Cortisol

Cortisol is a steroid hormone in the glucocorticoid class and is also a stress hormone. When used as medication, it is referred to as hydrocortisone.

Cortisol is produced in many animals, primarily by the zona fasciculata of the adrenal cortex in an adrenal gland. In other tissues, its production is lower. Cortisol is released in a diurnal cycle and increases in response to stress and low blood-glucose concentration. Its functions include raising blood sugar through gluconeogenesis, suppressing the immune system, aiding in metabolism, and reducing bone formation. These actions occur when cortisol binds to glucocorticoid or mineralocorticoid receptors within a cell, affecting gene expression by binding to DNA.

Health effects

Metabolic response

Metabolism of glucose

Cortisol is crucial in regulating glucose metabolism, promoting gluconeogenesis (glucose synthesis) and glycogenesis (glycogen synthesis) in the liver, and glycogenolysis (breakdown of glycogen) in skeletal muscle. It raises blood glucose levels by reducing glucose uptake in muscle and adipose tissue, decreasing protein synthesis, and increasing lipolysis. These processes collectively elevate blood glucose levels, fueling the brain and other tissues during the fight-or-flight response. Cortisol also releases amino acids from muscle, aiding gluconeogenesis. Its effects are complex and varied.

Overall, cortisol stimulates gluconeogenesis (the synthesis of 'new' glucose from non-carbohydrate sources, mainly in the liver, but also in the kidneys and small intestine under certain conditions). This results in increased blood glucose levels, further supported by decreased sensitivity of peripheral tissue to insulin, preventing glucose uptake from the blood.

Cortisol allows hormones like glucagon and adrenaline to increase glucose production.

Cortisol indirectly influences liver and muscle glycogenolysis (breaking down glycogen to glucose-1-phosphate and glucose) through glucagon and adrenaline. It also facilitates glycogen phosphorylase activation, necessary for adrenaline's effect on glycogenolysis.

Interestingly, cortisol promotes both gluconeogenesis (biosynthesis of glucose) in the liver and glycogenesis (polymerization of glucose into glycogen), thus stimulating glucose/glycogen turnover in the liver. In contrast, in skeletal muscle, cortisol promotes glycogenolysis (breakdown of glycogen into glucose) indirectly through catecholamines, working with them to break down muscle glycogen into glucose for muscle use.

Metabolism of proteins and lipids

Prolonged elevated cortisol levels can lead to proteolysis (protein breakdown) and muscle wasting, providing substrates for gluconeogenesis. Cortisol's effects on lipid metabolism are complex; while chronic high cortisol levels lead to lipogenesis, an acute increase promotes lipolysis. This discrepancy is explained by cortisol-induced high blood glucose stimulating insulin release, which promotes lipogenesis over time.

Immune response

Cortisol inhibits the release of substances causing inflammation and treats conditions from overactive B-cell antibody responses, like inflammatory and rheumatoid diseases, and allergies. Low-dose topical hydrocortisone, available over-the-counter in some countries, treats skin issues like rashes and eczema.

Cortisol suppresses interleukin 12 (IL-12), interferon gamma (IFN-gamma), IFN-alpha, and tumor necrosis factor alpha (TNF-alpha) production by antigen-presenting cells (APCs) and T helper cells (Th1 cells), while upregulating interleukin 4, interleukin 10, and interleukin 13 by Th2 cells, shifting towards a Th2 immune response. This shift during infection is protective, preventing excessive inflammation.

Cortisol weakens the immune system by preventing T-cell proliferation, making interleukin-2 producing T-cells unresponsive to interleukin-1 and unable to produce IL-2. Cortisol downregulates the IL-2R receptor on helper T-cells, favoring a Th2 immune response and B-cell antibody production.

Cortisol negatively feeds back on IL-1. An immune stressor causes peripheral immune cells to release IL-1 and other cytokines like IL-6 and TNF-alpha, stimulating the hypothalamus to release corticotropin-releasing hormone (CRH), which stimulates adrenocorticotropic hormone (ACTH) production in the adrenal gland, increasing cortisol production. Cortisol then inhibits TNF-alpha production and reduces immune cell responsiveness to IL-1.

This system regulates the immune response to the correct level, like a thermostat. However, in severe infections or when the immune system is overly sensitized, the correct set point may not be reached. Due to cortisol and other signaling molecules downregulating Th1 immunity, certain infections (like Mycobacterium tuberculosis) can trigger an incorrect immune response.

Lymphocytes, including B-cell lymphocytes, are key agents of humoral immunity. Increased lymphocytes in lymph nodes, bone marrow, and skin enhance the humoral immune response, releasing antibodies that neutralize pathogens, promote opsonization, and activate complement pathways. Antibodies neutralize pathogens, target them for destruction, and activate complement molecules to enhance immune response.

