipolysis as part of its glucocorticoid activity, playing a central role in glucose homeostasis and insulin sensitivity. 1

• Acute cortisol withdrawal decreases basal energy expenditure by 10% and increases glucose oxidation, while increasing insulin sensitivity through increased glucose oxidation and decreased endogenous glucose production. 3

• Chronic cortisol excess is associated with insulin resistance and visceral obesity, with elevated cortisol and psychological distress correlating with abdominal fat distribution. 4

• High cortisol levels are independently associated with hypertension and diabetes mellitus, with urinary glucocorticoid excretion linking directly to metabolic syndrome components including blood pressure, fasting glucose, insulin levels, and waist circumference. 4, 5

Cardiovascular Effects

• Chronic hypercortisolism causes persistent hypertension that may not fully resolve even after achieving biochemical remission, according to the Endocrine Society. 6

• Elevated cortisol triggers sympathetic nervous system activation, increasing catecholamine levels and causing tachycardia in healthy individuals. 6

• In active Cushing's disease, standardized mortality ratios range from 4.1 to 16, with myocardial infarction and stroke being primary causes. 6

• Cortisol blunts the vascular effect of angiotensin II, norepinephrine and vasopressin in adrenal dysfunction, leading to further sympathetic nervous system activity and worsening cardio-circulatory dysfunction. 2

Immune and Inflammatory Modulation

• 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" including decreased appetite, fatigue, mood changes, and poor cognitive function. 2, 1

Mechanism of Action

Cellular Level

• Cortisol is highly lipophilic, allowing passive diffusion across cell membranes to reach intracellular glucocorticoid receptors. 1

• In plasma, cortisol is extensively protein-bound, with 60-80% binding to cortisol-binding globulin (CBG) and 15-35% to albumin, leaving only approximately 5-10% as free, biologically active hormone. 1, 7

• The pharmacological effect of metyrapone is to reduce cortisol and corticosterone production by inhibiting the 11-beta-hydroxylation reaction in the adrenal cortex, demonstrating cortisol's feedback mechanism. 8

Neuroendocrine Effects

• Cortisol downregulates its own production via negative feedback loops in the brain that use glucocorticoid receptors; children with fewer glucocorticoid receptors have higher cortisol levels and are more irritable and harder to console. 2

• Cortisol acts on rapidly developing brain structures, with the amygdala becoming overactive, hippocampus underactive, and prefrontal cortex not accessible, showing preliminary association with more severe clinical course in major depressive disorder. 2

• Methylation patterns are impacted by threat and mediated by cortisol, with methyl groups attaching to or coming off promoter regions of genes, leading to transcription or lack of transcription affecting adult stress and reactivity behavior. 2

Developmental and Behavioral Involvement

• Cortisol in breast milk may influence infant neurodevelopment and behavior, with evidence suggesting sex-specific effects on temperament and fear reactivity. 2, 1

• Milk glucocorticoids are absorbed through the infant gut into systemic circulation and may impact programming of the neuroendocrine stress axis, a key determinant for the risk of developing psychopathologies later in life. 2, 1

• Higher neonatal milk cortisol concentrations predicted less impulsivity on cognitive tasks at 6 months of age in rhesus monkeys, though effects on global social behaviors were mixed. 2

Clinical Measurement Context

• Serum cortisol assays measure total cortisol and their results can be misleading in patients with altered serum protein concentrations. 7

• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) offers improved specificity and sensitivity for measuring cortisol in plasma, urine, and saliva samples. 9, 7

• Salivary cortisol reflects changes in unbound serum cortisol and offers a reliable alternative to measuring free cortisol in serum, with baseline salivary cortisol <1.8 ng/ml suggestive of relative adrenal insufficiency. 2