Cortisol

Cortisol (hydrocortisone) is a steroid hormone, or glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat, protein and carbohydrate metabolism. It also decreases bone formation. During pregnancy, increased production of cortisol between weeks 30-32 initiates production of fetal lung surfactant to promote maturation of the lungs. Various synthetic forms of cortisol are used to treat a variety of diseases.

Production and release
Cortisol is produced by the adrenal gland in the zona fasciculata, the second of three layers comprising the outer adrenal cortex. This release is controlled by the hypothalamus, a part of the brain. The secretion of corticotropin-releasing hormone (CRH) by the hypothalamus triggers anterior pituitary secretion of adrenocorticotropic hormone (ACTH). ACTH is carried by the blood to the adrenal cortex, where it triggers glucocorticoid secretion.

Main functions in the body

 * increasing blood sugar through gluconeogenesis
 * suppressing the immune system
 * aiding in fat, protein, and carbohydrate metabolism

It suppresses the immune system by "muting" the white blood cells

Another function is to decrease bone formation. Cortisol is used to treat diseases such as Addison’s disease, inflammatory and rheumatoid diseases, and allergies. Low-potency hydrocortisone, available over the counter in some countries, is used to treat skin problems such as rashes, eczema and others.

Cortisol prevents the release of substances in the body that cause inflammation. It stimulates gluconeogenesis (the breakdown of protein and fat to provide metabolites that can be converted to glucose in the liver) and it activates anti-stress and anti-inflammatory pathways.

Patterns
The amount of cortisol present in the blood undergoes diurnal variation; the level peaks in the early morning (approximately 8 am) and reaches its lowest level at about midnight-4 am, or three to five hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. This pattern is not present at birth; estimates of when it begins vary from two weeks to nine months of age.

Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and physiological stressors such as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion, or temperature extremes. Cortisol levels may also differ for individuals with autism or Asperger's syndrome.

There is also significant individual variation, although a given person tends to have consistent rhythms.

Normal levels
Using the molecular weight of 362.460 g/mole, the conversion factor from µg/dl to nmol/L is approximately 27.6; thus, 10 µg/dl is approximately equal to 276 nmol/L.

A urinary value smaller than 200 nmol/24h (72 µg/24h ) strongly indicates absence of Cushing's syndrome.

Effects
Cortisol is released in response to stress, acting to restore homeostasis. However, prolonged cortisol secretion (which may be due to chronic stress or the excessive secretion seen in Cushing's syndrome) results in significant physiological changes.

Cortisol counteracts insulin, contributes to hyperglycemia-causing hepatic gluconeogenesis and inhibits the peripheral utilization of glucose (insulin resistance) by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane. However, cortisol increases glycogen synthesis (glycogenesis) in the liver. The permissive effect of cortisol on insulin action in liver glycogenesis is observed in hepatocyte culture in the laboratory, although the mechanism for this is unknown.
 * Insulin:

In laboratory rats, cortisol-induced collagen loss in the skin is ten times greater than in any other tissue. Cortisol (as opticortinol) may inversely inhibit IgA precursor cells in the intestines of calves. Cortisol also inhibits IgA in serum, as it does IgM; however, it is not shown to inhibit IgE.
 * Collagen:

Cortisol stimulates gastric-acid secretion. Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to stimulate the excretion of ammonium ions by deactivating the renal glutaminase enzyme. Net chloride secretion in the intestines is inversely decreased by cortisol in vitro (methylprednisolone).
 * Gastric and renal secretion:

Cortisol inhibits sodium loss through the small intestine of mammals. Sodium depletion, however, does not affect cortisol levels so cortisol cannot be used to regulate serum sodium. Cortisol's original purpose may have been sodium transport. This hypothesis is supported by the fact that freshwater fish utilize cortisol to stimulate sodium inward, while saltwater fish have a cortisol-based system for expelling excess sodium.
 * Sodium:

A sodium load augments the intense potassium excretion by cortisol; corticosterone is comparable to cortisol in this case. In order for potassium to move out of the cell, cortisol moves an equal number of sodium ions into the cell. This should make pH regulation much easier (unlike the normal potassium-deficiency situation, in which two sodium ions move in for each three potassium ions that move out—closer to the deoxycorticosterone effect). Nevertheless, cortisol consistently causes serum alkalosis; in a deficiency, serum pH does not change. The purpose of this may be to reduce serum pH to an optimum value for some immune enzymes during infection, when cortisol declines. Potassium is also blocked from loss in the kidneys by a decline in cortisol (9 alpha fluorohydrocortisone).
 * Potassium:

Cortisol acts as a diuretic hormone, controlling one-half of intestinal diuresis; it has also been shown to control kidney diuresis in dogs. The decline in water excretion following a decline in cortisol (dexamethasone) in dogs is probably due to inverse stimulation of antidiuretic hormone (ADH or arginine vasopressin), which is not overridden by water loading. Humans and other animals also use this mechanism.
 * Water:

Cortisol stimulates many copper enzymes (often to 50% of their total potential), probably to increase copper availability for immune purposes. This includes lysyl oxidase, an enzyme which is used to cross-link collagen and elastin. Especially valuable for immune response is cortisol's stimulation of the superoxide dismutase, since this copper enzyme is almost certainly used by the body to permit superoxides to poison bacteria. Cortisol causes an inverse four- or fivefold decrease of metallothionein (a copper storage protein) in mice; however, rodents do not synthesize cortisol themselves. This may be to furnish more copper for ceruloplasmin synthesis or to release free copper. Cortisol has an opposite effect on aminoisobuteric acid than on the other amino acids. If alpha-aminoisobuteric acid is used to transport copper through the cell wall, this anomaly might be explained.
 * Copper:

Cortisol can weaken the activity of the immune system. Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor. Cortisol also has a negative-feedback effect on interleukin-1. IL-1 must be especially useful in combating some diseases; however, endotoxic bacteria have gained an advantage by forcing the hypothalamus to increase cortisol levels (forcing the secretion of CRH hormone, thus antagonizing IL-1). The suppressor cells are not affected by glucosteroid response-modifying factor (GRMF), so the effective setpoint for the immune cells may be even higher than the setpoint for physiological processes (reflecting leukocyte redistribution to lymph nodes, bone marrow, and skin). Rapid administration of corticosterone (the endogenous Type I and Type II receptor agonist) or RU28362 (a specific Type II receptor agonist) to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are not affected by cortisol.
 * Immune system:

Cortisol reduces bone formation, favoring long-term development of osteoporosis. It transports potassium out of cells in exchange for an equal number of sodium ions (see above). This can trigger the hyperkalemia of metabolic shock from surgery. Cortisol also reduces calcium absorption in the intestine.
 * Bone metabolism:

Cortisol works with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future. However, long-term exposure to cortisol damages cells in the hippocampus; this damage results in impaired learning. Furthermore, it has been shown that cortisol inhibits memory retrieval of already stored information.
 * Memory:


 * Additional effects:
 * Increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine; in the absence of cortisol, widespread vasodilation occurs


 * Inhibits secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH (Adrenocorticotropic hormone or corticotropin) secretion. Some researchers believe that this normal feedback system may become dysregulated when animals are exposed to chronic stress


 * Causes the kidneys to produce hypotonic urine


 * Shuts down the reproductive system, resulting in an increased chance of miscarriage and (in some cases) temporary infertility.  Fertility returns after cortisol levels return to normal


 * Has anti-inflammatory properties, reducing histamine secretion and stabilizing lysosomal membranes. Stabilization of lysosomal membranes prevents their rupture, preventing damage to healthy tissues


 * Stimulates hepatic detoxification by inducing tryptophan oxygenase (reducing serotonin levels in the brain), glutamine synthase (reducing glutamate and ammonia levels in the brain), cytochrome P-450 hemoprotein (mobilizing arachidonic acid), and metallothionein (reducing heavy metals in the body)


 * In addition to cortisol's effects in binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone it also binds to the mineralocorticoid receptor. Aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor; however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids and allow selective mineralocorticoid action. This enzyme—11-beta hydroxysteroid dehydrogenase type II (Protein:HSD11B2)—catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites


 * There are potential links between cortisol, appetite and obesity.

