Cortisol
Template:Short description Template:About Template:Distinguish Template:Use dmy dates Template:Use American English Template:Cs1 config Template:Chembox Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone.
Cortisol is produced in many animals, mainly by the zona fasciculata of the adrenal cortex in an adrenal gland.<ref name="light">Template:Cite journal</ref> In other tissues, it is produced in lower quantities.<ref>Template:Cite journal</ref> By a diurnal cycle, cortisol is released and increases in response to stress and a low blood-glucose concentration.<ref name=light/> It functions to increase blood sugar through gluconeogenesis, suppress the immune system, and aid in the metabolism of calories.<ref name="Marieb">Template:Cite book</ref> It also decreases bone formation.<ref name="pmid6690287">Template:Cite journal</ref> 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.<ref name=light/><ref>Template:Cite journal</ref> Template:TOC limit
Health effects
Metabolic response
Metabolism of glucose
Cortisol plays a crucial role in regulating glucose metabolism and promotes gluconeogenesis (glucose synthesis) in the liver, producing glucose to provide to other tissues.<ref>Template:Citation</ref> It also increases blood glucose levels by reducing glucose uptake in muscle and adipose 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.<ref name=light/> Its impact is complex and diverse.<ref name="pmid11724664">Template:Cite journal</ref>
In general, cortisol stimulates gluconeogenesis (the synthesis of 'new' glucose from non-carbohydrate sources, which occurs mainly in the liver, but also in the kidneys and small intestine 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, 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 and adrenaline.<ref name=":0">Template:Cite book</ref>
Cortisol also plays an important, but indirect, role in liver and muscle glycogenolysis (the breaking down of glycogen to glucose-1-phosphate and glucose) which occurs as a result of the action of glucagon and adrenaline. Additionally, cortisol facilitates the activation of glycogen phosphorylase, which is necessary for adrenaline to have an effect on glycogenolysis.<ref name="Martin_2003" /><ref name="pmid1905485">Template:Cite journal</ref>
It is paradoxical that cortisol promotes not only gluconeogenesis (biosynthesis of glucose molecules) in the liver, but also glycogenesis (polymerization of glucose molecules into glycogen): cortisol is thus better thought of as stimulating glucose/glycogen turnover in the liver.<ref>Template:Cite journal</ref> This is in contrast to cortisol's effect in the skeletal muscle where glycogenolysis is promoted indirectly through catecholamines.<ref>Template:Cite book</ref> In this way, cortisol and catecholamines work synergistically to promote the breakdown of muscle glycogen into glucose for use in the muscle tissue.<ref name="pmid10769296">Template:Cite journal</ref>
Metabolism of proteins and lipids
Elevated levels of cortisol, if prolonged, can lead to proteolysis (breakdown of proteins) and muscle wasting.<ref>Template:Cite journal</ref> The reason for proteolysis is to provide the relevant tissue with a feedstock for gluconeogenesis; see glucogenic amino acids.<ref name=":0"/> The effects of cortisol on lipid metabolism are more complicated since lipogenesis is observed in patients with chronic, raised circulating glucocorticoid (i.e. cortisol) levels,<ref name=":0"/> although an acute increase in circulating cortisol promotes lipolysis.<ref name="pmid12067858">Template:Cite journal</ref> The usual explanation to account for this apparent discrepancy is that the raised blood glucose concentration (through the action of cortisol) will stimulate insulin 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. 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. Low-dose topical hydrocortisone, available as a nonprescription medicine in some countries, is used to treat skin problems such as rashes and eczema.
Cortisol inhibits production of interleukin 12 (IL-12), interferon gamma (IFN-gamma), IFN-alpha, and tumor necrosis factor alpha (TNF-alpha) by antigen-presenting cells (APCs) and T helper cells (Th1 cells), but upregulates interleukin 4, interleukin 10, and interleukin 13 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.<ref>Template:Cite journal</ref>
Cortisol can weaken the activity of the immune system. It prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1, 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.<ref name="pmid6461917">Template:Cite journal</ref>
Cortisol also has a negative-feedback effect on IL-1.<ref name="Besedovsky_1986">Template:Cite book</ref> The way this negative feedback works is that an immune stressor causes peripheral immune cells to release IL-1 and other cytokines such as IL-6 and TNF-alpha. These cytokines stimulate the hypothalamus, causing it to release corticotropin-releasing hormone (CRH). CRH in turn stimulates the production of adrenocorticotropic hormone (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.<ref name="Tietz_2008">Template:Cite book</ref>
Through this system, as long as an immune stressor is small, the response will be regulated to the correct level. In general, Template:Clarify span 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) or there is a massive flood of antigens (as can happen with endotoxic bacteria) Template:Clarify span Also because of downregulation of Th1 immunity by cortisol and other signaling molecules, certain types of infection (notably Mycobacterium tuberculosis) 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.Template:Tone inline
Lymphocytes include the B-cell lymphocytes that are the antibody-producing cells of the body, and are thus the main agents of humoral immunity. 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, and complement activation. 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.<ref name="Janeway_2012">Template:Cite book</ref>
On the other side of things,Template:Which? there are natural killer cells; these cells have the ability to take down larger in size threats like bacteria, parasites, and tumor cells. A separate study<ref name="pmid15654827">Template:Cite journal</ref> found that cortisol effectively disarmed natural killer cells, downregulating the expression of their natural cytotoxicity receptors. Prolactin has the opposite effect. It increases the expression of cytotoxicity receptors on natural killer cells, increasing their firepower.Template:Citation neededTemplate:Tone inline
Cortisol stimulates many copper enzymes (often to 50% of their total potential), including lysyl oxidase, an enzyme that cross-links collagen and elastin. Especially valuable for immune response is cortisol's stimulation of the superoxide dismutase,<ref name="isbn0-12-642760-7">Template:Cite book</ref> since this copper enzyme is almost certainly used by the body to permit superoxides to poison bacteria.
Some viruses, such as influenza and SARS-CoV-1 and SARS-CoV-2, are known to suppress the secretion of stress hormones to avoid the organism's immune response. 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.<ref name="cancer2019">Template:Cite journal</ref><ref name="pmid32346813">Template:Cite journal</ref><ref name="pmid15488660">Template:Cite journal</ref> 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.<ref name="pmid18461094">Template:Cite journal</ref><ref name="pmid32346813"/><ref name="pmid15488660" />
Other effects
Metabolism
Glucose
Cortisol counteracts insulin, contributes to hyperglycemia by stimulating gluconeogenesis and inhibits the peripheral use of glucose (insulin resistance)<ref name="pmid33995272">Template:Cite journal</ref> by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.<ref name=light/><ref name="isbn0-07-144578-1">Template:Cite book</ref> Cortisol also increases glycogen synthesis (glycogenesis) in the liver, storing glucose in easily accessible form.<ref name="isbn0-323-05371-8">Template:Cite book</ref>
Bone and collagen
Cortisol reduces bone formation,<ref name="pmid6690287"/> favoring long-term development of osteoporosis (progressive bone disease). The mechanism behind this is two-fold: cortisol stimulates the production of RANKL by osteoblasts which stimulates, through binding to RANK receptors, the activity of osteoclasts, cells responsible for calcium resorption from bone, and also inhibits the production of osteoprotegerin (OPG) which acts as a decoy receptor and captures some RANKL before it can activate the osteoclasts through RANK.<ref name=":0" /> 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 out of cells in exchange for an equal number of sodium ions (see above).<ref name="pmid13233328" /> This can trigger the hyperkalemia of metabolic shock from surgery. Cortisol also reduces calcium absorption in the intestine.<ref name="pmid346457">Template:Cite journal</ref> Cortisol down-regulates the synthesis of collagen.<ref name="pmid3062759">Template:Cite journal</ref>
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.<ref name="Manchester_1964">Template:Cite encyclopedia</ref> Cortisol (as opticortinol) may inversely inhibit IgA precursor cells in the intestines of calves.<ref name="pmid4207041">Template:Cite journal</ref> Cortisol also inhibits IgA in serum, as it does IgM; however, it is not shown to inhibit IgE.<ref name="pmid712020">Template:Cite journal</ref>
Electrolyte balance
Cortisol increases glomerular filtration rate,<ref name="pmid27344357">Template:Cite journal</ref> and renal plasma flow from the kidneys thus increasing phosphate excretion,<ref name="pmid3351211">Template:Cite journal</ref><ref name="pmid24715567">Template:Cite journal</ref> as well as increasing sodium and water retention and potassium excretion by acting on mineralocorticoid receptors. It also increases sodium and water absorption and potassium excretion in the intestines.<ref>Template:Cite book</ref>
Sodium
Cortisol promotes sodium absorption through the small intestine of mammals.<ref name="pmid7323700">Template:Cite journal</ref> Sodium depletion, however, does not affect cortisol levels<ref name="pmid592808">Template:Cite journal</ref> 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.<ref name="isbn0-471-06266-9">Template:Cite book</ref>
Potassium
A sodium load augments the intense potassium excretion by cortisol. Corticosterone is comparable to cortisol in this case.<ref name="Muller O'Connor">Template:Cite book</ref> For potassium to move out of the cell, cortisol moves an equal number of sodium ions into the cell.<ref name="pmid13233328">Template:Cite journal</ref> 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.<ref name="Soffer_1961">Template:Cite book</ref> 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.<ref name="Kokshchuk_1979">Template:Cite journal</ref>
Memory
Cortisol works with adrenaline (epinephrine) 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.<ref name="The Doctors' Medical Library">Template:Cite web</ref> However, long-term exposure to cortisol damages cells in the hippocampus;<ref name="pmid19320982">Template:Cite journal</ref> this damage results in impaired learning.
Diurnal cycles
Diurnal cycles of cortisol levels are found in humans.<ref name="Martin_2003">Template:Cite book</ref>
Stress
Sustained stress can lead to high levels of circulating cortisol (regarded as one of the more important of the several "stress hormones").<ref>Template:Cite book</ref>
Effects during pregnancy
During human pregnancy, increased fetal production of cortisol between weeks 30 and 32 initiates production of fetal lung pulmonary surfactant 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,<ref name="pmid2573">Template:Cite journal</ref> 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.<ref name="pmid7130892">Template:Cite journal</ref> Although the timing of fetal cortisol concentration elevation in sheep may vary somewhat, it averages about 11.8 days before the onset of labor.<ref name="pmid7379742">Template:Cite journal</ref> 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,<ref name="pmid6933207">Template:Cite journal</ref><ref name="pmid10972299">Template:Cite journal</ref> the prepartum fetal cortisol surge induces placental enzymatic conversion of progesterone to estrogen. (The elevated level of estrogen stimulates prostaglandin secretion and oxytocin 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 marmosets, 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.<ref>Template:Cite journal</ref>
Cortisol face
Template:See also 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.<ref>Template:Cite news</ref><ref>Template:Cite news</ref><ref>Template:Cite news</ref>
Synthesis and release
Cortisol is produced in the human body by the adrenal gland's zona fasciculata, the second of three layers comprising the adrenal cortex.<ref name=light/> 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 by the hypothalamus triggers cells in its neighboring anterior pituitary to secrete adrenocorticotropic hormone (ACTH) into the vascular system, through which blood carries it to the adrenal cortex.<ref name=light/> ACTH stimulates the synthesis of cortisol and other glucocorticoids, mineralocorticoid aldosterone, and dehydroepiandrosterone.<ref name=light/>
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.<ref name="pmid31012054">Template:Cite journal</ref><ref name="pmid31161807">Template:Cite journal</ref><ref name="pmid37501014">Template:Cite journal</ref> An individual's cortisol levels can be detected in blood, serum, urine, saliva, and sweat.<ref>Template:Cite journal</ref>
| Time | Lower limit | Upper limit | Unit |
|---|---|---|---|
| 09:00 am | 140<ref name=goodhope>Biochemistry Reference Ranges at Good Hope Hospital Retrieved 8 November 2009</ref><ref name="pmid16909051">Template:Cite journal</ref> | 700<ref name=goodhope /> | nmol/L |
| 5<ref name="cortisol-derived">Derived from molar values using molar mass of 362 g/mol</ref> | 25<ref name="cortisol-derived" /> | μg/dL | |
| Midnight | 80<ref name=goodhope /> | 350<ref name=goodhope /> | nmol/L |
| 2.9<ref name="cortisol-derived" /> | 13<ref name="cortisol-derived" /> | μg/dL |
Using the molecular weight of 362.460 g/mole, the conversion factor from μg/dL to nmol/L is approximately 27.6;<ref name="pmid31381072">Template:Cite journal</ref><ref name="pmid7700725">Template:Cite journal</ref> thus, 10 μg/dL is about 276 nmol/L.
| Lower limit | Upper limit | Unit |
|---|---|---|
| 28<ref name="cortisol-mass">Converted from μg/24h, using molar mass of 362.460 g/mol</ref> or 30<ref name=Gorges1999>Template:Cite journal</ref> | 280<ref name="cortisol-mass" /> or 490<ref name=Gorges1999 /> | nmol/24h |
| 10<ref name="medlineplus">Template:MedlinePlusEncyclopedia</ref> or 11<ref name="cortisol-molar">Converted from nmol/24h, using molar mass of 362.460 g/mol</ref> | 100<ref name=medlineplus /> or 176<ref name="cortisol-molar" /> | μg/24 h |
Cortisol follows a circadian rhythm, 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.<ref name="pmid33792492">Template:Cite journal</ref><ref name="pmid24275191">Template:Cite journal</ref><ref name="pmid18227002">Template:Cite journal</ref><ref name="pmid24356273">Template:Cite journal</ref>
Cortisol is lipophilic, and is transported bound to transcortin (also known as corticosteroid-binding globulin (CBG)) and albumin, while only a small part of the total serum cortisol is unbound and has biological activity.<ref name="pmid29194043">Template:Cite journal</ref> This binding of cortisol to transcortin is accomplished through hydrophobic interactions in which cortisol binds in a 1:1 ratio.<ref>Template:Cite journal</ref> 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.<ref name="pmid30904918">Template:Cite journal</ref><ref name="pmid21371536">Template:Cite journal</ref><ref name="pmid34684123">Template:Cite journal</ref><ref name="pmid19632788">Template:Cite journal</ref> Transcortin particles are too large to pass through this barrier,<ref>Template:Cite journal</ref> that consists of epithelial cell layers of the oral mucosa and salivary glands.<ref name="pmid32842479">Template:Cite journal</ref>
Cortisol may be incorporated into hair from blood, sweat, and sebum. 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.<ref name="pmid25560699">Template:Cite journal</ref>
Automated immunoassays 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.<ref name="pmid28068807">Template:Cite journal</ref>
Disorders of cortisol production
Some medical disorders are related to abnormal cortisol production, such as:
- Primary hypercortisolism (Cushing's syndrome): excessive levels of cortisol<ref>Template:Cite web</ref>
- Secondary hypercortisolism (pituitary tumor resulting in Cushing's disease,<ref name=NIH2008>Template:Cite web</ref><ref>Template:Cite book</ref> pseudo-Cushing's syndrome)
- Primary hypocortisolism (Addison's disease, Nelson's syndrome): insufficient levels of cortisol
- Secondary hypocortisolism (pituitary tumor, Sheehan's syndrome)
Regulation
The primary control of cortisol is the pituitary gland peptide, ACTH, which probably controls cortisol by controlling the movement of calcium into the cortisol-secreting target cells.<ref>Template:Cite journal</ref> 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.<ref name="pmid3015567">Template:Cite journal</ref> (In swine, which do not produce arginine vasopressin, lysine vasopressin acts synergistically with CRH.<ref name="pmid8385088">Template:Cite journal</ref>)
When activated macrophages start to secrete IL-1, which synergistically with CRH increases ACTH,<ref name="Besedovsky_1986" /> 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.<ref name="pmid6228602">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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<ref name="Besedovsky_1986" />—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,<ref name="pmid6228602" /> 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.<ref name="pmid3084123">Template:Cite journal</ref>
High-potassium media (which stimulates aldosterone secretion in vitro) also stimulate cortisol secretion from the fasciculata zone of canine adrenals<ref>Template:Cite journal</ref><ref name="Ameer Saadallah Al – Zacko">Template:Cite web</ref>—unlike corticosterone, upon which potassium has no effect.<ref name="pmid168026">Template:Cite journal</ref>
Potassium loading also increases ACTH and cortisol in humans.<ref name="pmid6283190">Template:Cite journal</ref> 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.<ref name="Bauman_Muller_1972">Template:Cite journal</ref> This may also have a role in rheumatoid-arthritis pain; cell potassium is always low in RA.<ref name="LaCelle_1964">Template:Cite journal</ref>
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.<ref name="pmid11862365">Template:Cite journal</ref>
Factors increasing cortisol levels
- Viral infections increase cortisol levels through activation of the HPA axis by cytokines.<ref>Template:Cite journal</ref>
- Intense (high VO2 max) or prolonged aerobic exercise transiently increases cortisol levels to increase gluconeogenesis and maintain blood glucose;<ref name="pmid10190775">Template:Cite journal</ref> however, cortisol declines to normal levels after eating (i.e., restoring a neutral energy balance).<ref name="Exercise neuroendocrine effects">Template:Cite journal</ref>
- Severe trauma or stressful events can elevate cortisol levels in the blood for prolonged periods.<ref name="isbn0-495-11657-2">Template:Cite book</ref>
- Low-carbohydrate diets cause a short-term increase in resting cortisol (≈3 weeks), and increase the cortisol response to aerobic exercise in the short- and long-term.<ref>Template:Cite journal</ref>
- Increase in the concentration of ghrelin, the hunger stimulating hormone, increases levels of cortisol.<ref>Template:Cite journal</ref>
Biochemistry
Biosynthesis
Cortisol is synthesized from cholesterol. Synthesis takes place in the zona fasciculata of an adrenal cortex.<ref>Template:Cite book</ref><ref name="yyy">Template:Cite journal</ref><ref name="pmid15583024">Template:Cite journal</ref>
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.<ref name="etymonline">Template:Cite web</ref>
While the adrenal cortex in humans also produces aldosterone in the zona glomerulosa and some sex hormones in the zona reticularis, cortisol is its main secretion in humans and several other species.<ref name="yyy"/> In cattle, corticosterone levels may approach<ref name="pmid5062063">Template:Cite journal</ref> or exceed<ref name="Martin_2003" /> cortisol levels.<ref>Template:Cite web</ref><ref>Template:Cite web</ref> In humans, the medulla of the adrenal gland lies under its cortex, mainly secreting the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation.<ref>Template:Cite book</ref>
Synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland 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).<ref name="Margioris_Tsatsanis_2011">Template:Cite book</ref>
Metabolism
11beta-hydroxysteroid dehydrogenases
Cortisol is metabolized reversibly to cortisone<ref name="pmid10487705">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>
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.Template:Medical citation needed
Cytochrome P450, family 3, subfamily A monooxygenases
Cortisol is also metabolized irreversibly into 6β-hydroxycortisol by cytochrome p450-3A monooxygenases, mainly, CYP3A4.<ref>Template:Cite web</ref><ref name="pmid11798083">Template:Cite journal</ref><ref name="pmid10487705"/><ref name="pmid34402388">Template:Cite journal</ref> Drugs that induce CYP3A4 may accelerate cortisol clearance.<ref name="pmid34633961">Template:Cite journal</ref>
Chemistry
Cortisol is a naturally occurring pregnane corticosteroid 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,<ref name="Staaveren">Template:Cite journal</ref> saliva,<ref name="Staaveren" /> urine,<ref name="Schalke">Template:Cite journal</ref> hair,<ref name="Accorsi">Template:Cite journal</ref> and faeces.<ref name="Accorsi" /><ref name="Messmann">Template:Cite journal</ref>
See also
- Cortisone, a hormone
- Cortisol awakening response
- List of corticosteroids
- Membrane glucocorticoid receptor
References
External links
Template:Hormones Template:Endogenous steroids Template:Glucocorticoid receptor modulators Template:Mineralocorticoid receptor modulators Template:Authority control