Cortisol is a
steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wit ...
in the
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
class of hormones and a
stress hormone
Stress hormones are secreted by endocrine glands to modify one's internal environment during times of stress. By performing various functions such as mobilizing energy sources, increasing heart rate, and downregulating metabolic processes which ...
. When used as medication, it is known as
hydrocortisone
Hydrocortisone is the name for the hormone cortisol when supplied as a medication. It is a corticosteroid and works as an anti-inflammatory and by immune suppression. Uses include conditions such as adrenocortical insufficiency, adrenogenit ...
.
Cortisol is produced in many animals, mainly by the ''
zona fasciculata
The ''zona fasciculata'' (sometimes, fascicular or fasciculate zone) constitutes the middle and also the widest zone of the adrenal cortex, sitting directly beneath the ''zona glomerulosa''. Constituent cells are organized into bundles or "fasc ...
'' of the
adrenal cortex
The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. I ...
in an
adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...
.
In other tissues, it is produced in lower quantities. By a
diurnal cycle
A diurnal cycle (or diel cycle) is any pattern that recurs every 24 hours as a result of one full Earth's rotation, rotation of the planet Earth around its axis. Earth's rotation causes surface diurnal temperature variation, temperature fluctuati ...
, cortisol is released and increases in response to
stress and a low
blood-glucose concentration.
[ It functions to increase blood sugar through ]gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
, suppress the immune system
The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
, and aid in the metabolism
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
of calories. It also decreases bone formation. These stated functions are carried out by cortisol binding to glucocorticoid or mineralocorticoid receptors inside a cell, which then bind to DNA to affect gene expression.[
]
Health effects
Metabolic response
Metabolism of glucose
Cortisol plays a crucial role in regulating glucose metabolism and promotes gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
(glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
synthesis) and glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanis ...
(breakdown of glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.
Glycogen functions as one of three regularly used forms ...
) in the liver, producing glucose to provide to other tissues. It also increases blood glucose levels by reducing glucose uptake in muscle and adipose
Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...
tissue, decreasing protein synthesis, and increasing the breakdown of fats into fatty acids (lipolysis). All of these metabolic steps have the net effect of increasing blood glucose levels, which fuel the brain and other tissues during the fight-or-flight response. Cortisol is also responsible for releasing amino acids from muscle, providing a substrate for gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
.[ Its impact is complex and diverse.]
In general, cortisol stimulates gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
(the synthesis of 'new' glucose from non-carbohydrate sources, which occurs mainly in the liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, but also in the kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s and small intestine
The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...
under certain circumstances). The net effect is an increase in the concentration of glucose in the blood, further complemented by a decrease in the sensitivity of peripheral tissue to insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
, thus preventing this tissue from taking the glucose from the blood. Cortisol has a permissive effect on the actions of hormones that increase glucose production, such as glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...
and adrenaline
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
.
Cortisol also plays an important, but indirect, role in liver and muscle glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanis ...
(the breaking down of glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.
Glycogen functions as one of three regularly used forms ...
to glucose-1-phosphate
Glucose 1-phosphate (also called Cori ester) is a glucose molecule with a phosphate group on the 1'-carbon. It can exist in either the α- or β-anomeric form.
Reactions of α-glucose 1-phosphate Catabolic
In glycogenolysis, it is the direct pro ...
and glucose) which occurs as a result of the action of glucagon and adrenaline. Additionally, cortisol facilitates the activation of glycogen phosphorylase
Glycogen phosphorylase is one of the phosphorylase enzymes (). Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphor ...
, which is necessary for adrenaline to have an effect on glycogenolysis.
It is paradoxical that cortisol promotes not only gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
(biosynthesis of glucose molecules) in the liver, but also glycogenesis
Glycogenesis is the process of glycogen synthesis or the process of converting glucose into glycogen in which glucose molecules are added to chains of glycogen for storage. This process is activated during rest periods following the Cori cycl ...
(polymerization
In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many fo ...
of glucose molecules into glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.
Glycogen functions as one of three regularly used forms ...
): cortisol is thus better thought of as stimulating glucose/glycogen turnover in the liver. This is in contrast to cortisol's effect in the skeletal muscle where glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanis ...
(breakdown of glycogen into glucose molecules) is promoted indirectly through catecholamines
A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
...
. In this way, cortisol and catecholamines work synergistically to promote the breakdown of muscle glycogen into glucose for use in the muscle tissue.
