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
Clinical data
Pregnancy cat. C
Legal status Rx only (U.S.) (excluding 1–2% strength topical)
Routes Oral tablets, intravenous, topical
Identifiers
CAS number 50-23-7 Y
ATC code A01AC03 A07EA02 C05AA01 D07AA02 D07XA01 H02AB09 S01BA02 S01CB03 S02BA01
PubChem CID 5754
DrugBank DB07886
ChemSpider 5551 Y
UNII WI4X0X7BPJ Y
KEGG D00088 Y
ChEBI CHEBI:17650 Y
ChEMBL CHEMBL389621 Y
Chemical data
Formula C21H30O5 
Mol. mass 362.460 g/mol
SMILES eMolecules & PubChem
 Y(what is this?)  (verify)

Cortisol (hydrocortisone) is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland.[1] It is released in response to stress and 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.[1] It also decreases bone formation. During pregnancy, increased production of cortisol between weeks 30 and 32 initiates production of fetal lung surfactant to promote maturation of the lungs. Various synthetic forms of cortisol are used to treat a variety of diseases.

Contents

Physiology

Production and release

Cortisol is produced by the adrenal gland in the zona fasciculata, the second of three layers comprising the outer adrenal cortex. This release is controlled by the hypothalamus, a part of the brain. The secretion of corticotropin-releasing hormone (CRH) by the hypothalamus triggers anterior pituitary secretion of adrenocorticotropic hormone (ACTH). ACTH is carried by the blood to the adrenal cortex, where it triggers glucocorticoid secretion.

Main functions in the body

It suppresses the immune system by "muting" the white blood cells. Another function is to decrease bone formation.

Cortisol is used to treat diseases such as Addison’s disease, inflammatory and rheumatoid diseases, and allergies. Low-potency hydrocortisone, available over the counter in some countries, is used to treat skin problems such as rashes, eczema and others.

Cortisol prevents the release of substances in the body that cause inflammation. It stimulates gluconeogenesis (the breakdown of protein and fat to provide metabolites that can be converted to glucose in the liver) and it activates anti-stress and anti-inflammatory pathways.[2]

Patterns

The amount of cortisol present in the blood undergoes diurnal variation; the level peaks in the early morning (approximately 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.[3]

Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, 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.[4]

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

Normal levels

Reference ranges for blood plasma content of free cortisol
Time Lower limit Upper limit Unit
09:00 am 140[5] 700[5] nmol/L
5[6] 25[6] μg/dL
Midnight 80[5] 350[5] nmol/L
2.9[6] 13[6] 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 approximately equal to 276 nmol/L.

Reference ranges for urinalysis of free cortisol
Lower limit Upper limit Unit
28[7] or 30[8] 280[7] or 490[8] nmol/24h
10[9] or 11[10] 100[9] or 176[10] µg/24 h

Effects

See also: Glucocorticoid#Therapeutic use

Cortisol is released in response to stress, acting to restore homeostasis. However, prolonged cortisol secretion (which may be due to chronic stress or the excessive secretion seen in Cushing's syndrome) results in significant physiological changes.[1]

Insulin

Cortisol counteracts insulin, contributes to hyperglycemia-causing hepatic gluconeogenesis[11] and inhibits the peripheral utilization of glucose (insulin resistance) [11] by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.[12][13] However, cortisol increases glycogen synthesis (glycogenesis) in the liver.[14] 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.

Collagen

In laboratory rats, cortisol-induced collagen loss in the skin is ten times greater than in any other tissue.[15][16] Cortisol (as opticortinol) may inversely inhibit IgA precursor cells in the intestines of calves.[17] Cortisol also inhibits IgA in serum, as it does IgM; however, it is not shown to inhibit IgE.[18]

Gastric and renal secretion

Cortisol stimulates gastric-acid secretion.[19] 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.[20] Net chloride secretion in the intestines is inversely decreased by cortisol in vitro (methylprednisolone).[21]

Sodium

Cortisol inhibits sodium loss through the small intestine of mammals.[22] Sodium depletion, however, does not affect cortisol levels[23] 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 utilize cortisol to stimulate sodium inward, while saltwater fish have a cortisol-based system for expelling excess sodium.[24]

