Cortisol, also known as hydrocortisone, is a steroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior hormone A hormone is a chemical released by a cell in one part of the body, that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. It is essentially a chemical messenger that transports a signal from one cell to another. All multicellular organisms produce hormones; or glucocorticoid Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the metabolism of glucose, their synthesis in the adrenal cortex, and their steroidal structure ( produced by the adrenal gland In mammals, the adrenal glands are the triangular-shaped endocrine glands that sit on top of the kidneys. They are chiefly responsible for releasing hormones in conjunction with stress through the synthesis of corticosteroids and catecholamines, including cortisol and adrenaline (epinephrine), respectively.^[1] It is released in response to stress Stress is a term in psychology and biology, first coined in the 1930s, which has in more recent decades become a commonplace of popular parlance. It refers to the consequence of the failure of an organism – human or animal – to respond appropriately to emotional or physical threats, whether actual or imagined, or to a low level of blood glucocorticoids. Its primary functions are to increase blood sugar The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally, in mammals the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM (mmol/L, ie, millimoles/liter). It is tightly regulated as a part of metabolic homeostasis through gluconeogenesis, suppress the immune system, and aid in fat, protein and carbohydrate metabolism.^[2] It also decreases bone formation. Various synthetic forms of cortisol are used to treat a variety of different illnesses.

Physiology

Production & Release

Cortisol is produced by the zona fasciculata The zona fasciculata constitutes the middle zone of the adrenal cortex, sitting directly beneath the zona glomerulosa. Constituent cells are organized into bundles or "fascicles" of the adrenal cortex Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis, which is one of two parts of the adrenal gland In mammals, the adrenal glands are the triangular-shaped endocrine glands that sit on top of the kidneys. They are chiefly responsible for releasing hormones in conjunction with stress through the synthesis of corticosteroids and catecholamines, including cortisol and adrenaline (epinephrine), respectively.^[1]

It is released in response to stress Stress is a term in psychology and biology, first coined in the 1930s, which has in more recent decades become a commonplace of popular parlance. It refers to the consequence of the failure of an organism – human or animal – to respond appropriately to emotional or physical threats, whether actual or imagined, or to a low level of blood glucocorticoids, and this release is controlled by the hypothalamus The hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland, a part of the brain.The secretion of corticotropin-releasing hormone (CRH) Corticotropin-releasing hormone , originally named corticotropin-releasing factor (CRF), and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response by the hypothalamus triggers pituitary secretion of adrenal corticotrophic hormone (ACTH Adrenocorticotropic hormone , also known as 'corticotropin', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress (along with corticotropin-releasing hormone from the hypothalamus). Its); ACTH is carried by the blood to the adrenal cortex where it triggers glucocorticoid secretion.

Patterns and Rhythms of Release

The amount of cortisol hormone present in the blood Blood is a specialized bodily fluid that delivers necessary substances to the body's cells – such as nutrients and oxygen – and transports waste products away from those same cells undergoes diurnal variation, with the highest levels present in the early morning (approximately 8am), and the lowest levels present around 12-4am, or 3–5 hours after the onset of sleep Sleep is a naturally recurring altered state of consciousness of relatively suspended sensory and motor activity, characterized by the inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and unconsciousness since it is more easily reversible than hibernation or coma. Information about the light/dark cycle A circadian rhythm is a roughly 24-hour cycle in the biochemical, physiological, or behavioural processes of living entities, including plants, animals, fungi and cyanobacteria . The term "circadian" comes from the Latin circa, "around", and diem or dies, "day", meaning literally "approximately one day". The is transmitted from the retina The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical events that ultimately trigger nerve impulses. These to the paired suprachiasmatic nuclei The suprachiasmatic nucleus or nuclei , abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regulate many different body functions in a 24-hour cycle in the hypothalamus The hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland. The pattern is not present at birth (estimates of when it starts vary from two weeks to 9 months).^[3]

Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH Adrenocorticotropic hormone , also known as 'corticotropin', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress (along with corticotropin-releasing hormone from the hypothalamus). Its levels, clinical depression Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities. The term "major depressive disorder" was selected by the American Psychiatric Association to designate this symptom cluster as a mood disorder, psychological stress Stress is a term in psychology and biology, first coined in the 1930s, which has in more recent decades become a commonplace of popular parlance. It refers to the consequence of the failure of an organism – human or animal – to respond appropriately to emotional or physical threats, whether actual or imagined, and such physiological stressors as hypoglycemia Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood" . It can produce a variety of symptoms and effects but the principal problems arise from an inadequate supply of glucose to the brain, resulting in impairment of function (, illness, fever Fever is a common medical sign characterized by an elevation of temperature above the normal range of 36.5–37.5 °C (98–100 °F) due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering, trauma, surgery Surgery is a medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, to help improve bodily function or appearance, and sometimes for religious reasons. An act of performing surgery may be called a surgical procedure, operation, or simply, fear Fear is an emotional response to a perceived threat. It is a basic survival mechanism occurring in response to a specific stimulus, such as pain or the threat of danger. Some psychologists such as John B. Watson, Robert Plutchik, and Paul Ekman have suggested that fear is one of a small set of basic or innate emotions. This set also includes such, pain Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. It is the feeling common to such experiences as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone", physical exertion or extremes of temperature Historically, two equivalent concepts of temperature have developed, the thermodynamic description and a microscopic explanation based on statistical physics. Since thermodynamics deals entirely with macroscopic measurements, the thermodynamic definition of temperature, first stated by Lord Kelvin, is stated entirely in empirical, measurable. Cortisol levels may also be different for people with autism Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their synapses connect and organize; how this occurs is not or Asperger's syndrome Asperger syndrome is an autism spectrum disorder, and people with it therefore show significant difficulties in social interaction, along with restricted and repetitive patterns of behavior and interests. It differs from other autism spectrum disorders by its relative preservation of linguistic and cognitive development. Although not required for.^[4]

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

Effects

Under normal circumstances, cortisol, like other glucocorticoid Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the metabolism of glucose, their synthesis in the adrenal cortex, and their steroidal structure ( agents, has widespread actions which help restore homeostasis Homeostasis is the property of a system, either open or closed, that regulates its internal environment and tends to maintain a stable, constant condition. Typically used to refer to a living organism, the concept came from that of milieu interieur that was created by Claude Bernard and published in 1865. Multiple dynamic equilibrium adjustment after stress Stress is a term in psychology and biology, first coined in the 1930s, which has in more recent decades become a commonplace of popular parlance. It refers to the consequence of the failure of an organism – human or animal – to respond appropriately to emotional or physical threats, whether actual or imagined. Although cortisol secretion is a natural Endogenous substances are those that originate from within an organism, tissue, or cell . Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates. Their proviruses remain in the genome and are passed on to the next generation function, prolonged cortisol secretion due to chronic stress Chronic stress is the response of the brain to unpleasant events for a prolonged period over which an individual perceives he has no control. It involves an endocrine system response in which occurs a release of corticosteroids. This if continuous for a long time can cause damage to an individual's physical and mental health causes the physiological consequences associated with chronic stress.^[5]

Insulin

Cortisol counteracts insulin Insulin is a hormone that is central to regulate energy and glucose metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, contributing to hyperglycemia by stimulation of hepatic gluconeogenesis Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids^[6] and inhibition of the peripheral utilization of glucose^[6] by decreasing the translocation of glucose transporters Glucose is an essential substrate for the metabolism of most cells. Because glucose is a polar molecule, transport through biological membranes requires specific transport proteins to the cell membrane,^[7] specially GLUT4.^[8] However cortisol increases glycogen Glycogen is the molecule that functions as the secondary long-term energy storage in animal and fungi cells. It is made primarily by the liver and the muscles, but can also be made by glycogenesis within the brain and stomach. Glycogen is the analogue of starch, a less branched glucose polymer in plants, and is commonly referred to as animal synthesis (glycogenesis Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage. This process is activated during rest periods following the Cori cycle, in the liver, and also activated by insulin in response to high glucose levels, for example after a carbohydrate containing meal) in the liver The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion. The liver is necessary for survival; there is currently no way to compensate for the absence of liver function.^[9] Permissive effect of cortisol on insulin action on liver glycogenesis is observed in hepatocyte culture in laboratory, although the mechanism is unknown.