Metabolism of proteins and lipids
Elevated levels of cortisol, if prolonged, can lead to proteolysis
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...
(breakdown of proteins) and muscle wasting. The reason for proteolysis is to provide the relevant tissue with a feedstock for gluconeogenesis; see glucogenic amino acid
A glucogenic amino acid (or glucoplastic amino acid) is an amino acid that can be converted into glucose through gluconeogenesis. This is in contrast to the ketogenic amino acids, which are converted into ketone bodies.
The production of glucose ...
s. The effects of cortisol on lipid metabolism are more complicated since lipogenesis
In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into Adipose tissue, fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in adipose, fat. Lipogenesis encompasses both fatty aci ...
is observed in patients with chronic, raised circulating glucocorticoid (i.e. cortisol) levels, although an acute increase in circulating cortisol promotes lipolysis
Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolysis, hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in Adipose tissue, fat adip ...
. The usual explanation to account for this apparent discrepancy is that the raised blood glucose concentration (through the action of cortisol) will stimulate insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
release. Insulin stimulates lipogenesis, so this is an indirect consequence of the raised cortisol concentration in the blood but it will only occur over a longer time scale.
Immune response
Cortisol prevents the release of substances in the body that cause inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
. It is used to treat conditions resulting from overactivity of the B-cell-mediated antibody response. Examples include inflammatory and rheumatoid diseases, as well as allergies
Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...
. Low-dose topical hydrocortisone
Topical hydrocortisone is a drug under the Drug class, class of corticosteroids, which is used for the treatment of skin inflammation, itchiness and Allergy, allergies. Some examples include insect bites, dermatitis and rash.
Hydrocortisone was ...
, available as a nonprescription medicine in some countries, is used to treat skin problems such as rashes
A rash is a change of the skin that affects its color, appearance, or texture.
A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked ...
and eczema
Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
.
Cortisol inhibits production of interleukin 12
Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B-lymphoblast, lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the ...
(IL-12), interferon gamma
Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...
(IFN-gamma), IFN-alpha, and tumor necrosis factor alpha
Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
(TNF-alpha) by antigen-presenting cells
An antigen-presenting cell (APC) or accessory cell is a cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes u ...
(APCs) and T helper cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
s (Th1 cells), but upregulates interleukin 4
The interleukin 4 (IL4, IL-4) is a cytokine that induces differentiation of naive helper T cells ( Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 ...
, interleukin 10
Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti- inflammatory cytokine. In humans, interleukin 10 is encoded by the ''IL10'' gene. IL-10 signals through a receptor complex consisting of two IL- ...
, and interleukin 13
Interleukin 13 (IL-13) is a protein that in humans is encoded by the ''IL13'' gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The sec ...
by Th2 cells. This results in a shift toward a Th2 immune response rather than general immunosuppression. The activation of the stress system (and resulting increase in cortisol and Th2 shift) seen during an infection is believed to be a protective mechanism which prevents an over-activation of the inflammatory response.
Cortisol can weaken the activity of the immune system
The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
. It prevents proliferation of T-cells by rendering the interleukin-2
Interleukin-2 (IL-2) is an interleukin, which is a type of cytokine signaling molecule forming part of the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) ...
producer T-cell
T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...
s unresponsive to interleukin-1
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Discovery
Discovery of these cytokines began with studies on t ...
, and unable to produce the T-cell growth factor IL-2. Cortisol downregulates the expression of the IL2 receptor IL-2R on the surface of the helper T-cell which is necessary to induce a Th1 'cellular' immune response, thus favoring a shift towards Th2 dominance and the release of the cytokines listed above which results in Th2 dominance and favors the 'humoral' B-cell mediated antibody immune response.
Cortisol also has a negative-feedback effect on IL-1.
The way this negative feedback works is that an immune stressor causes peripheral immune cells to release IL-1 and other cytokines
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
such as IL-6 and TNF-alpha. These cytokines stimulate the hypothalamus, causing it to release corticotropin-releasing hormone
Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that b ...
(CRH). CRH in turn stimulates the production of adrenocorticotropic hormone
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
(ACTH) among other things in the adrenal gland, which (among other things) increases production of cortisol. Cortisol then closes the loop as it inhibits TNF-alpha production in immune cells and makes them less responsive to IL-1.
