Cortisol

Yoshinao Katsu , Michael E. Baker , in Handbook of Hormones (Second Edition), 2021

Abstract

Cortisol is one of the major glucocorticoids synthesized in the zona fasciculate of the adrenal cortex. Cortisol secretion is regulated by the hypothalamic hormone, CRH, and the pituitary hormone, ACTH, in the hypothalamus-pituitary-adrenal axis. Cortisol is known as a stress hormone involved in the response to physical and/or emotional stress. Cortisol also participates in various homeostatic maintenance actions such as blood pressure, immune system, antiinflammatory action, and the metabolism of protein, carbohydrate, and adipose. A decrease of cortisol induces Addison's disease while the overproduction of cortisol is related to Cushing's syndrome.

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Cortisol

Yoshinao Katsu , Taisen Iguchi , in Handbook of Hormones, 2016

Abstract

Cortisol is one of the major glucocorticoids synthesized in the zona fasciculata of the adrenal cortex. Cortisol secretion is regulated by the hypothalamic hormone, CRH, and the pituitary hormone, ACTH, in the hypothalamus-pituitary-adrenal axis. Cortisol is known as a stress hormone involved in the response to physical and/or emotional stress. Cortisol also participates in various homeostatic maintenance actions: blood pressure; immune system; metabolism of protein, carbohydrate, and adipose; and anti-inflammatory action. Decrease of cortisol induces Addison's disease, while overproduction of cortisol is related to Cushing's syndrome.

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Pharmacology for the Interventional Pain Physician

Magdalena Anitescu , ... Renata Variakojis , in Practical Management of Pain (Fifth Edition), 2014

Pharmacokinetics and Pharmacodynamics of the Steroids

Cortisol circulates in the blood in three forms: free cortisol (5%), protein-bound cortisol, and cortisol metabolites. 2 It is this unbound (free) portion that is the physiologically active hormone. Approximately 90% of cortisol is bound to cortisol-binding globulin (CBG), also known as transcortin, and albumin. CBG has a high affinity for cortisol but is present in small amounts. The second serum-binding protein, albumin, binds cortisol with less affinity but is abundantly present. During stress, there is a characteristic increase in total cortisol blood levels, including an increase in the unbound percentage. 13 The level of CBG is increased in high-estrogen states, in pregnancy, and during administration of contraceptives. 2 Most synthetic glucocorticoids have less affinity for CBG (approximately 70% binding), and this may account for their propensity to produce cushingoid symptoms at low doses. Cortisol primarily is metabolized in the liver, with subsequent renal excretion of the metabolites.

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Western approach to pregnancy

Suzanne Yates BA(Hons) DipHSEC MRSS(T) APNT PGCE(PCET) , in Pregnancy and Childbirth, 2010

Cortisol

Oestrogen stimulates adrenal cortisol production by inhibiting the metabolism of cortisol and increasing the synthesis of cortisol-binding protein (transcortin). Progesterone increases tissue resistance to cortisol by competing at the receptor level and binding to the cortisol-binding protein. During pregnancy there is an increase in cortisol production:

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Cortisol levels increase in response to the increased cardiac output and decreased fasting glucose levels in the second trimester.

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Cortisol increases greatly in the third trimester and may contribute to depression.

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High levels of cortisol are linked with premature labour.

Effects of cortisol

This increase in cortisol serves to aid:

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Glucose metabolism.

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Regulation of blood pressure.

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Insulin release.

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Immune and inflammatory response.

It has a positive effect on certain conditions such as rheumatoid arthritis and eczema.

Excessive cortisol production, however, will negatively affect cognitive performance, the thyroid gland, blood sugar levels, decrease bone density and muscle tissue, raise blood pressure and immune response.

Emotionally, the more 'wired' 'stressed' effects of cortisol are balanced by the more calming effects of progesterone and oestrogen. The impact of cortisol is to make the woman more alert and vigilant about her safety, nutrition and surroundings.

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Glucocorticoid Treatment

Peter C. Hindmarsh , Kathy Geertsma , in Congenital Adrenal Hyperplasia, 2017

Cortisol binding globulin

Cortisol is no exception to this rule and it attaches itself to a special protein called cortisol binding globulin (CBG). This means that in the blood at any particular point, there is cortisol which is not attached to any protein known as free cortisol and cortisol which is attached to CBG is known as a bound cortisol ( Fig. 18.2).

Figure 18.2. The interaction in the blood between cortisol and cortisol binding globulin (CBG).

When we carry out a blood test, we measure both the free and the bound cortisol and this is called the total cortisol concentration (Fig. 18.3). In fact, we do not always call it this, we simply refer to it as the plasma cortisol concentration but to be technically correct, we should really call it the total plasma cortisol concentration.