Collagen

In laboratory rats, cortisol-induced collagen loss in the skin is ten times greater than any other tissue.^[10][11] Cortisol (as opticortinol) may inversely inhibit IgA Immunoglobulin A is an antibody that plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined; between 3 and 5g is secreted into the intestinal lumen each day. IgA has two subclasses (IgA1 and IgA2) and can exist in a dimeric form called secretory IgA (sIgA). In its secretory form, precursor cells in the intestines of calves.^[12] Cortisol also inhibits IgA in serum, as it does IgM Immunoglobulin M, or IgM for short, is a basic antibody that is present on B cells. It is the primary antibody against A and B antigens on red blood cells. IgM is by far the physically largest antibody in the human circulatory system. It is produced after an animal has been exposed to an antigen for an extended time or when an animal is exposed to, but is not shown to inhibit IgE In biology, Immunoglobulin E is a class of antibody (or immunoglobulin "isotype") that has only been found in mammals. IgE is a monomeric antibody with 4 Ig-like domains (CH1->CH4). It plays an important role in allergy, and is especially associated with type 1 hypersensitivity. IgE has also been implicated in immune system responses.^[13]

Gastric and renal secretion

Cortisol stimulates gastric acid secretion.^[14] Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to stimulate excretion of ammonium ion by inactivation of renal glutaminase enzyme.^[15] Net chloride secretion in the intestines is inversely decreased by cortisol in vitro (methylprednisolone Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug. It is sold in the USA and Canada under the brand names Medrol, Solu-Medrol and Cadista. It is also available as a generic drug).^{[16][disambiguation needed]}

Sodium

Cortisol inhibits sodium loss through the small intestine of mammals.^[17] Sodium depletion, however, does not affect cortisol,^[18] so cortisol cannot be used to regulate serum sodium. Cortisol's purpose may originally have been to transport sodium; 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.^{[19][disambiguation needed]}

Potassium

Sodium load augments the intense potassium excretion by cortisol, and corticosterone Corticosterone is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands is comparable to cortisol in this case.^[20] In order for potassium to move out of the cell, cortisol moves in an equal number of sodium ions.^[21] It can be seen that this should make pH In chemistry, pH is a measure of the acidity or basicity of a solution. It approximates but is not equal to p[H], the negative logarithm of the molar concentration of dissolved hydronium ions (H3O+); a low pH indicates a high concentration of hydronium ions, while a high pH indicates a low concentration. Crudely, this negative of the logarithm regulation much easier, unlike the normal potassium deficiency situation in which about 2 sodium ions move in for each 3 potassium ions that move out, which is closer to the deoxycorticosterone Deoxycorticosterone is a steroid hormone produced by the adrenal gland that possess mineralocorticoid activity and acts as a precursor to aldosterone effect. Nevertheless, cortisol consistently causes alkalosis Alkalosis refers to a condition reducing hydrogen ion concentration of arterial blood plasma . Generally alkalosis is said to occur when pH of the blood exceeds 7.45. The opposite condition is acidosis of the serum, while in a deficiency pH does not change. Perhaps this may be for the purpose of bringing serum pH to a value most optimum for some of the immune enzymes during infection in those times when cortisol declines. Potassium is also blocked from loss in the kidneys directly somewhat by decline of cortisol (9 alpha fluorohydrocortisone).^[22]

Water

Cortisol also acts as an anti-diuretic hormone. Half the intestinal diuresis is so controlled.^[17] Kidney diuresis is also controlled by cortisol in dogs. The decline in water excretion upon decline of cortisol (dexamethasone) in dogs is probably due to inverse stimulation of antidiuretic hormone (ADH or arginine vasopressin), the inverse stimulation of which is not overridden by water loading.^[23] Humans also use this mechanism^[24] and other different animal mechanisms operate in the same direction.^{[disambiguation needed]}

Copper

It is probable that increasing copper availability for immune purposes is the reason many copper enzymes are stimulated to an extent which is often 50% of their total potential by cortisol.^[25] This includes lysyl oxidase, an enzyme which is used to cross link collagen and elastin.^[26] Particularly valuable for immunity is the stimulation of superoxide dismutase by cortisol^[27] since this copper enzyme is almost certainly used by the body to permit superoxide to poison bacteria. Cortisol causes an inverse four- or fivefold decrease of metallothionein, a copper storage protein, in mice^[28] (however rodents do not synthesize cortisol themselves). This may be to furnish more copper for ceruloplasmin synthesis or release of free copper. Cortisol has an opposite effect on alpha aminoisobuteric acid than on the other amino acids.^[29] If alpha aminoisobuteric acid is used to transport copper through the cell wall, this anomaly would possibly be explained.

