Cortisol

Cushing's syndrome (CS) is characterized by excessive exposure to cortisol, mostly caused by an ACTH-producing pituitary adenoma (Cushing's disease; CD) or a cortisol-producing adrenal adenoma, and it is associated with metabolic and behavioral abnormalities.

From: Encyclopedia of Behavioral Neuroscience, 2nd edition, 2022

Hydrocortisone

Jennifer Minigh, in xPharm: The Comprehensive Pharmacology Reference, 2008

Hydrocortisone; aeroseb hc; alphaderm; barseb hc; 11beta, 17alpha,21 trihydroxypregn 4 ene3, 20 dione; 11beta,17,21trihydroxypregn 4 ene 3,20 dione; cetacort; cobadex; compound f; cort dome; cortef; cortenema; cortibel; cortifan; cortifoam; cortiment; cortiphate; cortisol; cortisole; cortispray; cortoderm; cortril; dermolate; dioderm; duomedihaler; ef cortelan; efcortelan; egocort; eksalb; eldecort; ficortril; hebcort; hebcort v; hycort; hydracort; hydrasson; hydroadreson; hydroadreson; hydrocort; hydrocorticosteroid; hydrocortisate; hydrocortison; hydrocortisone acetonide; hydrocortisone ointment; hydrocortisone plussaline; hydrocortisone steroid; hydrocortisone, topical; hydrocortisyl; hydrocortone; hydroderm; hydro ricortex; 17hydroxycorticosterone; hysone; hytone; incortin h; medihaler cort; medihalerduo; mildison lipocream; munitren; neo cortef; neocortef; novohydrocort; nsc10483; nsc 741; nutracort; otosone f; penecort; prepcort; pro cort; procort; proctocort; proctosone; rectocort; schericur; scherosone f; solu cortef mix ovial; substance m; synacort; vasocort; Hydrocortisone; 11beta,17, 21trihydroxypregn 4 ene 3, 20 dione; 4 pregnene 11beta, 17alpha,21 triol 3,20dione; 4 pregnene 3,20 dione n beta, 17alpha,21 triol; hydrocortisone plussaline; nsc10483

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Hydrocortisone

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

What is hydrocortisone?

Hydrocortisone is a synthetic preparation of the steroid hormone cortisol. Hydrocortisone is a glucocorticoid because by definition it increases the amount of glucose in the blood. We looked at the glucose cortisol relationship in Chapter 19. Hydrocortisone also has some salt retaining properties which distinguishes it from prednisolone and dexamethasone as they do not have the same salt retaining property.

Hydrocortisone comes in various forms and the one used in replacing cortisol are tablets that are taken orally. There are other preparations which are administered either by subcutaneous infusion using the pump method, intramuscular injections, or intravenously as well as suppositories. Each preparation works differently once administered and we discuss the other preparations in more detail in Chapter 27.

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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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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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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:

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

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

High levels of cortisol are linked with premature labour.

Effects of cortisol

This increase in cortisol serves to aid:

Glucose metabolism.

Regulation of blood pressure.

Insulin release.

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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Intravenous, Intramuscular and Other Forms of Hydrocortisone

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

Conclusions

Oral hydrocortisone tablets are the mainstay for the treatment of CAH. The other preparation the buccal tablets should not be used for cortisol replacement. Intravenous hydrocortisone can be used in emergency situations and prior to anaesthesia. Where a procedure lasts longer than 90 minutes, it is probably better to follow the intravenous bolus with an infusion of hydrocortisone.

Both intramuscular and intravenous hydrocortisone produce good levels of cortisol. However, these levels only last for about 4 hours so it is important they are repeated. It also means that if an intramuscular injection of hydrocortisone is given in an emergency situation, the person is assessed within 4 hours, as otherwise cortisol will start falling and the person may become unwell again.

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Clinical Neuroendocrinology

Kelly Cheer, Peter J. Trainer, in Handbook of Clinical Neurology, 2014

Cortisol production in health

Cortisol production from the adrenal glands occurs in response to ACTH secretion from the pituitary, which in turn is secreted after stimulation by corticotropin-releasing hormone (CRH) and also by vasopressin (AVP) from the hypothalamus.

There is a clinical spectrum associated with ACTH deficiency. With severe deficiency, patients present with features of marked hypotension, oliguria, and deranged electrolytes. In other circumstances, patients may have adequate HPA axis function for day-to-day health, but lack the reserve to increase cortisol levels in times of stress, such as surgery, trauma, or sepsis. Whilst this latter group of patients may not need long-term replacement of hydrocortisone, they must be aware of the need to introduce “sick-day” hydrocortisone in the case of intercurrent illness or physiologic stress.

It is important to note that there can be considerable variation in serum cortisol measurements between laboratories, according to the assays utilized and their methodology (Clarke et al., 1998). Comparison of cortisol responses between different laboratories can therefore be difficult. When measuring a serum cortisol level, this refers to the total cortisol level, the majority of which is bound to cortisol-binding globulin (CBG) in the serum and therefore biologically inactive. Only 5–10% of cortisol is in the free and biologically active form. Serum cortisol measurements are therefore affected by changes in CBG level, and this is increased in pregnancy, or with oral estrogen therapy. Oral estrogen should therefore be discontinued where possible, at least 6 weeks prior to evaluation of the HPA axis, as the induction of CBG will artificially increase the total cortisol level. As well as CBG, around 15% of cortisol is bound to albumin and as such, testing can be more complex in patients with disorders affecting their albumin, such as nephrotic syndrome or hepatic cirrhosis. Salivary cortisol is a surrogate marker for serum free cortisol and is a potential means of minimizing the effect of estrogen therapy on CBG (Laudat et al., 1988).

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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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