cortisol

 

(kôr'tĭsôl') or hydrocortisone, steroid hormone that in humans is the major circulating hormone of the cortex, or outer layer, of the adrenal gland. Like cortisone, cortisol is classed as a glucocorticoid; it stimulates liver glycogen formation while it decreases the rate of glucose utilization in body cells. A main effect of cortisol is to reduce the reserves of protein in all body cells except cells of the liver and gastrointestinal tract. It also makes fatty acids available for metabolic use. Cortisol is synthesized and secreted by the adrenal cortex in response to the stimulating substance adrenocorticotropic hormone (ACTH). In turn, cortisol is the major regulator of ACTH production in the pituitary gland; it acts by negative feedback inhibition, i.e., a rise in the level of cortisol in the blood inhibits ACTH secretion by the pituitary. Cortisol, usually referred to as hydrocortisone when used medicinally, is more potent than cortisone with respect to metabolic and anti-inflammatory effects. See also corticosteroid drug; steroids.

Cortisol
Systematic (IUPAC) name
11,17,21-trihydroxy-,(11beta)- pregn-4-ene-3,20-dione
Identifiers
CAS number	50-23-7
ATC code	H02AB09 (and others)
PubChem	5754
Chemical data
Formula	C21H30O5
Mol. mass	362.465
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	C
Legal status
Routes	Oral tablets, intravenously, topical

Cortisol is a corticosteroid hormone produced by the adrenal cortex (in the adrenal gland). It is a vital hormone that is often referred to as the "stress hormone" as it is involved in the response to stress. It increases blood pressure, blood sugar levels and has an immunosuppressive action. In pharmacology, the synthetic form of cortisol is referred to as hydrocortisone, and is used as an antagonist in the treatment of allergies and inflammation as well as substitute supplementation in cortisol production deficiencies. When first introduced as a treatment for rheumatoid arthritis, it was referred to as Compound E.

Physiology

Diurnal variation

The amount of cortisol present in the serum undergoes diurnal variation, with the highest levels present in the early morning, and the lowest levels present around midnight, 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.^[1])

Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of temperature.

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

Effects

See also Medical uses and effects of high dose glucocorticoids

In normal release, cortisol (like other glucocorticoid agents) has widespread actions which help restore homeostasis after stress. (These normal endogenous functions are the basis for the physiological consequences of chronic stress - prolonged cortisol secretion.)

• It acts as a physiological antagonist to insulin by decreasing glycogenesis (formation of glycogen) and promotes breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood). There is a decreased glycogen formation in the liver . ^[2] Prolonged cortisol secretion causes hyperglycemia.

• It 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.^[3] 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.

• It lowers bone formation thus favoring development of osteoporosis in the long term. Cortisol moves potassium into cells in exchange for an equal number of sodium ions.^[4] This can cause a major problem with the hyperkalemia of metabolic shock from surgery.

• It may help to create memories when exposure is short-term; this is the proposed mechanism for storage of flash bulb memories. However, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning.

• It increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine. In the absence of cortisol, widespread vasodilation occurs.

• It inhibits the secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH secretion. Some researchers believe that this normal feedback system may break down when animals are exposed to chronic stress.

• It increases the effectiveness of catecholamines.

• It allows for the kidneys to produce hypotonic urine.

• It has anti-inflammatory effects by reducing histamine secretion and stabilizing lysosomal membranes. The stabilization of lysosomal membranes prevents their rupture, thereby preventing damage to healthy tissues.

• It stimulates hepatic detoxification by inducing tryptophan oxygenase (to reduce serotonin levels in the brain), glutamine synthase (reduce glutamate and ammonia levels in the brain), cytochrome P-450 hemoprotein (mobilizes arachidonic acid), and metallothionein (reduces heavy metals in the body).

In addition to the effects caused by cortisol binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone, it also binds to the mineralocorticoid receptor. (It binds with less affinity to it than aldosterone does, but the concentration of blood cortisol is higher than that of blood aldosterone.)

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 most receptors.

Diseases and disorders

• Hypercortisolism: Excessive levels of cortisol in the blood result in Cushing's syndrome.

• Hypocortisolism, or adrenal insufficiency: If on the other hand the adrenal glands do not produce sufficient amounts of cortisol, Addison's disease is the consequence.

The relationship between cortisol and ACTH is as follows:

THE DISORDERS OF CORTISOL SECRETION

	Plasma Cortisol	Plasma ACTH
Primary Hypercortisolism (Cushing's syndrome)	↑	↓
Secondary Hypercortisolism (pituitary, Cushing's disease)	↑	↑
Primary Hypocortisolism (Addison's disease)	↓	↑
Secondary Hypocortisolism (pituitary)	↓	↓

Pharmacology

Hydrocortisone is the chemical form of cortisol used for oral administration or intravenous injection. 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 is given by topical application for its anti-inflammatory effect in allergic rashes, eczema, psoriasis and certain other inflammatory 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 0.5% to 2.5%, depending on local regulations, with stronger forms available with prescriptions only.

Biochemistry

Biosynthesis

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 (more epinephrine is produced than norepinephrine, in a ratio 4:1).

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). The cholesterol is converted to pregnenolone, catalysed by Cytochrome P450SCC (side chain cleavage).

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.

• 11-beta HSD1 utilizes the cofactor NADPH to convert biologically inert cortisone to biologically active cortisol.
• 11-beta HSD2 utilizes the cofactor NAD+ to convert cortisol to cortisone.

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. The Hippocampus (memory) is affected by cortisol.

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 the metabolic syndrome.

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).

See also

• Cushing's syndrome
• HPA axis
• Hypopituitarism
• Post-traumatic stress disorder
• Central serous retinopathy
• CortiSlim
• Relacore, a pill which claims to reduce Cortisol.

Additional images

Steroidogenesis

11-Deoxycortisol

References

External links

Endocrine system: hormones/endocrine glands (Peptide hormones, Steroid hormones)
Hypothalamic-pituitary	Hypothalamus: TRH, CRH , GnRH, GHRH, somatostatin, dopamine - Posterior pituitary: vasopressin, oxytocin - Anterior pituitary: α (FSH, LH, TSH), GH, prolactin, POMC (ACTH, MSH, endorphins, lipotropin)
Adrenal axis	Adrenal medulla: epinephrine, norepinephrine - Adrenal cortex: aldosterone, cortisol, DHEA
Thyroid axis	Thyroid: thyroid hormone (T3 and T4) - calcitonin - Parathyroid: PTH
Gonadal axis	Testis: testosterone, AMH, inhibin - Ovary: estradiol, progesterone, inhibin/activin, relaxin (pregnancy)
Other end. glands	Pancreas: glucagon, insulin, somatostatin - Pineal gland: melatonin
Non-end. glands	Placenta: hCG, HPL, estrogen, progesterone - Kidney: renin, EPO, calcitriol, prostaglandin - Heart atrium: ANP - Stomach: gastrin, ghrelin - Duodenum: CCK, GIP, secretin, motilin, VIP - Ileum: enteroglucagon - Adipose tissue: leptin, adiponectin, resistin - Thymus: Thymosin - Thymopoietin - Skeleton: Osteocalcin - Liver/other: Insulin-like growth factor (IGF-1, IGF-2)
Target-derived	NGF, BDNF, NT-3

Corticosteroids - glucocorticoid/receptor and mineralocorticoid/receptor (A07EA, C05AA, D07, D10AA, H02, R01AD, R03BA, S01BA, S02B, and S03B)
Endogenous	Aldosterone, Cortisone, Hydrocortisone/cortisol, Desoxycortone
Others	Alclometasone, Amcinonide, Beclometasone, Betamethasone, Budesonide, Ciclesonide, Clobetasol, Clobetasone, Clocortolone, Cloprednol, Cortivazol, Deflazacort, Deoxycorticosterone, Desonide, Desoximetasone, Dexamethasone, Diflorasone, Diflucortolone, Difluprednate, Fluclorolone, Fludrocortisone, Fludroxycortide, Flumetasone, Flunisolide, Fluocinolone acetonide, Fluocinonide, Fluocortin, Fluocortolone, Fluorometholone, Fluperolone, Fluprednidene, Fluticasone, Formocortal, Halcinonide, Halometasone, Hydrocortisone aceponate, Hydrocortisone buteprate, Hydrocortisone butyrate, Loteprednol, Medrysone, Meprednisone, Methylprednisolone,Methylprednisolone aceponate, Mometasone furoate, Paramethasone, Prednicarbate, Prednisone, Prednisolone, Prednylidene, Rimexolone, Tixocortol, Triamcinolone, Ulobetasol

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) - other (Miconazole, Broxyquinoline, Acetarsol, Nifuroxazide, Nifurzide)
Intestinal adsorbents	Charcoal - Bismuth - Pectin - Kaolin - Crospovidone - Attapulgite - Diosmectite
Antipropulsives	Diphenoxylate - Opium - Loperamide - Difenoxin - Loperamide oxide
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 - Racecadotril

Otologicals (S02)
Anti-infectives	Chloramphenicol - Nitrofural - Boric acid - Aluminium acetotartrate - Clioquinol - Hydrogen peroxide - Neomycin - Tetracycline - Chlorhexidine - Acetic acid - Polymyxin B - Rifamycin - Miconazole - Gentamicin
Corticosteroids	Hydrocortisone - Prednisolone - Dexamethasone - Betamethasone
Other otologicals	Lidocaine - Cocaine

Donate to Wikimedia