Cortisol

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Image:Cortisol-2D-skeletal.png
Image:Cortisol-3D-vdW.png
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 that is involved in the response to stress; it increases blood pressure, blood sugar levels, may cause infertility in women, and suppresses the immune system. In pharmacology, cortisol is referred to as hydrocortisone, and is used to treat allergies and inflammation. When first introduced as a treatment for rheumatoid arthritis, it was referred to as Compound E.

Contents 1 Physiology 1.1 Diurnal variation 1.2 Effects 1.3 Binding 2 Diseases and disorders 3 Pharmacology 4 Biochemistry 4.1 Biosynthesis 4.2 Metabolism 5 See also 6 Additional images 7 References 8 External links

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 Glucocorticoid#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 promoting gluconeogenesis, breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased blood glucose concentrations, resulting in increased glycogen formation in the liver. ^[2] Prolonged cortisol secretion causes hyperglycemia.

• It lowers the activity of the immune system in the blood. 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. Cortisol moves potassium out of 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 helps 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.

• 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.

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 syndrome)	↑	↑
Primary Hypocortisolism (Addison's disease)	↓	↑
Secondary Hypocortisolism (pituitary)	↓	↓

Pharmacology

As an oral or injectable drug, cortisol is also known as hydrocortisone. 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 and certain other inflammatory conditions. Brand names include Aveeno®, Emocort®, Epifoam®, Sigmacort®, Hyderm®, NovoHydrocort® Cortoderm®, Efcortelan®, Fucidin-H®, Cortizone-10®, Cortaid®, and Lanacort®

It may also be injected into inflamed joints resulting from diseases such as gout.

Compared to prednisolone, hydrocortisone is about 1/4th the strength. Dexamethasone is about 40 times stronger than hydrocortisone. For side effects, see corticosteroid and prednisolone. Nonprescription 0.5% or 1% hydrocortisone cream or ointment is available; stronger forms are prescription only.[1]

Biochemistry

Biosynthesis

Cortisol is synthesized from pregnenolone. The change involves hydroxylation of C-11, C-17, and C-21, the oxidation of C-3, and the isomerization of the C-5 double bond to C-4. 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 reticulosa), 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 norepinephrine is produced than epinephrine).

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.

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.

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
• Cortitrol, a supplement marketed by pharmanex, which claims to reduce cortisol.
• Relacore, a pill which claims to reduce Cortisol.

Additional images

Steroidogenesis

11-Deoxycortisol

References

1. ^ de Weerth C, Zijl R, Buitelaar J (2003). "Development of cortisol circadian rhythm in infancy". Early Hum Dev 73 (1-2): 39-52. PMID 12932892. 
2. ^ Freeman, Scott (2002). Biological Science. Prentice Hall; 2nd Pkg edition (December 30, 2004). ISBN 0-13-218746-9.
3. ^ Palacios R., Sugawara I. (1982). "Hydrocortisone abrogates proliferation of T cells in autologous mixed lymphocyte reaction by rendering the interleukin-2 Producer T cells unresponsive to interleukin-1 and unable to synthesize the T-cell growth factor". Scand J Immunol 15 (1): 25-31. PMID 6461917. 
4. ^ Knight, R.P., Jr. Kornfield, D.S. Glaser, G.H. Bondy, P.K. (1955). "Effects of intravenous hydrocortisone on electrolytes of serum and urine in man". J Clin Endocrinol Metab 15 (2): 176-81. PMID 13233328. 

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