Potassium

A sodium load augments the intense potassium excretion by cortisol; corticosterone is comparable to cortisol in this case.[25] In order for potassium to move out of the cell, cortisol moves an equal number of sodium ions into the cell.[26] 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). Nevertheless, cortisol consistently causes serum alkalosis; in a deficiency, serum pH does not change. The purpose of this may be to reduce serum pH to an optimum value for some immune enzymes during infection, when cortisol declines. Potassium is also blocked from loss in the kidneys by a decline in cortisol (9 alpha fluorohydrocortisone).[27]

Water

Cortisol acts as a diuretic hormone, controlling one-half of intestinal diuresis;[22] it has also been shown to control kidney diuresis in dogs. The decline in water excretion following a decline in cortisol (dexamethasone) in dogs is probably due to inverse stimulation of antidiuretic hormone (ADH or arginine vasopressin), which is not overridden by water loading.[28] Humans and other animals also use this mechanism.[29]

Copper

Cortisol stimulates many copper enzymes (often to 50% of their total potential), probably to increase copper availability for immune purposes.[30] This includes lysyl oxidase, an enzyme which is used to cross-link collagen and elastin.[31] Especially valuable for immune response is cortisol's stimulation of the superoxide dismutase,[32] since this copper enzyme is almost certainly used by the body to permit superoxides to poison bacteria. Cortisol causes an inverse four- or fivefold decrease of metallothionein (a copper storage protein) in mice;[33] however, rodents do not synthesize cortisol themselves. This may be to furnish more copper for ceruloplasmin synthesis or to release free copper. Cortisol has an opposite effect on aminoisobuteric acid than on the other amino acids.[34] If alpha-aminoisobuteric acid is used to transport copper through the cell wall, this anomaly might 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.[35] Cortisol also has a negative-feedback effect on interleukin-1.[36] IL-1 must be especially useful in combating some diseases; however, endotoxic bacteria have gained an advantage by forcing the hypothalamus to increase cortisol levels (forcing the secretion of CRH hormone, thus antagonizing IL-1). The suppressor cells are not affected by glucosteroid response-modifying factor (GRMF),[37] 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 not affected by cortisol.[38]

Bone metabolism

Cortisol reduces bone formation, favoring long-term development of osteoporosis. It transports potassium out of cells in exchange for an equal number of sodium ions (see above).[39] This can trigger the hyperkalemia of metabolic shock from surgery. Cortisol also reduces calcium absorption in the intestine.[40]

Memory

Cortisol works 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 damages cells in the hippocampus;[41] this damage results in impaired learning. Furthermore, it has been shown that cortisol inhibits memory retrieval of already stored information.[42][43]

Additional effects

Binding

Most serum cortisol (all but about 4%) is bound to proteins, including corticosteroid binding globulin (CBG) and serum albumin. Free cortisol passes easily through cellular membranes, where they bind intracellular cortisol receptors.[46]

Regulation

The primary control of cortisol is the pituitary gland peptide, adrenocorticotropic hormone (ACTH). ACTH probably controls cortisol by controlling the movement of calcium into the cortisol-secreting target cells.[47] 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.[48] When activated macrophages start to secrete interleukin-1 (IL-1), which synergistically with CRH increases ACTH,[36] T-cells also secrete glucosteroid response modifying factor (GRMF or GAF) as well as IL-1; both increase the amount of cortisol required to inhibit almost all the immune cells.[37] Immune cells then assume their own regulation, but at a higher cortisol setpoint. The increase in cortisol in diarrheic calves is minimal over healthy calves, however, and falls over time.[49] The cells do not lose all their fight-or-flight override because of interleukin-1's synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1[36]—especially useful for those diseases which gain an advantage by forcing the hypothalamus to secrete too much CRH, such as those caused by endotoxic bacteria. The suppressor immune cells are not affected by GRMF,[37] so the immune cells' effective setpoint may be even higher than the setpoint for physiological processes. GRMF (known as GAF in this reference) primarily affects the liver (rather than the kidneys) for some physiological processes.[50]

High potassium media (which stimulates aldosterone secretion in vitro) also stimulate cortisol secretion from the fasciculata zone of canine adrenals [51]—unlike corticosterone, upon which potassium has no effect.[52] Potassium loading also increases ACTH and cortisol in humans.[53] This is probably the reason why potassium deficiency causes cortisol to decline (as mentioned) and causes a decrease in conversion of 11-deoxycortisol to cortisol.[54] This may also have a role in rheumatoid-arthritis pain; cell potassium is always low in RA.[55]

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.[87][88]

Pharmacology

Hydrocortisone is the pharmaceutical term for cortisol used in 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 perioperatively in patients on longterm steroid treatment to prevent 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 hydrocortisone, prednisolone is about four times as strong and dexamethasone about forty times as strong, in their anti-inflammatory effect. For side effects, see corticosteroid and prednisolone.

Hydrocortisone creams and ointments are available in most countries without prescription in strengths ranging from 0.05% to 2.5% (depending on local regulations) with stronger forms available by prescription only. Covering the skin after application increases the absorption and effect. Such enhancement is sometimes prescribed, but otherwise should be avoided to prevent overdose and systemic impact.

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.[89]

Biochemistry

Biosynthesis

Cortisol is synthesized from cholesterol. Synthesis takes place in the zona fasciculata of the adrenal cortex. (The name cortisol is derived 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, mainly secreting 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); ACTH production is in turn stimulated by corticotropin-releasing hormone (CRH), which is released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane, via regulation of the STAR (steroidogenic acute regulatory) protein. It also stimulates the main rate-limiting step in cortisol synthesis, in which cholesterol is converted to pregnenolone and catalyzed by Cytochrome P450SCC (side chain cleavage enzyme).[90]

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; 11-beta HSD2 serves to decrease 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 known as metabolic syndrome.[91]

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).

References

  1. ^ a b c Scott, Elizabeth (22 September 2011). "Cortisol and Stress: How Cortisol Affects Your Body, and How To Stay Healthy in the Face of Stress". Stress.about.com. http://stress.about.com/od/stresshealth/a/cortisol.htm. Retrieved 29 November 2011. 
  2. ^ hydrocortisoneshots.com
  3. ^ de Weerth C, Zijl R, Buitelaar J (2003). "Development of cortisol circadian rhythm in infancy". Early Hum Dev 73 (1-2): 39–52. doi:10.1016/S0378-3782(03)00074-4. PMID 12932892. 
  4. ^ "Asperger's stress hormone 'link'". BBC News. 2009-04-02. http://news.bbc.co.uk/2/hi/health/7976489.stm. Retrieved 2010-04-30. 
  5. ^ a b c d Biochemistry Reference Ranges at Good Hope Hospital Retrieved on Nov 8, 2009
  6. ^ a b c d Derived from molar values using molar mass of 362 g/mol
  7. ^ a b Converted from µg/24h, using molar mass of 362.460 g/mol
  8. ^ a b Görges, R.; Knappe, G.; Gerl, H.; Ventz, M.; Stahl, F. (1999). "Diagnosis of Cushing's syndrome: Re-evaluation of midnight plasma cortisol vs urinary free cortisol and low-dose dexamethasone suppression test in a large patient group". Journal of endocrinological investigation 22 (4): 241–249. PMID 10342356.  edit
  9. ^ a b MedlinePlus > Cortisol - urine. Update Date: 11/23/2009. Updated by: Ari S. Eckman. Also reviewed by David Zieve.
  10. ^ a b Converted from nmol/24h, using molar mass of 362.460 g/mol
  11. ^ a b USMLE Step 1 Secrets. 2003. p. 63. 
  12. ^ King, Michael W. (2005). Lange Q&A USMLE Step 1 (Sixth ed.). New York: McGraw-Hill, Medical Pub. Division. p. 82. ISBN 0071445781. 
  13. ^ Piroli, G. G.; Grillo, C. A.; Reznikov, L. R.; Adams, S.; McEwen, B. S.; Charron, M. J.; Reagan, L. P. (2007). "Corticosterone Impairs Insulin-Stimulated Translocation of GLUT4 in the Rat Hippocampus". Neuroendocrinology 85 (2): 71–80. doi:10.1159/000101694. PMID 17426391.  edit
  14. ^ Baynes, J., Dominiczak, M., Medical Biochemistry. Elsevier Limited; Third Edition (2009). ISBN 978-0-323-05371-6.
  15. ^ Houck JC, Sharma VK, Patel YM, Gladner JA. Induction of collagenolytic and proteolytic activities by anti-inflammatoes this by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis.. 
  16. ^ Manchester, K.L., “Sites of Hormonal Regulation of Protein Metabolism. p. 229”, Mammalian Protein [Munro, H.N., Ed.]. Academic Press, New York. On p273.
  17. ^ Husband AJ, Brandon MR, Lascelles AK (October 1973). "The effect of corticosteroid on absorption and endogenous production of immunoglobulins in calves". Aust J Exp Biol Med Sci 51 (5): 707–10. doi:10.1038/icb.1973.67. PMID 4207041. 
  18. ^ Posey WC, Nelson HS, Branch B, Pearlman DS (December 1978). "The effects of acute corticosteroid therapy for asthma on serum immunoglobulin levels". J. Allergy Clin. Immunol. 62 (6): 340–8. doi:10.1016/0091-6749(78)90134-3. PMID 712020. 
  19. ^ Soffer, L.J.; Dorfman, R.I.; Gabrilove, J.L,. “The Human Adrenal Gland”. Febiger, Phil.
  20. ^ Kokshchuk, G.I.; Pakhmurnyi, B.A. (1979) “Role of Glucocorticoids in Regulation of the Acid-Excreting Function of the Kidneys”. Fiziol. Z H SSR I.M.I.M. Sechenova 65: 751,.
  21. ^ Tai YH, Decker RA, Marnane WG, Charney AN, Donowitz M (May 1981). "Effects of methylprednisolone on electrolyte transport by in vitro rat ileum". Am. J. Physiol. 240 (5): G365–70. PMID 6112881. 
  22. ^ a b Sandle GI, Keir MJ, Record CO (1981). "The effect of hydrocortisone on the transport of water, sodium, and glucose in the jejunum. Perfusion studies in normal subjects and patients with coeliac disease". Scand. J. Gastroenterol. 16 (5): 667–71. doi:10.3109/00365528109182028. PMID 7323700. 
  23. ^ Mason PA, Fraser R, Morton JJ, Semple PF, Wilson A (August 1977). "The effect of sodium deprivation and of angiotensin II infusion on the peripheral plasma concentrations of 18-hydroxycorticosterone, aldosterone and other corticosteroids in man". J. Steroid Biochem. 8 (8): 799–804. doi:10.1016/0022-4731(77)90086-3. PMID 592808. 
  24. ^ Gorbman, A.; Dickhoff, W.W.; Vigna, S.R.; Clark, N.B.; Muller, A.F,. “Comparative Endocrinology”. John Wiley and Sons, New York.
  25. ^ Muller AF Oconnor CM, ed. (1958) “An International Symposium on Aldosterone”, page 58. Little Brown & Co.
  26. ^ KNIGHT RP, KORNFELD DS, GLASER GH, BONDY PK (February 1955). "Effects of intravenous hydrocortisone on electrolytes of serum and urine in man". J. Clin. Endocrinol. Metab. 15 (2): 176–81. doi:10.1210/jcem-15-2-176. PMID 13233328. 
  27. ^ BARGER AC, BERLIN RD, TULENKO JF (June 1958). "Infusion of aldosterone, 9-alpha-fluorohydrocortisone and antidiuretic hormone into the renal artery of normal and adrenalectomized, unanesthetized dogs: effect on electrolyte and water excretion". Endocrinology 62 (6): 804–15. doi:10.1210/endo-62-6-804. PMID 13548099. 
  28. ^ Boykin J, DeTorrenté A, Erickson A, Robertson G, Schrier RW (October 1978). "Role of plasma vasopressin in impaired water excretion of glucocorticoid deficiency". J. Clin. Invest. 62 (4): 738–44. doi:10.1172/JCI109184. PMC 371824. PMID 701472. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=371824. 
  29. ^ Dingman, J.F.; Gonzalez-Auvert Ahmed, A.B.J.; Akinura, A. (1965) “Antidiuretic Hormone in Adrenal Insufficiency”. Journal of Clinical Investigation 44: 1041,.
  30. ^ Weber, C.E (1984). “Copper Response to Rheumatoid Arthritis”. Medical Hypotheses 15: 333-348, on p337,.
  31. ^ Weber, C.E. (1984) “Copper Response to Rheumatoid Arthritis”. Medical Hypotheses 15: 333,.on p334.
  32. ^ Flohe, L.; Beckman, R.; Giertz, H.; Loschen, G. “Oxygen Centered Free Radicals as Mediators of Inflammation. p. 405”, Oxidative Stress (Sies H, ed) Academic Press, New York.
  33. ^ Piletz JE, Herschman HR (June 1983). "Hepatic metallothionein synthesis in neonatal Mottled-Brindled mutant mice". Biochem. Genet. 21 (5-6): 465–75. doi:10.1007/BF00484439. PMID 6870774. 
  34. ^ Chambers, J.W.; Georg, R.H. and Bass, A.D. (1965) “Effect of Hydrocortisone and Insulin on Uptake of Alpha Aminoisobutyric Acid by Isolated Perfused Rat Liver”. Mol. Pharmacol. 1: 66,.
  35. ^ 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. doi:10.1111/j.1365-3083.1982.tb00618.x. PMID 6461917. 
  36. ^ a b c Besedovsky, H.O.; Del Rey, A.; Sorkin, E. (1984) "Integration of Activated Immune Cell Products in Immune Endocrine Feedback Circuits." p. 200 in Leukocytes and Host Defense Vol. 5 [Oppenheim, J.J.; Jacobs, D.M., eds]. Alan R. Liss, New York,.
  37. ^ a b c Fairchild SS, Shannon K, Kwan E, Mishell RI (February 1984). "T cell-derived glucosteroid response-modifying factor (GRMFT): a unique lymphokine made by normal T lymphocytes and a T cell hybridoma". J. Immunol. 132 (2): 821–7. PMID 6228602. 
  38. ^ Onsrud M, Thorsby E (1981). "Influence of in vivo hydrocortisone on some human blood lymphocyte subpopulations. I. Effect on natural killer cell activity". Scand. J. Immunol. 13 (6): 573–9. PMID 7313552. 
  39. ^ 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. doi:10.1210/jcem-15-2-176. PMID 13233328. 
  40. ^ Shultz TD, Bollman S, Kumar R (June 1982). "Decreased intestinal calcium absorption in vivo and normal brush border membrane vesicle calcium uptake in cortisol-treated chickens: evidence for dissociation of calcium absorption from brush border vesicle uptake". Proc. Natl. Acad. Sci. U.S.A. 79 (11): 3542–6. doi:10.1073/pnas.79.11.3542. PMC 346457. PMID 6954501. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=346457. 
  41. ^ Mc Auley MM, Kenny RA, Kirkwood TT, Wilkinson DD, Jones JJ, Miller VM (March 2009). "A Mathematical Model of aging-related and cortisol induced hippocampal dysfunction". BMC Neurosci 10 (1): 26. doi:10.1186/1471-2202-10-26. PMC 2680862. PMID 19320982. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2680862. 
  42. ^ de Quervain, D et al., Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature, 394, 787-790 (1998)
  43. ^ de Quervain, D et al., Acute cortisone administration impairs retrieval of long-term declarative memory in humans. Nature Neuroscience, 3, 313-314 (2000)
  44. ^ An Introduction to Behavioral Endocrinology, Randy J Nelson, 3rd edition, Sinauer
  45. ^ Christine A. Maglione-Garves, Len Kravitz, and Suzanne Schneider. "Stress Cortisol Connection". Unm.edu. http://www.unm.edu/~lkravitz/Article%20folder/stresscortisol.html. Retrieved 2010-06-14. 
  46. ^ Boron and Boulpaep, Medical physiology 2009
  47. ^ Davies E., Keyon C.J., Fraser R. (1985). "The role of calcium ions in the mechanism of ACTH stimulation of cortisol synthesis". Steroids 45 (6): 557. PMID 3012830. 
  48. ^ Plotsky PM, Otto S, Sapolsky RM (September 1986). "Inhibition of immunoreactive corticotropin-releasing factor secretion into the hypophysial-portal circulation by delayed glucocorticoid feedback". Endocrinology 119 (3): 1126–30. doi:10.1210/endo-119-3-1126. PMID 3015567. 
  49. ^ Dvorak M (1971). "Plasma 17-Hydroxycorticosteroid Levels in Healthy and Diarrheic Calves". British Veterinarian Journal 127: 372. 
  50. ^ Stith RD, McCallum RE (1986). "General effect of endotoxin on glucocorticoid receptors in mammalian tissues". Circ. Shock 18 (4): 301–9. PMID 3084123. 
  51. ^ Mikosha, A.S.; Pushkarov, I.S.; Chelnakova, I.S.; Remennikov, G.Y.A. (1991) “Potassium Aided Regulation of Hormone Biosynthesis in Adrenals of Guinea Pigs Under Action of Dihydropyridines: Possible Mechanisms of Changes in Steroidogenesis Induced by 1,4, Dihydropyridines in Dispersed Adrenocorticytes.” Fiziol. [Kiev] 37: 60,.
  52. ^ Mendelsohn FA, Mackie C (July 1975). "Relation of intracellular K+ and steroidogenesis in isolated adrenal zona glomerulosa and fasciculata cells". Clin Sci Mol Med 49 (1): 13–26. PMID 168026. 
  53. ^ Ueda Y, Honda M, Tsuchiya M, et al. (April 1982). "Response of plasma ACTH and adrenocortical hormones to potassium loading in essential hypertension". Jpn. Circ. J. 46 (4): 317–22. PMID 6283190. 
  54. ^ Bauman K Muller J 1972 “Effect of potassium on the final status of aldosterone biosynthesis in the rat. I 18-hydroxylation and 18hydroxy dehydrogenation. II beta-hydroxylation.” Acta Endocrin. Copenh. 69; I 701-717, II 718-730.
  55. ^ LaCelle PL et al. (1964) “An investigation of total body potassium in patients with rheumatoid arthritis.” Proceedings of the Annual Meeting of the American Rheumatism Association, Arthritis and Rheumatism 7; 321.
  56. ^ Golf, S. H.; Happel, O.; Graef, V.; Seim, K. E. (Nov 1984). "Plasma aldosterone, cortisol and electrolyte concentrations in physical exercise after magnesium supplementation" (Free full text). Journal of clinical chemistry and clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie 22 (11): 717–721. ISSN 0340-076X. PMID 6527092. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+50-23-7.  edit
  57. ^ Golf, S. B.; Bender, S.; Grüttner, J. (Sep 1998). "On the significance of magnesium in extreme physical stress". Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. 12 2 (2suppl): 197–202. doi:10.1023/A:1007708918683. ISSN 0920-3206. PMID 9794094.  edit
  58. ^ Wilborn, D.; Kerksick, M.; Campbell, I.; Taylor, W.; Marcello, M.; Rasmussen, J.; Greenwood, C.; Almada, A. et al. (Dec 2004). "Effects of Zinc Magnesium Aspartate (ZMA) Supplementation on Training Adaptations and Markers of Anabolism and Catabolism" (Free full text). Journal of the International Society of Sports Nutrition 1 (2): 12–20. doi:10.1186/1550-2783-1-2-12. PMC 2129161. PMID 18500945. http://www.jissn.com/content/1/2/12.  edit
  59. ^ Bhathena, S. B.; Berlin, E.; Judd, J. T.; Kim, Y. C.; Law, J. S.; Bhagavan, H. N.; Ballard-Barbash, R.; Nair, P. P. (1 October 1991). "Effects of omega 3 fatty acids and vitamin E on hormones involved in carbohydrate and lipid metabolism in men" (Free full text). The American journal of clinical nutrition 54 (4): 684–688. ISSN 0002-9165. PMID 1832814. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=1832814.  edit
  60. ^ Delarue, J. M.; Matzinger, O.; Binnert, C.; Schneiter, P.; Chioléro, R.; Tappy, L. (Jun 2003). "Fish oil prevents the adrenal activation elicited by mental stress in healthy men" (Free full text). Diabetes & metabolism 29 (3): 289–295. doi:10.1016/S1262-3636(07)70039-3. ISSN 1262-3636. PMID 12909818. http://www.masson.fr/masson/MDOI-DM-06-2003-29-3-1262-3636-101019-ART12.  edit
  61. ^ Uedo, N. I.; Ishikawa, H.; Morimoto, K.; Ishihara, R.; Narahara, H.; Akedo, I.; Ioka, T.; Kaji, I. et al. (Mar 2004). "Reduction in salivary cortisol level by music therapy during colonoscopic examination" (Free full text). Hepato-gastroenterology 51 (56): 451–453. ISSN 0172-6390. PMID 15086180. http://www.nlm.nih.gov/medlineplus/colonoscopy.html.  edit
  62. ^ Field, T.; Hernandez-Reif, M.; Diego, M.; Schanberg, S.; Kuhn, C. (Oct 2005). "Cortisol decreases and serotonin and dopamine increase following massage therapy". The International journal of neuroscience 115 (10): 1397–1413. doi:10.1080/00207450590956459. ISSN 0020-7454. PMID 16162447.  edit
  63. ^ Berk et al.. "Cortisol and Catecholamine stress hormone decrease is associated with the behavior of perceptual anticipation of mirthful laughter". The FASEB Journal 22 (1): 946.11. http://www.fasebj.org/cgi/content/meeting_abstract/22/1_MeetingAbstracts/946.11. Retrieved 2010-06-14. 
  64. ^ "Crying; The Mystery of Tears" personal page of Frey WH with quote from his book
  65. ^ Hellhammer, J.; Fries, E.; Buss, C.; Engert, V.; Tuch, A.; Rutenberg, D.; Hellhammer, D. (Jun 2004). "Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress". Stress (Amsterdam, Netherlands) 7 (2): 119–126. doi:10.1080/10253890410001728379. ISSN 1025-3890. PMID 15512856.  edit
  66. ^ Starks MA, Starks SL, Kingsley M, Purpura M, Jäger R (2008). "The effects of phosphatidylserine on endocrine response to moderate intensity exercise". J Int Soc Sports Nutr 5: 11. doi:10.1186/1550-2783-5-11. PMC 2503954. PMID 18662395. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2503954. 
  67. ^ Vitamin C: Stress Buster Psychology today
  68. ^ "Black tea 'soothes away stress'". BBC News. 2006-10-04. http://news.bbc.co.uk/2/hi/health/5405686.stm. Retrieved 2010-04-30. 
  69. ^ Steptoe, A.; Gibson, E.; Vuononvirta, R.; Williams, E.; Hamer, M.; Rycroft, J.; Erusalimsky, J.; Wardle, J. (2007). "The effects of tea on psychophysiological stress responsivity and post-stress recovery: a randomised double-blind trial". Psychopharmacology 190 (1): 81–89. doi:10.1007/s00213-006-0573-2. PMID 17013636.  edit
  70. ^ Cynthia Quiroga Murcia, Stephan Bongard, and Gunter Kreutz (July 2009). "Emotional and Neurohumoral Responses to Dancing Tango Argentino - The Effects of Music and Partner". Music and Medicine 1 (1): 14–21. http://mmd.sagepub.com/content/1/1/14.full. Retrieved 2011-08-07. 
  71. ^ Scott, Elizabeth. "Cortisol and Stress: How to Stay Healthy". Cortisol and Your Body. http://stress.about.com/od/stresshealth/a/cortisol.htm. 
  72. ^ Lovallo WR, Farag NH, Vincent AS, Thomas TL, Wilson MF (March 2006). "Cortisol responses to mental stress, exercise, and meals following caffeine intake in men and women". Pharmacol. Biochem. Behav. 83 (3): 441–7. doi:10.1016/j.pbb.2006.03.005. PMC 2249754. PMID 16631247. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2249754. 
  73. ^ "Sleep loss results in an elevation of cortisol levels the next evening". Cat.inist.fr. http://cat.inist.fr/?aModele=afficheN&cpsidt=2068517. Retrieved 2010-06-14. 
  74. ^ Robson PJ, Blannin AK, Walsh NP, Castell LM, Gleeson M (February 1999). "Effects of exercise intensity, duration and recovery on in vitro neutrophil function in male athletes". Int J Sports Med 20 (2): 128–35. doi:10.1055/s-2007-971106. PMID 10190775. 
  75. ^ Gleeson, M. (Mar 2006). "Can nutrition limit exercise-induced immunodepression?". Nutrition reviews 64 (3): 119–131. doi:10.1111/j.1753-4887.2006.tb00195.x. ISSN 0029-6643. PMID 16572599.  edit
  76. ^ Kraemer WJ, Spiering BA, Volek JS, et al. (January 2009). "Recovery from a national collegiate athletic association division I football game: muscle damage and hormonal status". J Strength Cond Res 23 (1): 2–10. doi:10.1519/JSC.0b013e31819306f2 (inactive 2010-01-03). PMID 19077734. 
  77. ^ Shalev, I.; Lerer, E.; Israel, S.; Uzefovsky, F.; Gritsenko, I.; Mankuta, D.; Ebstein, P.; Kaitz, M. (Apr 2009). "BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions". Psychoneuroendocrinology 34 (3): 382–388. doi:10.1016/j.psyneuen.2008.09.017. ISSN 0306-4530. PMID 18990498.  edit
  78. ^ Cagnacci, A.; Soldani, R.; Yen, S. S. C. (Mar 1997). "Melatonin enhances cortisol levels in aged women: reversible by estrogens" (Free full text). Journal of pineal research 22 (2): 81–85. doi:10.1111/j.1600-079X.1997.tb00307.x. ISSN 0742-3098. PMID 9181519. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+50-23-7.  edit
  79. ^ Wingenfeld, K.; Schulz, M.; Damkroeger, A.; Rose, M.; Driessen, M. (Mar 2009). "Elevated diurnal salivary cortisol in nurses is associated with burnout but not with vital exhaustion". Psychoneuroendocrinology 34 (8): 1144–1151. doi:10.1016/j.psyneuen.2009.02.015. ISSN 0306-4530. PMID 19321266.  edit
  80. ^ Advanced Nutrition and Human Metabolism. 2008. p. 247. 
  81. ^ "Cortisol Release From Adipose Tissue by 11β-Hydroxysteroid Dehydrogenase Type 1 in Humans". Diabetes.diabetesjournals.org. 2008-10-13. http://diabetes.diabetesjournals.org/cgi/content/abstract/58/1/46. Retrieved 2010-06-14. 
  82. ^ Haas et al., 10.3945/ajcn.2008.26958. "Body composition changes in female adolescents with anorexia nervosa". American Journal of Clinical Nutrition. doi:10.3945/ajcn.2008.26958. http://www.ajcn.org/cgi/content/abstract/ajcn.2008.26958v1. Retrieved 2010-06-14. 
  83. ^ "New Clues about Genetic Influence of Stress on Men’s Health". Dukehealth.org. http://www.dukehealth.org/HealthLibrary/News/new_clues_about_genetic_influence_of_stress_on_men_s_health. Retrieved 2010-06-14. 
  84. ^ Raloff, Janet. (23 April 2009)."Birth control pills can limit muscle-training gains. Science News. Accessed 29 November 2011.
  85. ^ "The Impact of Mode and Mode Transfer on Commuter Stress, The Montclair Connection" (PDF). http://www.utrc2.org/research/assets/74/commuterstress2-report1.pdf. Retrieved 2010-06-14. 
  86. ^ Kotwica, G; Franczak A, Okrasa S, Koziorowski M, Kurowicka B. (March 2002). "Effects of mating stimuli and oxytocin on plasma cortisol concentration in gilts.". Reprod Biol. 2 (1): 25–37. PMID 14666160. 
  87. ^ "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. 
  88. ^ Terzolo, M.; Bovio, S.; Pia, A.; Conton, P.; Reimondo, G.; Dall'asta, C.; Bemporad, D.; Angeli, A. et al. (2005). "Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma". European journal of endocrinology / European Federation of Endocrine Societies 153 (2): 307–315. doi:10.1530/eje.1.01959. PMID 16061838.  edit
  89. ^ 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. 
  90. ^ Mechanism of ACTH action on adrenal cortical cells Andrew N. Margioris, M.D., and Christos Tsatsanis, Ph.D. Updated: December 4, 2006
  91. ^ Tomlinson, J. W.; Walker, E. A.; Bujalska, I. J.; Draper, N.; Lavery, G. G.; Cooper, M. S.; Hewison, M.; Stewart, P. M. (2004). "11 -Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response". Endocrine Reviews 25 (5): 831–866. doi:10.1210/er.2003-0031. PMID 15466942.  edit

External links

Mineralocorticoids
(3-one, 4-ene,
no FG at 16)
Glucocorticoids
(3-one, 4-ene,
11-FG,
17-hydroxy)
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
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)
Pregnatriene
(+2-ene)
Other/ungrouped
HALOGENATED: Loteprednol • HALOGENATED, WITH FG AT 16: Fludroxycortide • Formocortal • Mometasone furoate
Aldosterone antagonists
Synthesis modifiers

M: END

anat/phys/devp/horm

noco(d)/cong/tumr, sysi/epon

proc, drug (A10/H1/H2/H3/H5)
Mevalonate pathway
Geranyl-
Non-mevalonate pathway
DOXP · MEP · CDP-ME · CDP-MEP · MEcPP · HMB-PP · IPP · DMAPP
To Cholesterol
Steroid
Androgens
(C19 androstane)
Estrogens
(C18 estrane)
Nonhuman

M: MET

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

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

M: END

anat/phys/devp/horm

noco(d)/cong/tumr, sysi/epon

proc, drug (A10/H1/H2/H3/H5)
biochemical families: prot · nucl · carb (glpr, alco, glys) · lipd (fata/i, phld, strd, gllp, eico) · amac/i · ncbs/i · ttpy/i
Rehydration
Intestinal anti-infectives
Intestinal adsorbents
Antipropulsives (opioids)
Intestinal anti-inflammatory agents
Antidiarrheal micro-organisms
Other antidiarrheals

M: DIG

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

noco/cong/tumr, sysi/epon

proc, drug(A2A/2B/3/4/5/6/7/14/16), blte
Anti-infectives
Corticosteroids
Analgesics and anesthetics

M: EAR

anat(e/p)/phys/devp

noco/cong, epon

proc, drug(S2)