Immune system

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.^[30] Cortisol also has a negative feedback effect on interleukin-1.^[31] IL-1 must be especially useful in combating some diseases; however, endotoxin bacteria have gained an advantage by forcing the hypothalamus to increase cortisol levels via forcing secretion of CRH hormone, thus antagonizing IL-1 in this case. The suppressor cells are not affected by GRMF,^[32] so that the effective set point for the immune cells may be even higher than the set point for physiological processes. It reflects leukocyte redistribution to lymph nodes, bone marrow, and skin. Acute 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.^[33]

Bone metabolism

It lowers bone formation thus favoring development of osteoporosis in the long term. Cortisol moves potassium out of cells in exchange for an equal number of sodium ions as mentioned above.^[34] This can cause a major problem with the hyperkalemia of metabolic shock from surgery. Cortisol reduces calcium absorption in the intestine.^[35]

Memory

It cooperates 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 results in damage to cells in the hippocampus.^[36] This damage results in impaired learning.

Additional effects

• It increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine. In the absence of cortisol, widespread vasodilation occurs.^{[citation needed]}

• It inhibits the 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.^{[clarification needed][citation needed]}

• It allows for the kidneys to produce hypotonic urine.^{[citation needed]}

• It shuts down the reproductive system, resulting in an increase for the chance of miscarriage and, in some cases, temporary infertility. Fertility returns after cortisol levels are reduced back to normal levels.^[37]

• It has anti-inflammatory effects by reducing histamine secretion and stabilizing lysosomal membranes. The stabilization of lysosomal membranes prevents their rupture, thereby preventing damage to healthy tissues.^{[citation needed]}

• It stimulates hepatic detoxification by inducing tryptophan oxygenase (to reduce serotonin levels in the brain), glutamine synthase (reduce glutamate and ammonia levels in the brain), cytochrome P-450 hemoprotein (mobilizes arachidonic acid), and metallothionein (reduces heavy metals in the body).^{[citation needed]}

• In addition to the effects caused by cortisol binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone, it also binds to the mineralocorticoid receptor. Aldosterone and cortisol have 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.^{[clarification needed][citation needed]}

• There are potential links between cortisol, appetite and obesity^{[38][specify]}.

Binding

Most serum cortisol, all but about 4%, is bound to proteins including corticosteroid binding globulin (CBG), and serum albumin. Only free cortisol is available to receptors.^{[citation needed]}

Regulation

The primary control of cortisol is the pituitary gland peptide, adrenocorticotropic hormone (ACTH). ACTH probably controls cortisol by controlling movement of calcium into the cortisol secreting target cells.^[39] 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.^[40] When activated macrophages start to secrete interleukin-1 (IL-1), which synergistically with CRH increases ACTH,^[31] T-cells also secrete glucosteroid response modifying factor (GRMF or GAF) as well as IL-1, both of which increase the amount of cortisol required to inhibit almost all the immune cells.^[32] Thus immune cells take over their own regulation, but at a higher cortisol set point. Even so, the rise of cortisol in diarrheic calves is minimal over healthy calves and drops below with time.^[41] The cells do not lose all of the fight or flight override because of interleukin-1's synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1 ^[42] which must be especially useful for those diseases which gain an advantage by forcing the hypothalamus to secrete too much CRH, such as the endotoxin bacteria..The suppressor immune cells are not affected by GRMF,^[32] so that the effective set point for the immune cells may be even higher than the set point for physiological processes. GRMF (called GAF in this reference) primarily affects the liver rather than the kidneys for some physiological processes.^[43]

A high potassium media, which stimulates aldosterone secretion in vitro, also stimulates cortisol secretion from the fasciculata zone of dog adrenals ^[44] unlike corticosterone, upon which potassium has no effect.^[45] Potassium loading increases ACTH and cortisol in people also.^[46] This is no doubt the reason why a potassium deficiency causes cortisol to decline (as just mentioned) and why a potassium deficiency causes a decrease in conversion of 11deoxycortisol to cortisol.^[47] This probably contributes to the pain in rheumatoid arthritis since cell potassium is always low in that disease ^[48]