Figure 18.3. Actual sticking of free cortisol onto CBG in the blood which yields bound cortisol.

This means when we are interpreting cortisol levels we have to remember some is free and some is bound. Under normal circumstances this does not matter too much, but when CBG levels change, e.g. in people who take the oral contraceptive pill (Fig. 20.7), then the total cortisol concentration we measure will change as well. Using the oral contraceptive pill as an example, we know if we measure cortisol levels in the individual taking the pill, the plasma cortisol concentration, in other words total plasma cortisol concentration, will be high because more CBG is present which will bind more cortisol, raising the total cortisol concentration. What happens is the free cortisol concentration does not change much, at least initially. If you are taking hydrocortisone however, unless the dose is changed, more cortisol will be taken up and bound so there will be less free cortisol.

This becomes important because it is free cortisol which carries out all the action around the body. If more of your cortisol is bound, there is less free, so you might develop symptoms of being cortisol deficient even though when you measure and look at the total cortisol concentration, it looks normal because the extra is bound.

This all adds extra complexity but is extremely important to understand, because it influences many of the things we do with hydrocortisone replacement. We have seen one example with the oral contraceptive pill. Another example, is the whole question of whether you should double or triple or quadruple doses during illnesses. We all know that the standard teaching is to double the cortisol dose. The question is, what does doubling the dose, tripling or even quadrupling the dose achieve?

The answer is perhaps surprising at first. If you double and particularly triple the dose, e.g. go from 10 mg per day of hydrocortisone to 30 mg per day, you do not triple the amount of cortisol in the blood. So although you might triple the dose, in fact the cortisol concentrations in the blood barely double. This happens because of the presence of the binding proteins. When you give more cortisol, if you start to exceed blood levels of 450–500 nmol/l then the proteins (CBG) to which cortisol can attach, become saturated. In other words, there is a limit to how much cortisol can stick onto the protein. Once this threshold is reached there will be an increase in the amount of free cortisol, but because this is removed very easily by the liver and the kidney, the amount of total cortisol you actually achieve will not go up proportionately with the amount you are taking. This means if you double the dose of hydrocortisone when unwell, you probably will just about double the cortisol level. Although it might be tempting to triple the dose, this will not lead to a triple level of cortisol in the blood as the threshold will be exceeded and the extra cortisol that is being taken, will be lost in the urine. CBG plays a vital role in helping with the way cortisol works.

The real reason why we have these proteins, is not simply to act as a buffer and store, but because cortisol itself does not dissolve very easily in the blood. CBG binds up to 90% of all cortisol in the blood, which means there is only about 4–10% free in the blood to get into cells to act. The way in which cortisol attaches itself to CBG varies considerably between individuals, but even more importantly it is also influenced by body temperature. As body temperature increases, e.g. during a fever, the amount of cortisol which attaches itself to CBG decreases, so this becomes really important when we have a fever because the free cortisol that becomes available, particularly to the local tissues, nearly triples. This is a really interesting and important observation, because it is one of the ways in which the body protects itself and gets cortisol out to where it needs to be working in situations of stress and illness. So, although we do not necessarily double or triple the amount of cortisol in the blood when we double or triple the hydrocortisone dose, what will happen, particularly in local tissues, is that free cortisol will actually increase, so this is a very handy protective way the body has to ensure that during illness, the tissues of the body get exactly the right amount of extra cortisol they need.

What we are now going to consider is how cortisol instructs the cells of the body to do all the things that it is capable of. Nearly two thirds of human genes are regulated by cortisol. Cortisol influences our genes by instructing them to switch off or on and make proteins.

Free cortisol can cross easily into cells. Within the cell is a special docking station for cortisol, the cortisol receptor. On attaching to the receptor, the cortisol receptor complex moves into the nucleus of the cell. The nucleus contains all the genes that we have and once in there, the cortisol receptor complex attaches to specific parts of genes known as glucocorticoid response elements. It is through this attachment that cortisol then influences the gene to switch on and produce the proteins that it codes for, or to switch off (Fig. 18.4).

Figure 18.4. Cortisol gains entry into the cell where it docks with a special glucocorticoid or cortisol receptor.

This complex moves into the nucleus of the cell and attaches to a glucocorticoid response elements on DNA. This attachment tells the gene to make the mRNA that goes on to form the protein that cortisol regulates.

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Corticotropic axis

Kamyar M. Hedayat , Jean-Claude Lapraz , in The Theory of Endobiogeny, 2019

Immunologic system

Cortisol is antiinflammatory through mechanisms discussed above. It is also antiallergic through its reduction of the number of mast cells, and stabilization of mast cell membrane, inhibiting release of histamine. 135 Cortisol does not affect the activity of histamine already in circulation. We hypothesize that through its negative feedback on ACTH, cortisol can diminish the proliferation of histamine receptors.

