The hypothalamus is stimulated by increased stress to secrete corticotropin-releasing factor which stimulates the anterior pituitary to secrete corticotropin (ACTH). ACTH stimulates the adrenal cortex to synthesize and secrete aldosterone, cortisol, and androgens from zonas glomerulosa, fasciculata, and reticularis respectively. Cortisol acts directly on the pituitary to decrease ACTH secretion, as well as suppress CRF release. It also acts on the hypothalamus to suppress CRF release – negative feedback control.

Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every animal cell. GCs are part of the feedback mechanism in the immune system that turns immune activity down. They are used in to treat diseases that are caused by an overactive immune system, such as allergies, asthma, autoimmune diseases and sepsis. GCs have many diverse effects, including potentially harmful side effects. They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. GCs cause their effects by binding to the glucocorticoid receptor (GR). The activated GR complex in turn up-regulates the expression of anti-inflammatory proteins in the nucleus and represses the expression of pro-inflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus .

Cortisol is the principal human glucocorticoid. Its main actions are as follows:

Promote normal intermediary metabolism. Gluconeogenesis is favored. Amino acid uptake by the liver and kidney are increased and activities of gluconeogenic enzymes are elevated. Protein catabolism (except in the liver) and lipolysis are stimulated, providing for glucose synthesis.

Increase resistance to stress. Elevated levels of glucose prepare the body to handle stress. Vasoconstrictor actions of adrenergic stimuli on small vessels are enhanced, causing a modest increase in blood pressure.

Alter blood cell levels in plasma. Decreased eosinophils, basophils, monocytes and lymphocytes results from redistribution of these elements to the lymphoid tissue. Hemoglobin, erythrocytes, platelets and polymorphonuclear leukocytes are increased.

Anti-inflammatory actions. This is most important response therapeutically. Also causes immune suppression. Exact mechanism is not completely understood. Related to lowering and inhibition of peripheral lymphocytes and macrophages. COX-2 synthesis is reduced, lowering the availability of prostaglandins. Phospholipase A2 is indirectly inhibited, blocking the release of arachidonic acid. Mast cell degranulation interference lowers histamine release and capillary permeability.

Endocrine effects. Inhibition of corticotropin inhibits further glucocorticoid synthesis as well as further production of TSH. GH production is increased.

Other effects. Essential for normal GFR. Negative effects include: stimulation of gastric acid secretion and pepsin production, CNS effects, severe bone loss, and weakness due to myopathy.

Mineralocorticoid: Help control the body’s water volume and concentration of electrolytes, especially sodium and potassium. Principally aldosterone, which acts on the kidneys to provide active reabsorption of sodium and an associated passive reabsorption of water, as well as the active secretion of potassium in the principal cells of the cortical collecting tubule. This in turn results in an increase of blood pressure and blood volume.

Aldosterone: is produced in the cortex of the adrenal gland and its secretion is mediated principally by angiotensin II but also ACTH and local potassium levels.

Spironolactone: is a mineralcorticoid inhibitor, which is a renal competitive ANTAGONIST, and acts as a potassium-sparing diuretic. Used primarily to treat heart failure, ascites, low-renin hypertension, hypokalemia, secondary hyperaldosteronism (seen with hepatic cirrhosis), and also Conn’s syndrome.

Spironolactone works in the distal collecting tubule, where urine volume is modified. It inhibits the effect of aldosterone by competing for intracellular aldosterone receptors in the cortical collecting duct. This decreases the reabsorption of sodium and water, while decreasing the secretion of potassium. Spironolactone has a fairly slow onset of action, taking several days. Spironolactone often increases serum potassium levels and can cause hyperkalemia.

What is the difference between Cushing's syndrome and Cushing's disease?

Cushing’s syndrome: is a hormone disorder caused by high levels of cortisol FOR ANY REASON, can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or ACTH (adrenocorticotropic hormone) or CRH (cortico-releasing hormone).
- Fairly rare.
- More often women > men between ages 20-40.

Cushing disease: refers to one specific cause of the syndrome, an ADENOMA OF THE PITUITARY producing large amounts of ACTH leading to elevated cortisol is responsible for most cases.

Using information from Figure 26.4, describe how prednisone, methylprednisolone, dexamethasone, fludrocortisone and deoxycorticosterone compare with hydrocortisone.

Short acting glucocorticoid (1 - 12 h):
Hydrocortisone is a glucocorticoid which has anti-inflammatory and also salt-retaining effect. This is cortisol, the body's principal glucocorticoid. Hydrocortisone is the reference by which other steroids are compared.

Intermediate acting glucocorticoid (12 - 36 h):
Prednisone- Anti-inflammatory 4 times more potent than hydrocortisone, Salt retaining 0.8 times as potent as hydrocortisone.
Methylprednisone – Anti-inflammatory 5 times more potent than hydrocortisone, Salt retaining 0.5 times as potent as hydrocortisone.

Long acting glucocorticoid (36 - 55 h):
Dexamethasone – Anti –inflammatory 30 times as potent as hydrocortisone, NO salt effect.