Factors generally reducing cortisol levels

• Magnesium supplementation decreases serum cortisol levels after aerobic exercise,^[49][50] but not in resistance training.^[51]
• Omega 3 fatty acids, in a dose dependent manner (but not significantly),^[52] can lower cortisol release influenced by mental stress^[53] by suppressing the synthesis of interleukin-1 and 6 and enhance the synthesis of interleukin-2, where the former promote higher CRH release. Omega 6 fatty acids, on the other hand, acts inversely on interleukin synthesis.^{[citation needed]}
• Music therapy can reduce cortisol levels in certain situations.^[54]
• Massage therapy can reduce cortisol.^[55]
• Sexual intercourse can reduce cortisol levels.
• Laughing and the experience of humour can lower cortisol levels.^[56]
• One study by a Japanese cosmetics company has asserted that makeup reduces cortisol levels in a mental stress situation.^[57]
• Soy derived Phosphatidylserine interacts with cortisol but the right dosage is still unclear.^[58][59]
• Vitamin C may slightly blunt cortisol release in response to a mental stressor.^[60]
• Black tea may speed up recovery from a high cortisol condition.^[61][62]

Factors generally increasing cortisol levels

• Caffeine may increase cortisol levels.^[63]
• Sleep deprivation increases cortisol levels.^[64]
• Intense (high VO2 max) or prolonged physical exercise stimulate cortisol release in order to increase gluconeogenesis and maintain blood glucose.^[65] Proper nutrition^[66] and high-level conditioning^[67] can help stabilize cortisol release.
• Val/Val variation of the BDNF gene in men, and the Val/Met variation in women is associated with increased salivary cortisol in a stressful situation.^[68]
• Hypoestrogenism and melatonin supplementation increases cortisol levels in postmenopausal women.^[69]
• Burnout is associated with higher cortisol levels.^[70]
• Severe trauma or stress events can elevate cortisol levels in the blood for prolonged periods.^[71]
• Subcutaneous adipose tissue regenerates cortisol from cortisone.^[72]
• Anorexia nervosa may be associated with increased cortisol levels.^[73]
• The serotonin receptor gene 5HTR2C is associated with increased cortisol production in men.^[74]
• Some formulations of combined oral contraceptive pills increase cortisol levels in young women who perform whole-body resistance exercise training.^[75]
• Commuting increases cortisol levels, related to the length of the trip, the amount of effort involved and the predictability of the trip^[76]

Clinical chemistry

• Hypercortisolism: Excessive levels of cortisol in the blood.
• 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.^[77][78]

Pharmacology

Hydrocortisone is the pharmaceutical term for cortisol used for 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 peri-operatively in patients on long-term steroid treatment to prevent an 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 prednisolone, hydrocortisone is about 1/4 the strength for the anti-inflammatory effect, while dexamethasone is about 40 times as strong as hydrocortisone^{[citation needed]}. For side effects, see corticosteroid and prednisolone.

Hydrocortisone creams and ointments are available without prescription in strengths ranging from 0.05% to 2.5%, depending on local regulations, with stronger forms available with prescriptions only. Covering the skin after application increases the absorption and effect. Such enhancement is sometimes prescribed, but otherwise should be avoided to prevent over-dosing and systemic impacts.

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.^[79]

Biochemistry

Biosynthesis

Cortisol is synthesized from cholesterol. The synthesis takes place in the zona fasciculata of the cortex of the adrenal glands. (The name cortisol comes 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 and mainly secretes 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); production of ACTH is in turn stimulated by corticotropin-releasing hormone (CRH), released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane (via regulation of STAR (steroidogenic acute regulatory) protein). ACTH also stimulates the main rate-limiting step in cortisol synthesis where cholesterol is converted to pregnenolone, catalyzed by Cytochrome P450SCC (side chain cleavage enzyme).^[80]

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, while 11-beta HSD2 serves to decrease the 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, sometimes referred to as the metabolic syndrome.^[81]

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).^{[citation needed]}

Media

See also

• Adrenaline
• ACTH stimulation test
• Dexamethasone suppression test
• Corticotropin-releasing hormone
• Cushing's syndrome
• HPA axis
• Hypopituitarism
• Posttraumatic stress disorder
• Central serous retinopathy

References

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