Rapid administration of corticosterone or RU28362 in adrenalectomized animals changes leukocyte distribution.

Natural killer cells target larger threats like bacteria and tumors. Cortisol reduces their effectiveness by downregulating cytotoxicity receptors, while prolactin has the opposite effect, enhancing receptor expression and function.

Cortisol stimulates copper enzymes, including lysyl oxidase for collagen and elastin cross-linking, and superoxide dismutase, which helps poison bacteria.

Viruses like influenza and SARS-CoV suppress stress hormone secretion to evade immune responses. They produce a protein mimicking ACTH, leading to antibodies that suppress adrenal function and cortisol production, allowing immune evasion.

This viral strategy can severely impact the host, as cortisol is crucial for metabolism, blood pressure, inflammation, and immune response regulation. A lack of cortisol can cause adrenal insufficiency, with symptoms like fatigue, weight loss, low blood pressure, nausea, and abdominal pain, impairing the host's stress and infection response. By suppressing cortisol, viruses can evade the immune system and weaken host health and resilience.

Other effects

Metabolism

Glucose

Cortisol opposes insulin, contributes to hyperglycemia by promoting gluconeogenesis, and reduces peripheral glucose utilization (insulin resistance) by decreasing the movement of glucose transporters (particularly GLUT4) to the cell membrane. It also enhances glycogen synthesis (glycogenesis) in the liver, storing glucose in an easily accessible form.

Bone and collagen

Cortisol decreases bone formation, promoting the long-term development of osteoporosis (a progressive bone disease). This occurs through two mechanisms: cortisol stimulates RANKL production by osteoblasts, activating osteoclasts via RANK receptors, and inhibits osteoprotegerin (OPG) production, which acts as a decoy receptor for RANKL. When RANKL binds to OPG, no response occurs, unlike binding to RANK, which activates osteoclasts.

It transports potassium out of cells in exchange for an equal number of sodium ions. This can lead to hyperkalemia during metabolic shock post-surgery. Cortisol also decreases calcium absorption in the intestines and reduces collagen synthesis.

Amino acid

Cortisol increases free amino acids in the serum by inhibiting collagen formation, reducing amino acid uptake by muscles, and inhibiting protein synthesis. Cortisol (as opticortinol) may inversely suppress IgA precursor cells in the intestines of calves. It also inhibits IgA in serum, similar to IgM, but does not inhibit IgE.

Electrolyte balance

Cortisol enhances the glomerular filtration rate and renal plasma flow, increasing phosphate excretion, sodium and water retention, and potassium excretion by acting on mineralocorticoid receptors. It also increases sodium and water absorption and potassium excretion in the intestines.

Sodium

Cortisol facilitates sodium absorption in the small intestine of mammals. However, sodium depletion does not influence cortisol levels, so cortisol cannot regulate serum sodium. The original role of cortisol may have been sodium transport, supported by its function in freshwater and saltwater fish for sodium regulation.

Potassium

A sodium load enhances cortisol's promotion of potassium excretion. Corticosterone acts similarly to cortisol in this regard. For potassium to exit the cell, cortisol moves an equal number of sodium ions into the cell, easing pH regulation, unlike the typical potassium-deficient scenario where two sodium ions enter for every three potassium ions exiting, akin to the deoxycorticosterone effect.

Stomach and kidneys

Cortisol stimulates gastric acid production. Its only direct effect on kidney hydrogen-ion excretion is enhancing ammonium ion excretion by deactivating renal glutaminase.

Memory

Cortisol collaborates with adrenaline (epinephrine) to form memories of short-term emotional events, a proposed mechanism for storing flash bulb memories, possibly to remember what to avoid. However, prolonged cortisol exposure damages hippocampus cells, impairing learning.

Diurnal cycles

Diurnal cycles of cortisol levels occur in humans.

Stress

Prolonged stress can result in elevated levels of circulating cortisol (considered one of the key "stress hormones").

Effects during pregnancy

In human pregnancy, increased fetal cortisol production between weeks 30 and 32 starts the production of fetal lung pulmonary surfactant to aid lung maturation. In fetal lambs, glucocorticoids (mainly cortisol) rise after about day 130, causing a significant increase in lung surfactant by around day 135. While lamb fetal cortisol is primarily of maternal origin during the first 122 days, by day 136, 88% or more is derived from the fetus. Although the timing of increased fetal cortisol in sheep can vary, it typically occurs about 11.8 days before labor begins. In various livestock species (e.g., cattle, sheep, goats, and pigs), a late gestation fetal cortisol surge initiates parturition by removing the progesterone block on cervical dilation and myometrial contraction.

