Cortisol
Cortisol2.svg
Cortisol-3D-balls.png
Names
IUPAC name
11β,17α,21-Trihydroxypregn-4-ene-3,20-dione
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.019
KEGG
UNII
Properties
C21H30O5
Molar mass 362.460 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone.

It is produced in humans by the zona fasciculata of the adrenal cortex within the adrenal gland.[1] It is released in response to stress and low blood-glucose concentration. It functions to increase blood sugar through gluconeogenesis, to suppress the immune system, and to aid in the metabolism of fat, protein, and carbohydrates.[2] It also decreases bone formation.[3]

Health effects

Metabolic response

In the early fasting state, cortisol stimulates gluconeogenesis (the formation of glucose), and activates antistress and anti-inflammatory pathways. Cortisol also plays an important, but indirect, role in liver and muscle glycogenolysis, the breaking down of glycogen to glucose-1-phosphate and glucose. This is done through its passive influence on glucagon.[clarification needed] Additionally, cortisol facilitates the activation of glycogen phosphorylase, which is necessary for epinephrine to have an effect on glycogenolysis.[4][5]

In the late fasting state, the function of cortisol changes slightly and increases glycogenesis. This response allows the liver to take up glucose not being used by the peripheral tissue and turn it into liver glycogen stores to be used if the body moves into the starvation state.[citation needed]

Elevated levels of cortisol, if prolonged, can lead to proteolysis (breakdown of proteins) and muscle wasting.[6] Several studies have shown that cortisol can have a lipolytic effect (promote the breakdown of fat).[citation needed] Under some conditions, however, cortisol may somewhat suppress lipolysis.[7]

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-potency hydrocortisone, available as a nonprescription medicine in some countries, is used to treat skin problems such as rashes and eczema.

It inhibits production of interleukin (IL)-12, interferon (IFN)-gamma, IFN-alpha, and tumor-necrosis-factor (TNF)-alpha by antigen-presenting cells (APCs) and T helper (Th)1 cells, but upregulates IL-4, IL-10, and IL-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.[8]

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 (IL-1), and unable to produce the T-cell growth factor (IL-2).[9] Cortisol also has a negative-feedback effect on interleukin-1.[10]

Though IL-1 is useful in combating some diseases, endotoxic bacteria have gained an advantage by forcing the hypothalamus to increase cortisol levels (forcing the secretion of corticotropin-releasing hormone, thus antagonizing IL-1). The suppressor cells are not affected by glucosteroid response-modifying factor,[11] so the effective setpoint for the immune cells may be even higher than the setpoint for physiological processes (reflecting leukocyte redistribution to lymph nodes, bone marrow, and skin). Rapid administration of corticosterone (the endogenous type I and type II receptor agonist) or RU28362 (a specific type II receptor agonist) to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are affected by cortisol.[12]

Cortisol stimulates many copper enzymes (often to 50% of their total potential), probably to increase copper availability for immune purposes.[13]:337 This includes lysyl oxidase, an enzyme that cross-links collagen, and elastin.[13]:334 Especially valuable for immune response is cortisol's stimulation of the superoxide dismutase,[14] since this copper enzyme is almost certainly used by the body to permit superoxides to poison bacteria.

Other effects

Metabolism

Glucose

Cortisol counteracts insulin, contributes to hyperglycemia-causing hepatic gluconeogenesis[15] and inhibits the peripheral use of glucose (insulin resistance)[15] by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.[16] Cortisol also increases glycogen synthesis (glycogenesis) in the liver, storing glucose in easily accessible form.[17] The permissive effect of cortisol on insulin action in liver glycogenesis is observed in hepatocyte culture in the laboratory, although the mechanism for this is unknown.

