The Role of Cortisol in Human Physiology
Crucial for Stress Adaptation, Metabolism, and Reducing Inflammation
Apr 1, 2009
The human adrenal (suprarenal) glands sit above the kidneys and weigh about 4 grams each. Composing several layers of cellular tissue, each individual layer is responsible for unique hormone production. The outer layers (cortex) produce steroidal hormones like cortisol and aldosterone while the inner (medulla) layers create stimulating hormones of the sympathetic nervous system like epinephrine. Cortisol is created in a layer of the adrenal cortex called the zona fasciculata. Like other steroidal hormones it is a modified form of cholesterol.
The Hypothalamic-Pituitary Axis
The normal production of cortisol by cells of the adrenal cortex is dependent on two messengers in a chain called the hypothalamic-pituitary-adrenal axis (HPA axis). When any type of stress is experienced, the hypothalamus releases a messenger called corticotrophin releasing hormone (CRH). CRH travels down to the anterior pituitary and signals specialized cells to release adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH then makes its way to the adrenal glands where it signals cells of the zona fasciculata and reticularis layers of the adrenal cortex. These cells then step up production of cortisol and androgens.
Making Cortisol
Cells of the zona fasciculata modify cholesterol into a precursor called pregnenolone using the enzyme cholesterol desmolase (rate limiting step). Pregnenolone is then converted to the cortisol. When released into the blood, 90% is bound to the plasma proteins transcortin and albumin. This binding increases the effective half-life of this hormone to around 90 minutes and is thought to serve as a protective mechanism to reduce rapid hormone fluctuations and allow for more uniform distribution.
Rhythm of Release
Cortisol is released into the plasma in a diurnal fashion with the largest spike early in the morning and the lowest levels around midnight. Subjects with a normal sleep cycle would be expected to have values of approximately 20 mcg/dl just prior to rising and around 5 mcg/dl at midnight. This changes when acute stress is involved. When events like pain, mental stress, or strenuous exercise are experienced cortisol levels rise dramatically and may be sustained for protracted periods.
Deactivation and Elimination
After cortisol has performed its mission it is degraded into a less active form called cortisone. This is managed by the enzyme 11-beta-hydroxysteroid dehydrogenase-2 (11-BDHD-2) in a reversible process. Cortisone is then metabolized by the liver and excreted in the bile salts and urine.
Cortisol allows humans to adapt to mental and physical stress in ways that include:
- Modulation of plasma glucose levels
- Mobilization of amino acids and lipids into the plasma from cellular origins
- Suppression of inflammation
- Enhancement of wound healing
- Increased production of erythrocytes
- Electrolyte and fluid manipulation by inhibiting sodium loss while encouraging potassium excretion
Glucose Metabolism
Cortisol has a profound influence on glucose regulation, causing greater plasma concentrations. While inducing the liver to create glucose it negatively influences the effects of insulin. Since the brain primarily relies on glucose for fuel this may insure that it has ample amounts in times of increased activity.
Inflammation Suppression
Inflammation is a process instigated by the immune system that normally addresses wounds and infection. When unchecked, this reaction may do more damage than the initial offense. Cortisol powerfully suppresses immune function and modified forms have historically been used in the treatment of inflammation, autoimmunity, and organ transplant resistance.
Cortisol suppresses inflammation in several ways:
- Inhibits the release of proteolytic enzymes from damaged cells
- Inhibits the production of pro-inflammatory eicosanoids like prostaglandins and leukotrienes
- Inhibits the ability of white blood cells to proliferate and respond to Interleukin-1 and 2.
Supplementary Materials
Soma, R., M. Ikeda, et al. (1994). "Effect of glycyrrhizin on cortisol metabolism in humans." Endocr Regul 28(1): 31-4.
Stewart PM. The adrenal cortex. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Textbook of Endocrinology. 11th ed. Philadelphia, PA: Saunders Elsevier; 2008: chap 14.
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