Mineralcorticoids:
Fludrocortisone – Anti-Inflammatory 10 times as potent as hydrocortisone, Salt-retaining 125 times as potent as hydrocortisone
Deoxycorticosterone – Anti-Inflammatory NONE, Salt retaining effect 20 times as potent as hydrocortisone.

Diagnosis: If a patient is not in crisis, serum cortisol, ACTH, aldosterone, renin, potassium and sodium are tested before the decision is made if the ACTH stimulation test needs to be performed. X-rays or CT of the adrenals may also be done. If the person is in adrenal crisis, the ACTH stimulation test may be given. The best test for adrenal insufficiency of autoimmune origin is measurement of 21-hydroxylase autoantibodies.

In primary chronic adrenal insufficiency adrenal cortical hormones are deficient while ACTH levels are increased. In secondary patients serum levels of cortisol and androgen are low but normal aldosterone. When ACTH is administered exogenously in secondary, plasma cortisol levels promptly rise (not so in primary).

Management: Achieved by replacement therapy
Hydrocortisone, which is similar to natural cortisol is given to correct deficiency. Dosage is divided so that 2/3 of the normal daily dose is given in am and 1/3 given in pm. The goal of this regimen is to approximate the daily hormone levels resulting from circadian rhythm exhibited by cortisol, which causes plasma levels to be maximal around 8am and then decrease throughout the day to their lowest level at around 1am. (note that hydrocortisone = cortisol - JM)
Fludrocortisone (a potent synthetic mineralcorticoid with some gluocorticoid activity) may also be necessary to raise the mineralocorticoid activity to normal levels.

Adrenal crisis: Life threatening – dehydration, rapidly progressive hypotension and vascular collapse. Treated with IV fluids, IV corticosteroids  methylprednisolone/hydrocortisone), and rest. PO hydrocostisone, prednisone, or methylprednisolone may be used after crisis.

In cases of marked stress, such as illness-especially with high fever, or surgery, if our body cannot make enough cortisol, stress doses of the steroid medication are indicated to avoid severe consequences. If stress doses are not taken, the patient may initially have mild symptoms such as lack of energy or feeling weak, progressing to lethargy, vomiting, or eventually shock and in rare cases even death.

Know which patients may need perioperative steroid coverage. Specifically, if you have a patient who has been taking large doses of steroids for an extended period of time, you may demonstrate adrenal suppression for about 6-9 months following cessation of therapy. If you want to be very conservative, you should consider covering patients with stress-dose steroids if they have been on large doses of steroids for more than 1 week in the last 9 months. A brief course of steroids (5 days or less) will not lead to adrenal suppression. Patients having minor surgeries do not usually need stress-dose steroids.

Dexamethasone suppression test is designed to diagnose and differentiate among the various types of Cushing's syndrome and other hypercortisol states. Dexamethasone is an exogenous steroid that provides negative feedback to the pituitary to suppress the secretion of ACTH. When administered to patients with pituitary-dependent Cushing’s syndrome, dexamethasone suppresses cortisol release. It does not suppress cortisol release in patients with adrenal tumors.

Betamethasone and Dexamethasone would be alternative steroid therapies for a severly asthmatic patient who is suffering from siginificant fluid and sodium retention. They both offter long acting anti-inflammatory effects but do not have the salt-retaining effects.

Side effects of glucocorticoids:

Most common – osteoporosis d/t the ability of glucocorticoids to suppress intestinal calcium absorption, inhibit bone formation and decrease sex hormone synthesis.

Other side effects include: increased risk of infection , increased appetite, emotional disturbances, hypertension, peripheral edema, peptic ulcer, glaucoma, hypokalemia and hirsutism. Hyperglycemia may develop and lead to diabetes mellitus. Chronic treatment with high doses of glucocorticoid frequently causes iatrogenic Cushing’s syndrome. Glucocorticoids are the most common cause of secondary adrenal insufficiency.

Study note: Information shown in Figure 26.4 regularly shows up on various tests and CRNA board exams.

True:

Prednisone is a prodrug that is converted to the active drug prednisolone.

True or False

Cortisol is not the same as cortisone.

True

Several glucocorticoids are made in the zone fasciculata of the adrenal cortex: Cortisol (which derives its name from "cortex") has glucocorticoid and mineralocorticoid actions and is the same compound as hydrocortisone but is not the same as cortisone.

Note that ACTH = adrenocorticotropic hormone = corticotropin. It is easy to confuse the two names of the hormone and CRH.

ACTH/corticotropin is named after the hormone's action:  to stimulate the production and release of steroid hormones from the adrenal cortex. ACTH achieves this by stimulating the rate-limiting enzyme in steroid biosynthesis.

Principal MOA: Steroid hormones are lipophillic and traverse the cell membrane where they bind to a steroid receptor. The steroid-receptor complex translocates into the cell nucleus, binds to a hormone receptor element in the promoter region of target DNA, and enhances gene expression. mRNA is produced (transcription), leaves the nucleus through nucleopores, and delivers a message to ribosomes (translation). The result is protein synthesis.