Bone and collagen

Cortisol reduces bone formation,[3] favoring long-term development of osteoporosis (progressive bone disease). It transports potassium out of cells in exchange for an equal number of sodium ions (see above).[18] This can trigger the hyperkalemia of metabolic shock from surgery. Cortisol also reduces calcium absorption in the intestine.[19]

Collagen is an important component of connective tissue. It is vital for structural support and is found in muscles, tendons, and joints, as well as throughout the entire body. Cortisol down-regulates the synthesis of collagen.[20]

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.[21] Cortisol (as opticortinol) may inversely inhibit IgA precursor cells in the intestines of calves.[22] Cortisol also inhibits IgA in serum, as it does IgM; however, it is not shown to inhibit IgE.[23]

Wound healing

Cortisol and the stress response have known deleterious effects on the immune system. High levels of perceived stress and increases in cortisol have been found to lengthen wound-healing time in healthy, male adults. Those who had the lowest levels of cortisol the day following a 4 mm punch biopsy had the fastest healing time.[24] In dental students, wounds from punch biopsies took an average of 40% longer to heal when performed three days before an examination as opposed to biopsies performed on the same students during summer vacation.[25] This is in line with previous animal studies that show similar detrimental effects on wound healing, notably the primary reports showing that turtles recoil from cortisol.[26]

Electrolyte balance

Cortisol acts as a diuretic, increasing water diuresis, glomerular filtration rate, and renal plasma flow from the kidneys, as well as increasing sodium retention and potassium excretion. It also increases sodium and water absorption and potassium excretion in the intestines.[27]

Sodium

Cortisol promotes sodium absorption through the small intestine of mammals.[28] Sodium depletion, however, does not affect cortisol levels[29] 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.[30]

Potassium

A sodium load augments the intense potassium excretion by cortisol. Corticosterone is comparable to cortisol in this case.[31] For potassium to move out of the cell, cortisol moves an equal number of sodium ions into the cell.[18] 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.[32] 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.[33]

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.[34] However, long-term exposure to cortisol damages cells in the hippocampus;[35] this damage results in impaired learning. Furthermore, cortisol inhibits memory retrieval of already stored information.[36][37]

Sleep, stress, and mood

Diurnal cycles of cortisol levels are found in humans.[4] In humans, the amount of cortisol present in the blood undergoes diurnal variation; the level peaks in the early morning (around 8 am) and reaches its lowest level at about midnight-4 am, or three to five hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. This pattern is not present at birth; estimates of when it begins vary from two weeks to nine months of age.[38]

Sustained stress can lead to high levels of circulating cortisol, which can create an allostatic load.[39] An allostatic load can lead to various physical modifications in the body's regulatory networks.[39] Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, mood disorders such as major depressive disorder, anxiety disorders, psychological stress, and physiological stressors such as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion, or temperature extremes. Cortisol levels may also differ for individuals with autism or Asperger's syndrome.[40] Also, significant individual variation is seen, although a given person tends to have consistent rhythms.

Effects during pregnancy

During human pregnancy, increased fetal production of cortisol between weeks 30 and 32 initiates production of fetal lung 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,[41] 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.[42] Although the timing of fetal cortisol concentration elevation in sheep may vary somewhat, it averages about 11.8 days before the onset of labor.[43] 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,[44][45] 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 was 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.[46]

Synthesis and release

Cortisol is produced in the human body by the adrenal gland in the zona fasciculata,[1] the second of three layers comprising the adrenal cortex. The cortex forms the outer "bark" of each adrenal gland, situated atop the kidneys. The release of cortisol is controlled by the hypothalamus, a part of the brain. The secretion of corticotropin-releasing hormone by the hypothalamus[47] triggers cells in the neighboring anterior pituitary to secrete another hormone, the adrenocorticotropic hormone (ACTH), into the vascular system, through which blood carries it to the adrenal cortex. ACTH stimulates the synthesis of cortisol and other glucocorticoids, mineralocorticoids, and dehydroepiandrosterone.

Normal levels

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 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.

Reference ranges for blood plasma content of free cortisol
Time Lower limit Upper limit Unit
09:00 am 140[48] 700[48] nmol/L
5[49] 25[49] μg/dL
Midnight 80[48] 350[48] nmol/l
2.9[49] 13[49] μg/dl

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.

Reference ranges for urinalysis of free cortisol
Lower limit Upper limit Unit
28[50] or 30[51] 280[50] or 490[51] nmol/24h
10[52] or 11[53] 100[52] or 176[53] µg/24 h

Disorders of cortisol production

Disorders of cortisol production, and some consequent conditions, are: