Suggested reading: Chapter 77

Zona fasciculata: Middle layer of adrenal cortex – widest. Major secretion is cortisol (principal glucocorticoid), though does produce androgens and corticosterone in small amounts. Regulated by ACTH (excess or deficiency in this hormone alter its structure and function).

Zona reticularis: Inner zone of adrenal cortex. Secretes sex hormones and some glucocorticoids. It is stimulated by ACTH (excess or deficiency in this hormone alter its structure and function). Most prevalent adrenal androgens are dehydroepiandrosterone (DHEA) and androstenedione.

Catecholamines: Amine compound derived from catechol, such as epinephrine and norepinephrine which have sympathomimetic activity and are concerned with nervous transmission, vascular tone, and many metabolic activities. (Melloni’s Illustrated Medical Dictionary – 1993 – 3^rd Edition. The Partheron Publishing Group Inc.; pg.86.)

Corticosteroids: Hormones of the adrenal cortex that are synthesized from the steroid cholesterol, they all have similar chemical formulas. Include – mineralocorticoids, glucocorticoids, androgens.

Glucocorticoids: Steroid hormone of adrenal cortex (or synthetic steroid) concerned with gluconeogenesis from amino acids and catabolism of protein. Cortisol, accounts for 95% of all glucocorticoid activity – very potent and natural occuring. Corticosterone, is 4% of total glucocorticoid activity – much less potent than cortisol. This class of compounds has other activities including anti-inflammatory activity and ability to suppress the synthesis of ACTH and MSH. Synthetic compounds include: cortisone, prednisone, methylprednisone, and dexamethasone.

Mineralocorticoids: Steroid hormones in adrenal cortex that controls salt metabolism. Includes aldosterone (very potent) which accounts for about 90% of all mineralocorticoid activity. Others include desoxycorticosterone corticosterone, 9-a Fluorocortisal (synthetic), and slight amounts of cortisol and cortisone (synthetic).

Steroidogenesis: natural production of steroids (Melloni’s Illustrated Medical Dictionary – p. 450).

CRH (corticotropin releasing hormone): Causes release of adrenocorticotropin hypothalmic releasing hormone.

ACTH (Adrenocorticotropin): Hormone from anterior pituitary that stimulates adrenal cortex to secrete adrenocortical hormones. Controls almost entire secretion of cortisol from anterior pituitary and enhances production of adrenal androgens. It is a large polypeptide, chain length of 39 amino acids. Principal effect is to activate adenyl cyclase in cell membrane. It is necessary for any adrenocortical hormone to be formed.

Cortisol (hydrocortisone): 17-hydroxycorticosterone; steroid hormone isolated from the adrenal cortex. Of natural occuring adrenal cortical hormones, it is most capable of correcting by itself the effects of adrenalectomy; provides resistance to stresses and maintains a number of enzyme systems (Melloni’s-p.112).

Corticosteroid-binding globulin (CBG, transcortin): Combines with cortisol in blood. Transported in the bound form (94%) and 6% is free. Changes in CBG’s concentration can influence measurement of total cortisol.

Cushing’s Syndrome: Clinical condition caused by hypersecretion of the glucocorticoid, cortisol.

This is either from a cortisol secreting tumor of one adrenal cortex or general hyperplasia of both adrenal cortices. Hyperplasia is usually caused by increased secretion of ACTH by the anterior pituitary or by "ectopic secretion" of ACTH by a tumor elsewhere in the body. Most abnormalities of Cushing’s Syndrome are ascribable to abnormal amounts of cortisol. Secretion of androgens is also of significance. Special characteristics include mobilization of fat from lower part of body, with concomitant extra disposition of fat in the thoracic and upper abdominal regions – "buffalo torso", edematous appearance of the face –"moon face". Androgenic potency sometimes causes acne and hirsutism (excess growth of facial hair). Eighty percent of patient’s have hypertension-presumably because of slight mineralocorticoid effects of cortisol. Enhanced gluconeogenesis (blood glucose levels increase to as high as 200mg/dl after meals) is present; and also tissue proteins are greatly decreased due to lack of protein synthesis with exception of liver and plasma proteins (ie: severe weakness-muscle; suppressed immune system –lymphoid tissue; tearing of subcutaneous tissues-diminished protein collagen fibers; osteoporosis –diminished protein deposition in bones).

Cushing’s Disease: Category of Cushing’s Syndrome that is secondary to ACTH-producing pituitary microadenomas or hypothalmic lesions. (Principles and Practice of Adult Health Nursing – Beare PG, Myers JL, The CV Mosby Co. 1990, p.1439.)

Addison’s Disease: Insufficiency of the adrenal cortex to produce adrenocortical hormones. Maybe a primary disease of the adrenal cortex or adrenocortical failure caused by a deficiency of ACTH. Frequently caused by primary atrophy of the adrenal cortices – 80% (primary atrophy) caused by autoimmunity against the cortices. Mineralocorticoid deficiency is present - lack of aldosterone secretion. Extracellular fluid volume is decreased (because of decreased renal tubular sodium reabsorption - increase sodium, chloride and water loss to urine). Develop hyponatremia, hyperkalemia, and mild acidosis. Plasma volume is decreased, RBC concentration is increased, cardiac output decreases. Patient can die off shock if untreated in 4 days to 2 weeks after cessation of mineralocorticoid secetion. Glucocorticoid deficiency is present - loss of cortisol secretion which makes it impossible to maintain normal blood glucose concentration between meals. Can’t synthesize significant quantities of glucose by gluconeogenesis. Reduces also the mobilization of proteins and fats from tissues causing depression of other metabolic functions. There is sluggishness of energy mobilization and the person is highly susceptible to deteriorating effects of stress. Melanin pigmentation is not deposited evenly but in blotches – especially in thin skin areas. This due to cortisol depression (normal negative feedback to hypothalmus and anterior pituitary also depressed). There is increased rate of ACTH secretion as well as increased amounts of MSH (increase of ACTH stimulates formation of melanin in same way as MSH). Addisonian Crisis can occur during periods of stress (trauma, disease, and surgery) due to lack of critical need of increase of glucocorticoids. Likely need excessive amounts of glucocorticoids of ten times normal quantitiy.

Dexamethasone Supression Test: Procedure for screening cortisol excess. This can be a single-dose dexamethsone suppression test (ACTH suppression test) failure to suppress cortisol production is suggestive of Cushing’s syndrome; or Standard dexamethasone suppresion test (low- dose and high-dose tests). Patient’s with Cushing’s Syndrome fail to show suppression with low doses of dexamethosone but will show suppression with high doses. Patient with adrenal carcinoma will not show suppression in either case. (Principles and Practice of Adult Health Nursing).

1. Describe the functional anatomy of the adrenal cortex.
   Adrenal cortex is the outer part and the bulk of the adrenal gland. It secretes corticosteroids. The adrenal cortex is composed of three distinct layers: Zona glomerulosa – outermost layer,composed of very thin layer of cells. It is the exclusive site of enzyme aldosterone syntase. Its major secretion is principle mineralocorticoid aldosterone. This layer lacks the enzyme 17-hydroxylase so it cannot synthesize cortisol or sex hormones. It is regulated by the renin-angiotensin system. Zona fasciculata is the middle and widest layer. It secretes the glucocorticoids cortisol and corticosterone. It also secretes small amounts of sex hormones. The major controller of cortisol secretion is ACTH. Zona reticularis is the inner layer. It secretes sex hormones (mainly dehydroepiandrosterone or DHEA and androstenedione) and some glucocorticoids. It is also stimulated by ACTH. Conditions that increase the output of aldosterone and cause hypertophy of the zona glomerulosa have no effect on the other two layers. Conversely, factors that cause increase secretion of cortisol and adrenal androgens and cause hypertophy of the zona’s fasciculata an reticularis have little or no effect on the zona glomerulosa.
   