The mechanisms causing this effect on progesterone differ among species. In sheep, where the placenta produces sufficient progesterone to maintain pregnancy after about day 70, the prepartum fetal cortisol surge prompts the placental conversion of progesterone to estrogen. (The increased estrogen level stimulates prostaglandin secretion and oxytocin receptor development.)

Fetal exposure to cortisol during gestation can lead to various developmental outcomes, including changes in prenatal and postnatal growth patterns. In marmosets, a New World primate species, pregnant females exhibit varying cortisol levels during gestation, both within and among individuals. Infants born to mothers with high gestational cortisol in the first trimester had lower growth rates in body mass indices compared to those born to mothers with low gestational cortisol (about 20% lower). However, these high-cortisol infants experienced faster postnatal growth rates than low-cortisol infants later in postnatal periods, achieving complete growth catch-up by 540 days of age. These findings suggest that gestational cortisol exposure has significant potential fetal programming effects on both pre and postnatal growth in primates.

Cortisol face

Elevated cortisol levels can cause facial swelling and bloating, resulting in a round and puffy appearance known as "cortisol face."

Synthesis and release

Cortisol is synthesized in the human body by the adrenal gland's zona fasciculata, the second of the three layers of the adrenal cortex. This cortex forms the outer "bark" of each adrenal gland, located atop the kidneys. Cortisol release is regulated by the hypothalamus in the brain. The hypothalamus secretes corticotropin-releasing hormone, prompting cells in the adjacent anterior pituitary to release adrenocorticotropic hormone (ACTH) into the bloodstream, which carries it to the adrenal cortex. ACTH stimulates the production of cortisol and other glucocorticoids, the mineralocorticoid aldosterone, and dehydroepiandrosterone.

Testing of individuals

The normal values shown in the following tables apply to humans (normal levels vary among species). Measured cortisol levels, and thus reference ranges, depend on the sample type, analytical method used, and factors such as age and sex. Therefore, test results should always be interpreted using the reference range from the laboratory that provided the result. An individual's cortisol levels can be measured in blood, serum, urine, saliva, and sweat.

			Reference ranges for blood plasma content of free cortisol
Time	Lower limit	Upper limit	Unit
09:00 am	140	700	nmol/L
5	25	μg/dL
Midnight	80	350	nmol/L
2.9	13	μg/dL

With a molecular weight of 362.460 g/mole, the conversion factor from μg/dL to nmol/L is roughly 27.6; therefore, 10 μg/dL is approximately 276 nmol/L.

		Reference ranges for urinalysis of free cortisol (urinary free cortisol or UFC)
Lower limit	Upper limit	Unit
28 or 30	280 or 490	nmol/24h
10 or 11	100 or 176	μg/24 h

Cortisol adheres to a circadian rhythm, making it ideal to measure cortisol levels four times daily using saliva tests for accuracy. An individual might have normal overall cortisol but experience lower levels at specific times and higher levels at others. This variability leads some experts to question the clinical value of cortisol measurement.

Cortisol is lipophilic and is transported bound to transcortin (also known as corticosteroid-binding globulin (CBG)) and albumin. Only a small portion of total serum cortisol is unbound and biologically active. Cortisol binds to transcortin through hydrophobic interactions in a 1:1 ratio. Serum cortisol assays measure total cortisol, which can be misleading for patients with altered serum protein levels. The salivary cortisol test avoids this issue, as only free cortisol can cross the blood-saliva barrier. Transcortin particles are too large to traverse this barrier, which consists of epithelial cell layers in the oral mucosa and salivary glands.

Cortisol can be incorporated into hair from blood, sweat, and sebum. A 3-centimeter segment of scalp hair can represent 3 months of growth, although growth rates vary across different scalp areas. Hair cortisol is a reliable marker of chronic cortisol exposure.

Automated immunoassays lack specificity and exhibit significant cross-reactivity due to interactions with cortisol's structural analogs, resulting in differences across assays. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) enhances specificity and sensitivity.

Disorders of cortisol production

Certain medical conditions are associated with abnormal cortisol production, including:

• Primary hypercortisolism (Cushing's syndrome): excessive cortisol levels

  • Secondary hypercortisolism (pituitary tumor leading to Cushing's disease, pseudo-Cushing's syndrome)

    
    

• Primary hypocortisolism (Addison's disease, Nelson's syndrome): insufficient cortisol levels

  
  

  • Secondary hypocortisolism (pituitary tumor, Sheehan's syndrome)

Regulation

The primary regulation of cortisol is through the pituitary gland peptide, ACTH, which likely controls cortisol by managing calcium movement into cortisol-secreting target cells. ACTH is regulated by the hypothalamic peptide corticotropin-releasing hormone (CRH), which is under nervous control. CRH works synergistically with arginine vasopressin, angiotensin II, and epinephrine. (In swine, which do not produce arginine vasopressin, lysine vasopressin acts synergistically with CRH.)

When activated macrophages secrete IL-1, which synergizes with CRH to increase ACTH, T-cells also release glucosteroid response modifying factor (GRMF) and IL-1; both increase the cortisol needed to inhibit nearly all immune cells. Immune cells then regulate themselves, but at a higher cortisol setpoint. In diarrheic calves, the cortisol increase is minimal compared to healthy calves and decreases over time. Due to interleukin-1's synergism with CRH, the cells retain some fight-or-flight override. Cortisol has a negative feedback effect on interleukin-1, which is especially useful for treating diseases that cause excessive CRH secretion, such as those from endotoxic bacteria. Suppressor immune cells are unaffected by GRMF, so the effective setpoint for immune cells might be higher than that for physiological processes. GRMF primarily affects the liver rather than the kidneys for some physiological processes.

High-potassium media (which stimulates aldosterone secretion in vitro) also stimulate cortisol secretion from the fasciculata zone of canine adrenals—unlike corticosterone, which potassium does not affect.

Potassium loading also raises ACTH and cortisol in humans. This likely explains why potassium deficiency causes a decline in cortisol and decreases the conversion of 11-deoxycortisol to cortisol. This may also play a role in rheumatoid arthritis pain, as cell potassium is always low in RA.

Ascorbic acid, especially in high doses, has been shown to mediate responses to psychological stress and accelerate the reduction of circulating cortisol levels post-stress. This is evidenced by decreased systolic and diastolic blood pressures and reduced salivary cortisol levels after ascorbic acid treatment.

Factors increasing cortisol levels

• Viral infections raise cortisol levels through cytokine activation of the HPA axis.

  
  

• Intense (high VO2 max) or prolonged aerobic exercise temporarily increases cortisol levels to boost gluconeogenesis and maintain blood glucose; however, cortisol returns to normal after eating (restoring a neutral energy balance).

  
  

• Severe trauma or stressful events can elevate cortisol levels in the blood for extended periods.

  
  

• Low-carbohydrate diets cause a short-term increase in resting cortisol (≈3 weeks) and elevate the cortisol response to aerobic exercise in both the short and long term.

  
  

• An increase in ghrelin, the hunger-stimulating hormone, raises cortisol levels.

Biochemistry

Biosynthesis

Cortisol is produced from cholesterol. This process occurs in the zona fasciculata of the adrenal cortex. The term "cortisol" originates from 'cortex', meaning "the outer layer", which refers to the adrenal cortex where cortisol is formed.

In humans, the adrenal cortex also generates aldosterone in the zona glomerulosa and some sex hormones in the zona reticularis, but cortisol is its primary secretion in humans and many other species. In cattle, corticosterone levels can match or surpass cortisol levels. In humans, the adrenal gland's medulla, located beneath the cortex, primarily releases the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) during sympathetic activation.

The production of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland through ACTH, which is itself stimulated by CRH released by the hypothalamus. ACTH enhances cholesterol concentration in the inner mitochondrial membrane by regulating the steroidogenic acute regulatory protein. It also promotes the primary rate-limiting step in cortisol synthesis, converting cholesterol to pregnenolone, catalyzed by Cytochrome P450SCC (side-chain cleavage enzyme).

Metabolism

11beta-hydroxysteroid dehydrogenases

Cortisol is reversibly converted to cortisone by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which comprises two enzymes: 11-beta HSD1 and 11-beta HSD2. This conversion involves the oxidation of the hydroxyl group at the 11-beta position.

A-ring reductases (5alpha- and 5beta-reductases)

Cortisol is also irreversibly converted into 5-alpha tetrahydrocortisol (5-alpha THF) and 5-beta tetrahydrocortisol (5-beta THF), with 5-alpha reductase and 5-beta-reductase serving as the rate-limiting factors, respectively. 5-Beta reductase also limits the conversion of cortisone to tetrahydrocortisone.

Cytochrome P450, family 3, subfamily A monooxygenases

Cortisol is further metabolized irreversibly into 6β-hydroxycortisol by cytochrome p450-3A monooxygenases, primarily CYP3A4. Drugs that induce CYP3A4 can speed up cortisol clearance.

Chemistry

Cortisol is a naturally occurring pregnane corticosteroid and is also referred to as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione.