Cortisol

Not to be confused with cortisone, a similar compound with a similar name, genesis, and function.
Cortisol
Systematic (IUPAC) name
(11β)-​11,​17,​21-​trihydroxypregn-​4-​ene-​3,​20-​dione
Identifiers
CAS number 50-23-7
ATC code H02AB09 (and others)
PubChem CID 5754
ChemSpider 5551
Chemical data
Formula C21H30O5 
Mol. mass 362.460
SMILES eMolecules & PubChem
Therapeutic considerations
Pregnancy cat. C
Legal status Rx Only (U.S.) (excluding 1-2% strength topical)
Routes Oral tablets, intravenously, topical
 YesY(what is this?)  (verify)

Cortisol, also known as hydrocortisone, is a steroid hormone or glucocorticoid produced by the adrenal gland.[1] It is released in response to stress, and to a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis, suppress the immune system, and aid in fat, protein and carbohydrate metabolism.[2] It also decreases bone formation. Various synthetic forms of cortisol are used to treat a variety of different illnesses.

Contents

Physiology

Production & release

Cortisol is produced by the zona fasciculata of the adrenal cortex, which is one of two parts of the adrenal gland.[1]

It is released in response to stress, or to a low level of blood glucocorticoids, and this release is controlled by the hypothalamus, a part of the brain.The secretion of corticotropin-releasing hormone (CRH) by the hypothalamus triggers pituitary secretion of adrenal corticotrophic hormone (ACTH); ACTH is carried by the blood to the adrenal cortex where it triggers glucocorticoid secretion.

Patterns and rhythms of release

The amount of cortisol hormone present in the blood undergoes diurnal variation, with the highest levels present in the early morning (approximately 8am), and the lowest levels present around 12-4am, or 3–5 hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. The pattern is not present at birth (estimates of when it starts vary from two weeks to 9 months).[3]

Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors such as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of temperature. Cortisol levels may also be different for people with autism or Asperger's syndrome.[4]

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

Effects

See also: Glucocorticoid#Therapeutic use

Following stressful events, cortisol, like other glucocorticoid agents, has widespread actions which help restore homeostasis. Although cortisol secretion in response to stress is a natural function, prolonged cortisol secretion due to chronic stress could result in significant physiological changes.[5]

Insulin

Cortisol counteracts insulin, contributing to hyperglycemia via stimulation of hepatic gluconeogenesis[6] and inhibition of the peripheral utilization of glucose[6] by decreasing the translocation of glucose transporters to the cell membrane,[7] specially GLUT4.[8] However cortisol increases glycogen synthesis (glycogenesis) in the liver.[9] Permissive effect of cortisol on insulin action on liver glycogenesis is observed in hepatocyte culture in laboratory, although the mechanism is unknown.

Collagen

In laboratory rats, cortisol-induced collagen loss in the skin is ten times greater than any other tissue.[10][11] Cortisol (as opticortinol) may inversely inhibit IgA precursor cells in the intestines of calves.[12] Cortisol also inhibits IgA in serum, as it does IgM, but is not shown to inhibit IgE.[13]

Gastric and renal secretion

Cortisol stimulates gastric acid secretion.[14] Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to stimulate excretion of ammonium ion by inactivation of renal glutaminase enzyme.[15] Net chloride secretion in the intestines is inversely decreased by cortisol in vitro (methylprednisolone).[16]

Sodium

Cortisol inhibits sodium loss through the small intestine of mammals.[17] Sodium depletion, however, does not affect cortisol,[18] so cortisol cannot be used to regulate serum sodium. Cortisol's purpose may originally have been to transport sodium; this hypothesis is supported by the fact that freshwater fish utilize cortisol to stimulate sodium inward, while saltwater fish have a cortisol-based system for expelling excess sodium.[19]

Potassium

Sodium load augments the intense potassium excretion by cortisol, and corticosterone is comparable to cortisol in this case.[20] In order for potassium to move out of the cell, cortisol moves in an equal number of sodium ions.[21] It can be seen that this should make pH regulation much easier, unlike the normal potassium deficiency situation in which about 2 sodium ions move in for each 3 potassium ions that move out, which is closer to the deoxycorticosterone effect. Nevertheless, cortisol consistently causes alkalosis of the serum, while in a deficiency pH does not change. Perhaps this may be for the purpose of bringing serum pH to a value most optimum for some of the immune enzymes during infection in those times when cortisol declines. Potassium is also blocked from loss in the kidneys directly somewhat by decline of cortisol (9 alpha fluorohydrocortisone).[22]

Water

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

Copper

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

Immune system

Cortisol can weaken the activity of the immune system. Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor.[30] Cortisol also has a negative feedback effect on interleukin-1.[31] IL-1 must be especially useful in combating some diseases; however, endotoxin bacteria have gained an advantage by forcing the hypothalamus to increase cortisol levels via forcing secretion of CRH hormone, thus antagonizing IL-1 in this case. The suppressor cells are not affected by GRMF,[32] so that the effective set point for the immune cells may be even higher than the set point for physiological processes. It reflects leukocyte redistribution to lymph nodes, bone marrow, and skin. Acute administration of corticosterone (the endogenous Type I and Type II receptor agonist), or RU28362 (a specific Type II receptor agonist), to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are not affected by cortisol.[33]

Bone metabolism

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

Memory

It cooperates with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future. However, long-term exposure to cortisol results in damage to cells in the hippocampus.[36] This damage results in impaired learning.

Additional effects

Binding

Most serum cortisol, all but about 4%, is bound to proteins including corticosteroid binding globulin (CBG), and serum albumin. Only free cortisol is available to receptors.

Regulation

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

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

Factors generally reducing cortisol levels

Factors generally increasing cortisol levels

Clinical chemistry

The relationship between cortisol and ACTH, and some consequent conditions, are as follows:

THE DISORDERS OF CORTISOL SECRETION
Plasma ACTH
↓ ↑
Plasma Cortisol ↑ Primary hypercortisolism (Cushing's syndrome) Secondary hypercortisolism (pituitary or ectopic tumor, Cushing's disease, pseudo-Cushing's syndrome)
↓ Secondary hypocortisolism (pituitary tumor, Sheehan's syndrome) Primary hypocortisolism (Addison's disease, Nelson's syndrome)

A 2010 study has found that serum cortisol predicts increased cardiovascular mortality in patients with acute coronary syndrome.[76][77]

Pharmacology

Hydrocortisone is the pharmaceutical term for cortisol used for oral administration, intravenous injection, or topical application. It is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients who need steroid treatment but cannot take oral medication, and peri-operatively in patients on long-term steroid treatment to prevent an Addisonian crisis. It may be used topically for allergic rashes, eczema, psoriasis and certain other inflammatory skin conditions. It may also be injected into inflamed joints resulting from diseases such as gout.

Compared to prednisolone, hydrocortisone is about 1/4 the strength for the anti-inflammatory effect, while dexamethasone is about 40 times as strong as hydrocortisone . For side effects, see corticosteroid and prednisolone.

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

Advertising for the dietary supplement CortiSlim originally (and falsely) claimed that it contributed to weight loss by blocking cortisol. The manufacturer was fined $12 million by the Federal Trade Commission in 2007 for false advertising, and no longer claims in their marketing that CortiSlim is a cortisol antagonist.[78]

Biochemistry

Biosynthesis

Steroidogenesis, showing cortisol at right.

Cortisol is synthesized from cholesterol. The synthesis takes place in the zona fasciculata of the cortex of the adrenal glands. (The name cortisol comes from cortex.) While the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion. The medulla of the adrenal gland lies under the cortex and mainly secretes the catecholamines, adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation.

The synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with adrenocorticotropic hormone (ACTH); production of ACTH is in turn stimulated by corticotropin-releasing hormone (CRH), released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane (via regulation of STAR (steroidogenic acute regulatory) protein). ACTH also stimulates the main rate-limiting step in cortisol synthesis where cholesterol is converted to pregnenolone, catalyzed by Cytochrome P450SCC (side chain cleavage enzyme).[79]

Metabolism

Cortisol is metabolized by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2.

Overall the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically active cortisol in a given tissue, while 11-beta HSD2 serves to decrease the local concentrations of biologically active cortisol.

Cortisol is also metabolized into 5-alpha tetrahydrocortisol (5-alpha THF) and 5-beta tetrahydrocortisol (5-beta THF), reactions for which 5-alpha reductase and 5-beta reductase are the rate-limiting factors, respectively. 5-beta reductase is also the rate-limiting factor in the conversion of cortisone to tetrahydrocortisone (THE).

An alteration in 11-beta HSD1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance, sometimes referred to as the metabolic syndrome.[80]

An alteration in 11-beta HSD2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (SAME).

Media

11-Deoxycortisol

See also

References

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  2. ↑ First Aid USMLE Step 1 2009, Tao Le et al.
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  76. ↑ "Serum cortisol predicts increased cardiovascular mortality in patients with acute coronary syndrome". Endocrine-abstracts.org. http://www.endocrine-abstracts.org/ea/0022/ea0022OC4.6.htm. Retrieved 2010-06-14. 
  77. ↑ doi:10.1530/eje.1.01959
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  78. ↑ Iwata, Edward (January 5, 2007). "Diet pill sellers fined $25M". USA Today. http://www.usatoday.com/news/washington/2007-01-04-weight-loss-pills_x.htm. Retrieved 2008-10-26. 
  79. ↑ Mechanism of ACTH action on adrenal cortical cells Andrew N. Margioris, M.D., and Christos Tsatsanis, Ph.D. Updated: December 4, 2006
  80. ↑ [1] Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004 Oct;25(5):831-66.
Corticosteroids – glucocorticoids and mineralocorticoids (H02)
(also A07EA, C05AA, D07, D10AA, R01AD, R03BA, S01BA, S02B, and S03B)
Mineralocorticoids
(3-one, 4-ene,
no FG at 16)
Pregnenedione: ALDOSTERONE · 11-DEOXYCORTICOSTERONE · HALOGENATED AT 9: Fludrocortisone
Glucocorticoids
(3-one, 4-ene,
11-FG,
17-hydroxy)
Pregnene
Pregnenedione
(+20-one)
HYDROCORTISONE/CORTISOL# (Hydrocortisone aceponate, Hydrocortisone buteprate, Hydrocortisone butyrate) · Budesonide · Ciclesonide · Deflazacort · Medrysone · Tixocortol · HALOGENATED AT 6: Cloprednol · HALOGENATED, WITH FG AT 16: Halcinonide
Pregnadiene (+1-ene)
Rimexolone · HALOGENATED, WITH FG AT 16: Flunisolide · Triamcinolone · Amcinonide · Fluocinolone acetonide (Fluocinonide)
Pregnadienediol
(+21-hydroxy)
Prednisone (Meprednisone) · HALOGENATED AT 9: Fluorometholone · HALOGENATED, WITH FG AT 16: Fluocortolone (Clocortolone, Diflucortolone, Fluocortin) · Desoximetasone
Pregnadienetriol
(+11-hydroxy)
Prednisolone# (Methylprednisolone, Methylprednisolone aceponate, Prednicarbate, Prednylidene) · Desonide · HALOGENATED: Fluprednisolone (Difluprednate, Fluperolone) · HALOGENATED, WITH FG AT 16: Dexamethasone# · Betamethasone (Clobetasol, Clobetasone, Diflorasone, Halometasone, Ulobetasol) · Beclometasone · Paramethasone  · Alclometasone · Fluclorolone · Flumetasone · Fluprednidene
Pregnatriene
(+2-ene)
Cortivazol
HALOGENATED, WITH FG AT 16: Fluticasone (Fluticasone propionate, Fluticasone furoate)
Other/ungrouped
HALOGENATED: Loteprednol · HALOGENATED, WITH FG AT 16: Fludroxycortide · Formocortal · Mometasone furoate
Aldosterone antagonists
Spironolactone · Eplerenone · Potassium canrenoate · Canrenone
Synthesis modifiers
Trilostane · Carbenoxolone · Aminoglutethimide · Metyrapone
#WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III

: END

anat/phys/devp/horm/cell

noco(d)//tumr, sysi/

proc, drug (A10/H1/H2//)
Cholesterol and steroid metabolic intermediates
Mevalonate pathway
to HMG-CoA
Acetyl-CoA · Acetoacetyl-CoA · HMG-CoA
Ketone bodies
Acetone · Acetoacetic acid · beta-Hydroxybutyric acid
to DMAPP
Mevalonic acid · Phosphomevalonic acid · 5-Diphosphomevalonic acid · Isopentenyl pyrophosphate · Dimethylallyl pyrophosphate
Geranyl-
Geranyl pyrophosphate · Geranylgeranyl pyrophosphate
Prephytoene diphosphate · Phytoene
Non-mevalonate pathway
DOXP · MEP · CDP-ME · CDP-MEP · MEcPP · HMB-PP · IPP · DMAPP
To Cholesterol

Farnesyl pyrophosphate · Squalene · 2,3-Oxidosqualene · Lanosterol

Lanosterol · Lathosterol · 7-Dehydrocholesterol · Cholesterol

Lanosterol · Zymosterol · 7-Dehydrodesmosterol · Desmosterol · Cholesterol
Steroid
Corticosteroids
(C21 pregnane)
Mineralocorticoids
Pregnenolone · Progesterone · 11-Deoxycorticosterone · Corticosterone · Aldosterone

Pregnenolone · 17-Hydroxypregnenolone · 17-Hydroxyprogesterone · 11-Deoxycortisol · Cortisol

Cortisol · Cortisone
Sex steroids
Androgens
(C19 androstane)

DHEA · Androstenedione/5-Androstenediol · Testosterone · Dihydrotestosterone

DHEA sulfate · Epitestosterone
Estrogens
(C18 estrane)
Estrone · Estradiol · Estriol
Nonhuman
Phytosterols
Stigmasterol · Brassicasterol
Ergosterols
Ergosterol · Ergocalciferol

: MET

mt, r//c/p/i/y, f/s/l/o, a/u, n, h

rgcp//y, f/s/l/o, au, n, h,

m(A16, C10),i(//c//i/y, /s/o, a/u,n, h)

: END

anat/phys/devp/horm/cell

noco(d)//tumr, sysi/

proc, drug (A10/H1/H2//)
biochemical families: prot · nucl · carb (alco, glys, glpr) · lipd (fata, phld, strd, gllp, eico, ttpy) · amac · ncbs
Antidiarrheals, intestinal anti-inflammatory/anti-infective agents (A07)
Intestinal anti-infectives

Antibiotics (Neomycin, Nystatin, Natamycin, Streptomycin, Polymyxin B, Paromomycin, Amphotericin B, Kanamycin, Vancomycin, Colistin, Rifaximin)

Sulfonamides (Phthalylsulfathiazole, Sulfaguanidine, Succinylsulfathiazole)

Nitrofuran (Nifuroxazide, Nifurzide)

Imidazole (Miconazole)

Arsenical (Acetarsol)

Oxyquinoline (Broxyquinoline)
Intestinal adsorbents
Charcoal · Bismuth · Pectin · Kaolin · Crospovidone · Attapulgite · Diosmectite
Antipropulsives (opioids)

Opium Tincture (Laudanum) · Codeine · Morphine  · Camphorated Opium Tincture (Paregoric)

crosses BBB: Diphenoxylate · Difenoxin

does not cross BBB: Loperamide
Intestinal anti-inflammatory agents

corticosteroids acting locally (Prednisolone, Hydrocortisone, Prednisone, Betamethasone, Tixocortol, Budesonide, Beclometasone)

antiallergic agents, excluding corticosteroids (Cromoglicic acid)

aminosalicylic acid and similar agents (Sulfasalazine, Mesalazine, Olsalazine, Balsalazide)
Antidiarrheal micro-organisms
Saccharomyces boulardii
Other antidiarrheals
Albumin tannate · Ceratonia · Octreotide · Racecadotril

: DIG

anat(t, g, p)/phys/devp/cell/

noco/cong/tumr, sysi/

proc, drug(A2A/2B/3/4//6/7/14/16), blte
Otologicals (S02)
Anti-infectives
Acetic acid • Aluminium acetotartrate • Boric acid • Chloramphenicol • Chlorhexidine • Ciprofloxacin • Clioquinol • Gentamicin • Hydrogen peroxide • Miconazole • Neomycin • Nitrofurazone • Ofloxacin • Polymyxin B • Rifamycin • Tetracycline
Corticosteroids
Betamethasone • Dexamethasone • Fluocinolone acetonide • Hydrocortisone • Prednisolone
Analgesics and anesthetics
Lidocaine • Cocaine • Phenazone

: EAR

anat(e, )/phys/devp

noco/,

proc, drug(S2)