Through this system, as long as an immune stressor is small, the response will be regulated to the correct level. Like a thermostat controlling a heater, the hypothalamus uses cortisol to turn off the heat once the production of cortisol matches the stress induced on the immune system. But in a severe infection or in a situation where the immune system is overly sensitized to an antigen (such as in allergic reactions
Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...
) or there is a massive flood of antigens (as can happen with endotoxic
Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as ''E. coli'' and ''Salmonella'' with a common structural archite ...
bacteria) the correct set point might never be reached. Also because of downregulation of Th1 immunity by cortisol and other signaling molecules
In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukary ...
, certain types of infection, (notably Mycobacterium tuberculosis
''Mycobacterium tuberculosis'' (M. tb), also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis.
First discovered in 1882 by Robert Koch, ''M. tuberculosis'' ha ...
) can trick the body into getting locked in the wrong mode of attack, using an antibody-mediated humoral response when a cellular response is needed.
Lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...
include the B-cell lymphocytes that are the antibody-producing cells of the body, and are thus the main agents of humoral immunity
Humoral immunity is the aspect of immunity (medical), immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Humoral immunity is ...
. A larger number of lymphocytes in the lymph nodes, bone marrow, and skin means the body is increasing its humoral immune response. B-cell lymphocytes release antibodies into the bloodstream. These antibodies lower infection through three main pathways: neutralization, opsonization
Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed (i.e. ...
, and complement activation
The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote infla ...
. Antibodies neutralize pathogens by binding to surface adhering proteins, keeping pathogens from binding to host cells. In opsonization, antibodies bind to the pathogen and create a target for phagocytic immune cells to find and latch onto, allowing them to destroy the pathogen more easily. Finally antibodies can also activate complement molecules which can combine in various ways to promote opsonization or even act directly to lyse a bacteria. There are many different kinds of antibody and their production is highly complex, involving several types of lymphocyte, but in general lymphocytes and other antibody regulating and producing cells will migrate to the lymph nodes to aid in the release of these antibodies into the bloodstream.
Rapid administration of corticosterone
Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. In the very rare case of congenital adrenal hyperplasia due ...
(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.
On the other side of things, there are natural killer cell
Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells ...
s; these cells have the ability to take down larger in size threats like bacteria, parasites, and tumor cells. A separate study found that cortisol effectively disarmed natural killer cells, downregulating the expression of their natural cytotoxicity receptors. Prolactin
Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...
has the opposite effect. It increases the expression of cytotoxicity receptors on natural killer cells, increasing their firepower.
Cortisol stimulates many copper enzymes (often to 50% of their total potential), including lysyl oxidase
Lysyl oxidase (LOX), also known as protein-lysine 6-oxidase, is an enzyme that, in humans, is encoded by the ''LOX'' gene. It catalyzes the conversion of lysine residues into its aldehyde derivative allysine. Allysine form cross-links in extr ...
, an enzyme that cross-links collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
and elastin
Elastin is a protein encoded by the ''ELN'' gene in humans and several other animals. Elastin is a key component in the extracellular matrix of gnathostomes (jawed vertebrates). It is highly Elasticity (physics), elastic and present in connective ...
. Especially valuable for immune response is cortisol's stimulation of the superoxide dismutase
Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () anion radical into normal molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxy ...
, since this copper enzyme is almost certainly used by the body to permit superoxides to poison bacteria.
Some viruses, such as influenza
Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...
and SARS-CoV-1
Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), previously known as severe acute respiratory syndrome coronavirus (SARS-CoV), is a strain (biology), strain of coronavirus that causes severe acute respiratory syndrome (SARS), the ...
and SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...
, are known to suppress the secretion of stress hormones to avoid the organism's immune response, thus avoiding the immune protection of the organism. These viruses suppress cortisol by producing a protein that mimics the human ACTH hormone but is incomplete and does not have hormonal activity. ACTH is a hormone that stimulates the adrenal gland to produce cortisol and other steroid hormones. However, the organism makes antibodies against this viral protein, and those antibodies also kill the human ACTH hormone, which leads to the suppression of adrenal gland function. Such adrenal suppression is a way for a virus to evade immune detection and elimination. This viral strategy can have severe consequences for the host (human that is infected by the virus), as cortisol is essential for regulating various physiological processes, such as metabolism, blood pressure, inflammation, and immune response. A lack of cortisol can result in a condition called adrenal insufficiency, which can cause symptoms such as fatigue, weight loss, low blood pressure, nausea, vomiting, and abdominal pain. Adrenal insufficiency can also impair the ability of the host to cope with stress and infections, as cortisol helps to mobilize energy sources, increase heart rate, and downregulate non-essential metabolic processes during stress. Therefore, by suppressing cortisol production, some viruses can escape the immune system and weaken the host's overall health and resilience.
