Cortisol

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 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.[1] In other tissues, it is produced in lower quantities.[2] By a diurnal cycle, cortisol is released and increases in response to stress and a low blood-glucose concentration.[1] It functions to increase blood sugar through gluconeogenesis, suppress the immune system, and aid in energy metabolism.[3] It also decreases bone formation.[4] 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.[1][5]

Biological activity

Cortisol acts as an agonist of the corticosteroid receptors, including the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). It is also an agonist of membrane corticosteroid receptors, including membrane glucocorticoid receptors (mGRs) and membrane mineralocorticoid receptors (mMRs).

In addition to its corticosteroid receptor agonism, cortisol has been reported to be a highly potent biphasic regulator of the GABAA receptor, acting as a positive allosteric modulator at low concentrations (1–10 pM) and as a negative allosteric modulator at high concentrations (10–1,000 nM).[6][7][8]

Health effects

Metabolic response

Cortisol plays a crucial role in regulating glucose metabolism and promotes gluconeogenesis (glucose synthesis) in the liver, producing glucose to provide to other tissues.[9] 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.[1] Its impact is complex and diverse.[10]

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.[11]

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.[12][13]

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.[14] This is in contrast to cortisol's effect in the skeletal muscle where glycogenolysis is promoted indirectly through catecholamines.[15] In this way, cortisol and catecholamines work synergistically to promote the breakdown of muscle glycogen into glucose for use in the muscle tissue.[16]

Elevated levels of cortisol, if prolonged, can lead to proteolysis (breakdown of proteins) and muscle wasting.[17] The reason for proteolysis is to provide the relevant tissue with a feedstock for gluconeogenesis; see glucogenic amino acids.[11] 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,[11] although an acute increase in circulating cortisol promotes lipolysis.[18] 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.[19]

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. This thus favors 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.[20]

Cortisol also has a negative-feedback effect on IL-1.[21] 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.[22]

Through this system, as long as an immune stressor is small, the response will be regulated to the correct level. In general, the hypothalamus uses cortisol to reduce the response once the production of cortisol matches the stress induced[clarification needed] 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) the correct set point might never be reached[clarification needed] 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.[tone]

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.[23]

On the other side of things,[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[24] 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.[citation needed][tone]

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,[25] 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.[26][27][28] 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.[29][27][28]