Binding
Most serum cortisol (all but about 4%) is bound to proteins, including corticosteroid binding globulin (CBG) and serum albumin. Free cortisol passes easily through cellular membranes, where they bind intracellular cortisol receptors.

Regulation
The primary control of cortisol is the pituitary gland peptide, adrenocorticotropic hormone (ACTH). ACTH probably controls cortisol by controlling the movement of calcium into the cortisol-secreting target cells. ACTH is in turn controlled by the hypothalamic peptide corticotropin releasing hormone (CRH), which is under nervous control. CRH acts synergistically with arginine vasopressin, angiotensin II, and epinephrine. When activated macrophages start to secrete interleukin-1 (IL-1), which synergistically with CRH increases ACTH, T-cells also secrete glucosteroid response modifying factor (GRMF or GAF) as well as IL-1; both increase the amount of cortisol required to inhibit almost all the immune cells. Immune cells then assume their own regulation, but at a higher cortisol setpoint. The increase in cortisol in diarrheic calves is minimal over healthy calves, however, and falls over time. The cells do not lose all their fight-or-flight override because of interleukin-1's synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1 —especially useful for those diseases which gain an advantage by forcing the hypothalamus to secrete too much CRH, such as those caused by endotoxic bacteria. The suppressor immune cells are not affected by GRMF, so the immune cells' effective setpoint may be even higher than the setpoint for physiological processes. GRMF (known as GAF in this reference) 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, upon which potassium has no effect. Potassium loading also increases ACTH and cortisol in humans. This is probably the reason why potassium deficiency causes cortisol to decline (as mentioned) and causes a decrease in conversion of 11-deoxycortisol to cortisol. This may also have a role in rheumatoid-arthritis pain; cell potassium is always low in RA.

Factors generally reducing cortisol levels

 * Magnesium supplementation decreases serum cortisol levels after aerobic exercise, but not after resistance training.
 * Omega 3 fatty acids have a dose-dependent effect in slightly reducing cortisol release influenced by mental stress, suppressing the synthesis of interleukin-1 and -6 and enhancing the synthesis of interleukin-2; the former promotes higher CRH release. Omega 6 fatty acids, on the other hand, have an inverse effect on interleukin synthesis.
 * Music therapy can reduce cortisol levels in certain situations.
 * Massage therapy can reduce cortisol.
 * Laughing, and the experience of humour, can lower cortisol levels.
 * Crying can reduce cortisol levels. William H. Frey II, a biochemist at the University of Minnesota, proposed that people feel "better" after crying, due to the elimination of hormones associated with stress, specifically adrenocorticotropic hormone. This, paired with increased mucosal secretion during crying, could lead to a theory that crying is a mechanism developed in humans to dispose of this stress hormone when levels grow too high.
 * Soy-derived phosphatidylserine interacts with cortisol; the correct dose, however, is unclear.
 * Vitamin C blunts cortisol release in response to mental and physical stressors.
 * Black tea may hasten recovery from a high-cortisol condition.
 * Regular dancing to Argentine tango has been shown to lead to significant decreases in salivary cortisol concentrations.
 * Sexual intercourse.

Factors generally increasing cortisol levels

 * Caffeine may increase cortisol levels.
 * Sleep deprivation.
 * Intense (high VO2 max) or prolonged physical exercise stimulates cortisol release to increase gluconeogenesis and maintain blood glucose. Proper nutrition and high-level conditioning can help stabilize cortisol release.
 * The Val/Val variation of the BDNF gene in men, and the Val/Met variation in women, are associated with increased salivary cortisol in a stressful situation.
 * Hypoestrogenism and melatonin supplementation increase cortisol levels in postmenopausal women.
 * Burnout is associated with higher cortisol levels.
 * Severe trauma or stressful events can elevate cortisol levels in the blood for prolonged periods.
 * Subcutaneous adipose tissue regenerates cortisol from cortisone.
 * Anorexia nervosa may be associated with increased cortisol levels.
 * The serotonin receptor gene 5HTR2C is associated with increased cortisol production in men.
 * Some formulations of combined oral contraceptive pills increase cortisol levels in young women who perform whole-body-resistance exercise training.
 * Commuting increases cortisol levels relative to the length of the trip, its predictability and the amount of effort involved.
 * Stimuli associated with sexual intercourse can increase cortisol levels in Gilts (a young female pig that has not produced her first litter).

Clinical chemistry

 * Hypercortisolism: Excessive levels of cortisol in the blood. (See Cushing's syndrome.)
 * Hypocortisolism (adrenal insufficiency): Insufficient levels of cortisol in the blood.

The relationship between cortisol and ACTH, and some consequent conditions, are as follows:

A 2010 study has found that serum cortisol predicts increased cardiovascular mortality in patients with acute coronary syndrome.

Pharmacology
Hydrocortisone is the pharmaceutical term for cortisol used in oral administration, intravenous injection or topical application. It is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients who need steroid treatment but cannot take oral medication, and perioperatively in patients on longterm steroid treatment to prevent Addisonian crisis. It may be used topically for allergic rashes, eczema, psoriasis and certain other inflammatory skin conditions. It may also be injected into inflamed joints resulting from diseases such as gout.

Compared to hydrocortisone, prednisolone is about four times as strong and dexamethasone about forty times as strong, in their anti-inflammatory effect. For side effects, see corticosteroid and prednisolone.

Hydrocortisone creams and ointments are available in most countries without prescription in strengths ranging from 0.05% to 2.5% (depending on local regulations) with stronger forms available by prescription only. Covering the skin after application increases the absorption and effect. Such enhancement is sometimes prescribed, but otherwise should be avoided to prevent overdose and systemic impact.

Advertising for the dietary supplement CortiSlim originally (and falsely) claimed that it contributed to weight loss by blocking cortisol. The manufacturer was fined $12 million by the Federal Trade Commission in 2007 for false advertising, and no longer claims in their marketing that CortiSlim is a cortisol antagonist.

Biosynthesis


Cortisol is synthesized from cholesterol. Synthesis takes place in the zona fasciculata of the adrenal cortex. (The name cortisol is derived from cortex.) While the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion. The medulla of the adrenal gland lies under the cortex, mainly secreting the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation.

The synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with adrenocorticotropic hormone (ACTH); ACTH production is in turn stimulated by corticotropin-releasing hormone (CRH), which is released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane, via regulation of the STAR (steroidogenic acute regulatory) protein. It also stimulates the main rate-limiting step in cortisol synthesis, in which cholesterol is converted to pregnenolone and catalyzed by Cytochrome P450SCC (side chain cleavage enzyme).

Metabolism
Cortisol is metabolized by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2.
 * 11-beta HSD1 utilizes the cofactor NADPH to convert biologically-inert cortisone to biologically-active cortisol
 * 11-beta HSD2 utilizes the cofactor NAD+ to convert cortisol to cortisone

Overall, the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically-active cortisol in a given tissue; 11-beta HSD2 serves to decrease local concentrations of biologically-active cortisol.

Cortisol is also metabolized into 5-alpha tetrahydrocortisol (5-alpha THF) and 5-beta tetrahydrocortisol (5-beta THF), reactions for which 5-alpha reductase and 5-beta reductase are the rate-limiting factors respectively. 5-beta reductase is also the rate-limiting factor in the conversion of cortisone to tetrahydrocortisone (THE).

An alteration in 11-beta HSD1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance known as metabolic syndrome.

An alteration in 11-beta HSD2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (SAME).