In adaptative levels, cortisol diminishes the volume of the thymus and reduces the size of lymph nodes. Cortisol's effects on T-lymphocytes were discussed earlier. An adapted expression of cortisol aids in the regulation of the immune system by limiting the intensity of ongoing immune activity as well as its duration. However, cortisol also inhibits or delays wound healing, 54 which allows for the immune activity within the extravascular spaces to continue without premature discontinuation. Of course, prolonged or dysregulated cortisol activity will adversely affect this process through immune suppression and improperly delayed anabolism of tissue.

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The Adrenal Cortex

Les Perry , Sami Medbak , in The Immunoassay Handbook (Fourth Edition), 2013

Function

Cortisol is an essential hormone and has a wide variety of effects on most tissues in the body ( see Normal Adrenocortical Function). It is particularly important through its gluconeogenic action, in coping with situations of mental or physical stress such as infections and operations.

Most of the cortisol circulates bound to protein in plasma with small amounts circulating in the free, biologically active form. Predominantly, immunoassays measure the total cortisol in serum so concentrations can seem high in situations where concentrations of CBG are raised such as pregnancy and estrogen therapy. Some commercial analyzer reagents have been developed to measure the "free" cortisol fraction only. These assays have been developed for the measurement of cortisol in saliva samples.

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Sleep and Sleep Disorders Associated with Pregnancy

Bilgay Izci Balserak , Kathryn Aldrich Lee , in Principles and Practice of Sleep Medicine (Sixth Edition), 2017

Cortisol

Cortisol starts to increase from the 25th week of pregnancy, with a two-fold increase seen in late pregnancy, followed by rapid return to normal concentrations after birth of the infant. 6,7 This elevation is mostly due to placental secretion of corticotropin-releasing hormone and adrenocorticotropic hormone (ACTH), and to increased synthesis of cortisol-binding globulin by the liver. 18 Progesterone and cortisol also share binding sites on cortisol-binding globulin. 7 Consequently, an increase in the level of progesterone during pregnancy leads to higher levels of free cortisol. The normal diurnal rhythm in cortisol includes a nadir level around midnight and marked elevation during early morning hours. 7,19 In pregnant women, the morning peak is not obvious, probably owing to the blunting effect of placental ACTH on maternal cortisol concentrations. 6,7 Sleep loss has been found to result in elevated cortisol levels the next evening. 20 Experimental studies in humans showed that cortisol infusions reduce rapid eye movement (REM) sleep but increase slow wave sleep. 18 Pregnant women with poor sleep in the third trimester have lower cortisol-melatonin ratios compared with good sleepers in the same trimester, as a result of a lower early-morning peak in their cortisol levels and a relatively higher concentration of melatonin. 7,19

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HORMONAL CONTROL OF METABOLISM AND IONIC REGULATION | The Hormonal Control of Osmoregulation in Teleost Fish

S.D. McCormick , in Encyclopedia of Fish Physiology, 2011

Summary

Cortisol has long been known to have an important role in seawater acclimation of teleost fishes. Current evidence indicates that the GH/IGF-I axis also has a role in seawater acclimation, and that GH, IGF-I, and cortisol interact positively to promote salt secretion and the underlying physiological mechanisms. PRL has a well-established role in ion uptake and inhibition of salt secretion. In addition to its role in seawater acclimation, several studies indicate that cortisol is also involved in ion uptake and can interact positively with PRL, indicating that cortisol has a dual osmoregulatory function in teleosts. The action of cortisol in promoting ion uptake or secretion may therefore depend partly on its interaction with growth hormone and PRL: when growth hormone is high and PRL is low, cortisol may act primarily to promote salt secretion. Conversely, when growth hormone is low and PRL is elevated, cortisol will act to promote ion uptake.

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Heart and Neurologic Disease

Patrick Riordan , Matthew Davis , in Handbook of Clinical Neurology, 2021

Neuroendocrine

Cortisol levels and hypothalamic–pituitary axis function have also been extensively studied in various anxiety disorders and anxiety in general. Findings regarding basal cortisol levels in various anxiety disorders have been mixed, with reduced cortisol levels in PTSD representing the only relatively consistent finding ( Bandelow et al., 2017). However, atypical cortisol responses in response to stressors or anticipated stressors have been observed in some studies, particularly with phobias. Nonetheless, a lack of measurable cortisol response differences between control and anxiety disorder subjects has frequently been reported as well (Bandelow et al., 2017). There is also limited evidence linking anxiety disorders to immune responses and inflammatory medical conditions, including cardiovascular disease.

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