Other effects
Metabolism
Glucose
Cortisol counteracts insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
, contributes to hyperglycemia
Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating.
Blood gluc ...
by stimulating gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
and inhibits the peripheral use of glucose (insulin resistance
Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia.
Insulin is a horm ...
) by decreasing the translocation of glucose transporter
Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these transporte ...
s (especially GLUT4
Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the ''SLC2A4'' gene. GLUT4 is the insulin-regulated glucose transporter found primarily in ad ...
) to the cell membrane. Cortisol also increases glycogen synthesis (glycogenesis) in the liver, storing glucose in easily accessible form.
Bone and collagen
Cortisol reduces bone formation, favoring long-term development of osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk.
It is the most common reason f ...
(progressive bone disease). The mechanism behind this is two-fold: cortisol stimulates the production of RANKL
Receptor activator of nuclear factor kappa- ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiat ...
by osteoblast
Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...
s which stimulates, through binding to RANK
A rank is a position in a hierarchy. It can be formally recognized—for example, cardinal, chief executive officer, general, professor—or unofficial.
People Formal ranks
* Academic rank
* Corporate title
* Diplomatic rank
* Hierarchy ...
receptors, the activity of osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...
s – cells responsible for calcium resorption from bone – and also inhibits the production of osteoprotegerin
Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by th ...
(OPG) which acts as a decoy receptor and captures some RANKL before it can activate the osteoclasts through RANK. In other words, when RANKL binds to OPG, no response occurs as opposed to the binding to RANK which leads to the activation of osteoclasts.
It transports potassium
Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...
out of cells in exchange for an equal number of sodium
Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
ions (see above). This can trigger the hyperkalemia
Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0 mmol/L (3.5 and 5.0 mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Oc ...
of metabolic shock from surgery. Cortisol also reduces calcium
Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
absorption in the intestine. Cortisol down-regulates the synthesis of collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
.
Amino acid
Cortisol raises the free amino acids in the serum by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis. Cortisol (as opticortinol) may inversely inhibit IgA IGA or IgA may refer to:
Businesses and organizations
* IGA (supermarkets) (initially Independent Grocers Alliance), a name used by many independent supermarkets throughout the world
** IGA (Australian supermarket group), the local Australian v ...
precursor cells in the intestines of calves. Cortisol also inhibits IgA in serum, as it does IgM
Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen;
causing it to also ...
; however, it is not shown to inhibit IgE
Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isoform") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε ...
.
Electrolyte balance
Cortisol increases glomerular filtration rate, and renal plasma flow from the kidneys thus increasing phosphate excretion, as well as increasing sodium and water retention and potassium excretion by acting on mineralocorticoid receptor
The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...
s. It also increases sodium and water absorption and potassium excretion in the intestines.
Sodium
Cortisol promotes sodium absorption 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 use cortisol to stimulate sodium inward, while saltwater fish have a cortisol-based system for expelling excess sodium.
Potassium
A sodium load augments the intense potassium excretion by cortisol. Corticosterone
Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. In the very rare case of congenital adrenal hyperplasia due ...
is comparable to cortisol in this case. 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).
Stomach and kidneys
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.
Memory
Cortisol works with adrenaline
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
(epinephrine) to create memories
Memory is the faculty of the mind by which data or information is Encoding (memory), encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future Action (philosophy), action. I ...
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
The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
; this damage results in impaired learning.
Diurnal cycles
Diurnal cycle
A diurnal cycle (or diel cycle) is any pattern that recurs every 24 hours as a result of one full Earth's rotation, rotation of the planet Earth around its axis. Earth's rotation causes surface diurnal temperature variation, temperature fluctuati ...
s of cortisol levels are found in humans.
Stress
Sustained stress can lead to high levels of circulating cortisol (regarded as one of the more important of the several "stress hormones").
Effects during pregnancy
During human pregnancy, increased fetal production of cortisol between weeks 30 and 32 initiates production of fetal lung pulmonary surfactant
Pulmonary surfactant is a surface-active complex of phospholipids and proteins formed by Type II cells, type II alveolar cells. The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic regions. By adsorption, adso ...
to promote maturation of the lungs. In fetal lambs, glucocorticoids (principally cortisol) increase after about day 130, with lung surfactant increasing greatly, in response, by about day 135, and although lamb fetal cortisol is mostly of maternal origin during the first 122 days, 88% or more is of fetal origin by day 136 of gestation. Although the timing of fetal cortisol concentration elevation in sheep may vary somewhat, it averages about 11.8 days before the onset of labor. In several livestock species (e.g. cattle, sheep, goats, and pigs), the surge of fetal cortisol late in gestation triggers the onset of parturition by removing the progesterone block of cervical dilation and myometrial contraction. The mechanisms yielding this effect on progesterone differ among species. In the sheep, where progesterone sufficient for maintaining pregnancy is produced by the placenta after about day 70 of gestation, the prepartum fetal cortisol surge induces placental enzymatic conversion of progesterone to estrogen. (The elevated level of estrogen stimulates prostaglandin secretion and oxytocin
Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include Human bonding, ...
receptor development.)
Exposure of fetuses to cortisol during gestation can have a variety of developmental outcomes, including alterations in prenatal and postnatal growth patterns. In marmoset
The marmosets (), also known as zaris or sagoin, are twenty-two New World monkey species of the genera '' Callithrix'', '' Cebuella'', '' Callibella'', and ''Mico''. All four genera are part of the biological family Callitrichidae. The term ...
s, a species of New World primates, pregnant females have varying levels of cortisol during gestation, both within and between females. Infants born to mothers with high gestational cortisol during the first trimester of pregnancy had lower rates of growth in body mass indices than infants born to mothers with low gestational cortisol (about 20% lower). However, postnatal growth rates in these high-cortisol infants were more rapid than low-cortisol infants later in postnatal periods, and complete catch-up in growth had occurred by 540 days of age. These results suggest that gestational exposure to cortisol in fetuses has important potential fetal programming effects on both pre and postnatal growth in primates.
Cortisol face
Increased cortisol levels may lead to facial swelling and bloating, creating a round and puffy appearance, referred to as "cortisol face." This is not due to everyday stress, but due to rare hormonal disorders.
Synthesis and release
Cortisol is produced in the human body by the adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...
's zona fasciculata
The ''zona fasciculata'' (sometimes, fascicular or fasciculate zone) constitutes the middle and also the widest zone of the adrenal cortex, sitting directly beneath the ''zona glomerulosa''. Constituent cells are organized into bundles or "fasc ...
, the second of three layers comprising the adrenal cortex
The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. I ...
.[ This cortex forms the outer "bark" of each adrenal gland, situated atop the kidneys. The release of cortisol is controlled by the hypothalamus of a brain. Secretion of ]corticotropin-releasing hormone
Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that b ...
by the hypothalamus triggers cells in its neighboring anterior pituitary to secrete adrenocorticotropic hormone
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
(ACTH) into the vascular system, through which blood carries it to the adrenal cortex.[ ACTH stimulates the synthesis of cortisol and other glucocorticoids, mineralocorticoid aldosterone, and ]dehydroepiandrosterone
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It funct ...
.[
]
Testing of individuals
Normal values indicated in the following tables pertain to humans (normal levels vary among species). Measured cortisol levels, and therefore reference ranges, depend on the sample type, analytical method used, and factors such as age and sex. Test results should, therefore, always be interpreted using the reference range from the laboratory that produced the result. An individual's cortisol levels can be detected in blood, serum, urine, saliva, and sweat.
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 about 276 nmol/L.
Cortisol follows a circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...
, and to accurately measure cortisol levels is best to test four times per day through saliva. An individual may have normal total cortisol but have a lower than normal level during a certain period of the day and a higher than normal level during a different period. Therefore, some scholars question the clinical utility of cortisol measurement.
Cortisol is lipophilic, and is transported bound to transcortin
Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6, is a protein produced in the liver in animals. In humans it is encoded by the SERPINA6 gene. It is an alpha-globulin.
Function
This gene encodes an alpha-globulin pr ...
(also known as corticosteroid-binding globulin (CBG)) and albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...