2. Discuss the regulation of secretion of glucocorticoids.
   At least 95% of glucocorticoid activity of adrenalcortical secretions results from secretion of cortisol. Cortisol mediates most of its effects by binding with intracellular receptors in target tissues and inducing (or represssing) gene transcription resulting in synthesis of enzymes that alter cell function. ACTH stimulates cortisol secretion. Secretionof cortisol is under the control of the hypothalmic-pituitary, corticotropin releasing hormone (CRH)-ACTH axis. The release of ACTH from pituitary is dependent on the hypophysiotropic hormone CRH. Once ACTH secreted into blood, it has a rapid effect on the inner two layers of the adrenal cortex (especially zona fasciculata) to increase secretion of cortisol. ACTH binds to receptors on the cell surface and by increasing cAMP, stimulates the conversion of cholesterol to pregnenolone and is mediated via the second messenger cAMP (begins the cascade of steroid hormone production). Conversion of cholesterol to pregnenolone is rate-limiting step in adrenal steroidogenesis. Activation of cholesterol ester hydrolase increases the availability of free cholesterol. Blood levels of free (unbound) cortisol are controlled in a negative feedback fashion. Increasing plasma levels of cortisol decrease ACTH secretion through direct effect in the pituitary as well as indirect inhibition of CRH release from the hypothalmus. Secretion of cortisol is highest in early am and is lowest in late evening because of circadian rhythm in ACTH secretion related to CRH bursts from the hypothalmus (sleep cycles, light exposure). Other mechanisms of control include: stress (illness, surgery, trauma, starvation , anxiety, depression); feedback inibition by cortisol; stimulation by inflammatory cytokines. Cortisol has widespread effects on metabolism (CHO, fat, and protein).
   
3. Distinguish the physiological effects of glucorticoids in the normal and pharmacological state.
   
4. What are the manifestations of Cushing’s syndrome? Based on your understanding of glucorticoid mechanism of action, explain the reason for each.
   
5. What is a dexmethsaone suppression test?
   See above key word Dexamethasone Supression Test.
   Single-dose dexamethasone suppression test: Administer 1 to 2 mg of dexamethasone at 11pm and obtain collection of blood sample for serum cortisol at 8am.
   Standard dexamethasone suppression test: Test is useful in confirming Cushing’s syndrome and in differentiating Cushing’s syndrome from other types of hypercortisolism. Patients are either given low or high doses of dexamethasone, and the response is measured through urine 17-OHCS and free cortisol levels, and serum cortisol levels. Test involves collection of 24 hr urine specimen.
6. How do primary and secondary adrenal insufficiency differ?
   Primary Adrenal Insufficiency:
   Most cases of Addision’s disease caused by the body’s own immune system. About 70% of reported cases are due to autoimmune disorders in which the immune system makes antibodies that attack the body’s own tissues or organs and slowly destroy them. Adrenal insufficiency occurs when at least 90% of the adrenal cortex has been destroyed, resulting in a lack of both glucocorticoid and mineralocorticoid hormones.Somestimes only the adrenal gland is affected, sometimes other glands are affected as in polyendocrine deficiency disorder. TB accounts for about 20% of primary cases in developed countries. Less common causes include: chronic infections (mainly fungal); cancer cells spread from other parts of body to adrenal glands; amyloidosis (accumulation of an abnormal protein, amyloid, in various tissues of body); and surgical removal of the adrenal glands.
   Secondary Adrenal Insufficiency
   This form of Addision’s disease is traced to a lack of ACTH, which causes a drop in the adrenal glands’ production of cortisol but not aldosterone. A temporary form of this may occur when a person who has been receiving a glucocorticoid hormone (ex. Predisone) for a long time abruptly stops or interrupts taking the medication. Glucocorticoid hormones (used in treatment of rheumatoid arthritis, asthma, ulcerative colitis) block the release of both corticotropin-releasing hormone (CRH) and ACTH. If CRH levels drop, the pituitary is not stimulated to release ACTH, and the adrenals then fail to secrete sufficient levels of cortisol. Another cause is the surgical removal of benign ACTH-producing tumors of the pituitary gland (Cushing’s disease). The source of ACTH is suddenly removed and replacement hormone must be taken until normal ACTH and cortisol production resumes. Less commonly, insufficiency occurs when the pituitary gland either decreases in size or stops producing ACTH (from tumors, infection of area, loss of blood flow to the pituitary, radiation treatment of pituitary tumor or surgical removal of parts of the hypothalmus or the pituitary gland.
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