, while only a small part of the total serum cortisol is unbound and has biological activity. This binding of cortisol to transcortin is accomplished through hydrophobic interactions in which cortisol binds in a 1:1 ratio. Serum cortisol assays measures total cortisol, and its results may be misleading for patients with altered serum protein concentrations. The salivary cortisol test avoids this problem because only free cortisol can pass through the blood-saliva barrier. Transcortin particles are too large to pass through this barrier, that consists of epithelial cell layers of the oral mucosa and salivary glands.
Cortisol may be incorporated into hair from blood, sweat, and sebum
A sebaceous gland or oil gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur ...
. A 3 centimeter segment of scalp hair can represent 3 months of hair growth, although growth rates can vary in different regions of the scalp. Cortisol in hair is a reliable indicator of chronic cortisol exposure.
Automated immunoassay
An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassay ...
s lack specificity and show significant cross-reactivity due to interactions with structural analogs of cortisol, and show differences between assays. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) can improve specificity and sensitivity.
Disorders of cortisol production
Some medical disorders are related to abnormal cortisol production, such as:
* Primary hypercortisolism (Cushing's syndrome
Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, ...
): excessive levels of cortisol
** Secondary hypercortisolism (pituitary tumor resulting in Cushing's disease
Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (spec ...
, pseudo-Cushing's syndrome
Pseudo-Cushing's syndrome or non-neoplastic hypercortisolism is a medical condition in which patients display the signs, symptoms, and abnormal cortisol levels seen in Cushing's syndrome. However, pseudo-Cushing's syndrome is not caused by a prob ...
)
* Primary hypocortisolism
Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids (primarily cortisol), mineraloco ...
(Addison's disease
Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adr ...
, Nelson's syndrome Nelson's syndrome is a disorder that occurs in about one in four patients who have had both adrenal glands removed to treat Cushing's disease. In patients with pre-existing adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, loss of ad ...
): insufficient levels of cortisol
** Secondary hypocortisolism (pituitary tumor, Sheehan's syndrome
Sheehan's syndrome, also known as postpartum pituitary gland necrosis, occurs when the pituitary gland is damaged due to significant blood loss and hypovolemic shock (ischemic necrosis) or stroke, originally described during or after childbirth le ...
)
Regulation
The primary control of cortisol is the pituitary
The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
gland peptide, ACTH, which 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
Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...
, angiotensin II
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the ...
, and epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
. (In swine, which do not produce arginine vasopressin, lysine vasopressin acts synergistically with CRH.)
When activated macrophages start to secrete IL-1, which synergistically with CRH increases ACTH, T-cells also secrete glucosteroid response modifying factor (GRMF), 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 to treat diseases that force 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 affects primarily 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.
Ascorbic acid presence, particularly in high doses has also been shown to mediate response to psychological stress and speed the decrease of the levels of circulating cortisol in the body post-stress. This can be evidenced through a decrease in systolic and diastolic blood pressures and decreased salivary cortisol levels after treatment with ascorbic acid.
Factors increasing cortisol levels
* Viral infections increase cortisol levels through activation of the HPA axis
The pascal (symbol: Pa) is the unit of pressure in the International System of Units (SI). It is also used to quantify internal pressure, stress, Young's modulus, and ultimate tensile strength. The unit, named after Blaise Pascal, is an SI ...
by cytokines.
* Intense (high VO2 max) or prolonged aerobic exercise
Aerobic exercise, also known as cardio, is physical exercise of low to high intensity that depends primarily on the aerobic energy-generating process. "Aerobic" is defined as "relating to, involving, or requiring oxygen", and refers to the use of ...
transiently increases cortisol levels to increase gluconeogenesis and maintain blood glucose; however, cortisol declines to normal levels after eating (i.e., restoring a neutral energy balance Energy balance may refer to:
* Earth's energy balance, the relationship between incoming solar radiation, outgoing radiation of all types, and global temperature change.
* Energy accounting, a system used within industry, where measuring and analyz ...
).
* Severe trauma or stressful events can elevate cortisol levels in the blood for prolonged periods.
* Low-carbohydrate diet
Low-carbohydrate diets restrict carbohydrate consumption relative to the average diet (nutrition), diet. Foods high in carbohydrates (e.g., sugar, bread, pasta) are limited, and replaced with foods containing a higher percentage of fat and pro ...
s cause a short-term increase in resting cortisol (≈3 weeks), and increase the cortisol response to aerobic exercise
Aerobic exercise, also known as cardio, is physical exercise of low to high intensity that depends primarily on the aerobic energy-generating process. "Aerobic" is defined as "relating to, involving, or requiring oxygen", and refers to the use of ...
in the short- and long-term.
* Increase in the concentration of ghrelin, the hunger stimulating hormone, increases levels of cortisol.
Biochemistry
Biosynthesis
Cortisol is synthesized from cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
. Synthesis takes place in the zona fasciculata
The ''zona fasciculata'' (sometimes, fascicular or fasciculate zone) constitutes the middle and also the widest zone of the adrenal cortex, sitting directly beneath the ''zona glomerulosa''. Constituent cells are organized into bundles or "fasc ...
of an adrenal cortex
The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. I ...
.
The name "cortisol" is derived from the word 'cortex'. Cortex means "the outer layer"—a reference to the adrenal cortex, the part of the adrenal gland where cortisol is produced.
While the adrenal cortex in humans also produces aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...
in the zona glomerulosa
The ''zona glomerulosa'' (sometimes, glomerular zone) of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the renal capsule. Its cells are ovoid and arranged in clusters or arches (''glomus'' is Latin ...
and some sex hormone
Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...
s in the zona reticularis
The zona reticularis (sometimes, reticulate zone) is the innermost layer of the adrenal cortex, lying deep to the zona fasciculata and superficial to the adrenal medulla. The cells are arranged cords that project in different directions giving a n ...
, cortisol is its main secretion in humans and several other species. In cattle, corticosterone levels may approach or exceed cortisol levels. In humans, the medulla of the adrenal gland lies under its cortex, mainly secreting the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation.
Synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe
The anterior lobe of cerebellum is one of the lobes of the cerebellum responsible for mediating unconscious proprioception. Inputs into the anterior lobe of the cerebellum are mainly from the spinal cord. It is sometimes equated to the "paleocere ...
of the pituitary gland
The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...
with ACTH; ACTH production is, in turn, stimulated by CRH, which is released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane, via regulation of the 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
11beta-hydroxysteroid dehydrogenases
Cortisol is metabolized reversibly to cortisone
Cortisone is a pregnene (21-carbon) steroid hormone. It is a naturally-occurring corticosteroid metabolite that is also used as a pharmaceutical prodrug. Cortisol is converted by the action of the enzyme corticosteroid 11-beta-dehydrogenase ...
by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2. The metabolism of cortisol to cortisone involves oxidation of the hydroxyl group at the 11-beta position.
A-ring reductases (5alpha- and 5beta-reductases)
Cortisol is also metabolized irreversibly 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.
Cytochrome P450, family 3, subfamily A monooxygenases
Cortisol is also metabolized irreversibly into 6β-hydroxycortisol by cytochrome p450-3A monooxygenases, mainly, CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
. Drugs that induce CYP3A4 may accelerate cortisol clearance.
Chemistry
Cortisol is a naturally occurring
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...
pregnane
Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally all ...
corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
and is also known as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione.
Animals
In animals, cortisol is often used as an indicator of stress and can be measured in blood, saliva, urine, hair, and faeces.
See also
* Cortisone
Cortisone is a pregnene (21-carbon) steroid hormone. It is a naturally-occurring corticosteroid metabolite that is also used as a pharmaceutical prodrug. Cortisol is converted by the action of the enzyme corticosteroid 11-beta-dehydrogenase ...
, a hormone
* Cortisol awakening response
The cortisol awakening response (CAR) is an increase between 38% and 75% in cortisol levels peaking 30–45 minutes ''after'' awakening in the morning in some people. This rise is superimposed upon the late-night rise in cortisol which occ ...
* List of corticosteroids
This is a list of corticosteroids (glucocorticoids and mineralocorticoids) or derivative (chemistry), derivatives of cortisol (hydrocortisone). Most esters of these corticosteroids are not included in this list; for esters, see corticosteroid est ...
* Membrane glucocorticoid receptor Membrane glucocorticoid receptors (mGRs) are a group of receptors which bind and are activated by glucocorticoids such as cortisol and corticosterone, as well as certain exogenous glucocorticoids such as dexamethasone. Unlike the classical nuclear g ...
References
External links
Cortisol MS Spectrum
Cortisol: analyte monograph
– The Association for Clinical Biochemistry and Laboratory Medicine
{{Authority control
Anxiety
Corticosteroids
Glucocorticoids
Otologicals
Pregnanes
Steroid hormones
Steroids
Stress (biology)
Stress hormones