Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
BCH 560 (ADRENAL GLAND) Dr. Samina. Hyder Haq Dept. Of biochemistry King Saud university ADRENAL GLAND The adrenal glands are central components of the endocrine system. They play an important role in the regulation of the body's adaptive response to stress, in the maintenance of body water and salt balance, and in the control of blood pressure. The main hormones produced by the human adrenal glands are the steroid hormone cortisol, the mineralocorticoid aldosterone, the androgen dehydroepiandrosterone (DHEA), and the catecholamines norepinephrine and epinephrine. When studying the adrenal gland, it is important to keep in mind that like the pituitary, it has 2 different embryologic origins. The adrenal glands are located above the kidneys. They are small, averaging 3–5 cm in length, and weigh 1.5–2.5 g. They are made of 2 different components derived from 2 distinct embryologic origins: the cortex and the medulla . The outer adrenal cortex is derived from mesodermal tissue and accounts for about 90% of the weight of the adrenals. The cortex synthesizes the adrenal steroid hormones called glucocorticoids, mineralocorticoids, and androgens (eg, cortisol, aldosterone, and dehydroepiandrosterone [DHEA]) in response to hormone stimulation . The inner medulla is derived from a subpopulation of neural crest cells and makes up the remaining 10% of the mass of the adrenals. The medulla synthesizes catecholamines (eg, epinephrine and norepinephrine) in response to direct sympathetic stimulation TABLE 14-1 -- HISTORY OF THE ADRENAL CORTEX: IMPORTANT MILESTONES 1563 Eustachius describes the adrenals (published by Lancisi in 1714). 1849 Thomas Addison, while searching for the cause of pernicious anemia, “stumbles” on a bronzed appearance associated with the adrenal glands—“melasma suprarenale.” 1855 Thomas Addison describes the clinical features and autopsy findings of 11 cases of diseases of the suprarenal capsules, at least 6 of which were tuberculous in origin. 1856 In adrenalectomy experiments, Brown-Séquard demonstrates that the adrenal glands areb essential for life. 1896 William Osler gives an oral glycerine extract derived from pig adrenals and demonstrates clinical benefit in patients with Addison's disease. 1905 Bulloch and Sequeria describe patients with congenital adrenal hyperplasia. CONT 1929 Liquid extracts of cortical tissue are used to keep adrenalectomized cats alive indefinitely (Swingle and Pfiffner). Subsequently, this extract was used successfully to treat a patient with Addison's disease (Rowntree and Greene). 1932 Harvey Cushing associates the “polyglandular syndrome” of pituitary basophilism first described by him in 1912 with hyperactivity of the pituitary-adrenal glands. 1936 Concept of stress and its effect upon pituitary-adrenal function described by Seyle. 1937–1952 Isolation and structural characterisation of adrenocortical hormones (Kendall, Reichstein). 1943 Li and colleagues isolate pure adrenocorticotropic hormone from sheep pituitary. 1950 Hench, Kendall, and Reichstein share Nobel Prize in medicine for describing the antiinflammatory effects of cortisone in patients with rheumatoid arthritis. CONT1953 Isolation and analysis of the structure of aldosterone (Simpson and Tait). 1956 Conn describes primary aldosteronism. 1981 Characterization and synthesis of corticotropin-releasing hormone (Vale). 1980–present The “molecular era.” Cloning and functional characterization of steroid receptors, steroidogenic enzymes, and adrenal transcription factors. Definition of the molecular basis for human adrenaldiseases. DIFFERENT REGIONS OF ADRENAL GLAND Steroidogenic acute regulatory protein mediated uptake of cholestrol into mitochondria within adrenocortical cells, Aldosterone, glucocorticoid and androgens are synthesized through the co-ordinated action of series of steroidogenic enzymes in a zone specific fashion Chemical structure of Dehydroepiandrosterone (DHEA) The initial step in steroid hormone synthesis (steroidogenesis) is the conversion of cholesterol to pregnenolone. Cholesterol used for steroid hormone synthesis can be derived from the plasma membrane or from the cytosolic pool known as the steroidogenic cytoplasmic pool. Cholesterol is released by the action of the enzyme cholesterol esterase. Cholesterol is converted to pregnenolone by the action of the cytochrome P450 side-chain cleavage enzyme (P450scc), which is present in the inner mitochondrial membrane of all steroidogenic cells. For cholesterol to be a substrate for P450scc, free cholesterol must be transferred from the outer mitochondrial membrane to the inner mitochondrial membrane. This step is mediated by steroid acute regulatory protein. This delivery of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, where the P450scc enzyme is located, is considered the rate-limiting step in steroid hormone synthesis. This conversion of cholesterol to pregnenolone is the first step in a sequence of enzymatic reactions involved in the synthesis of steroid hormones. Because the cells that constitute the different sections of the adrenal cortex have specific enzymatic features, the synthetic pathway of steroid hormones will result in preferential synthesis of glucocorticoids, mineralocorticoids, or androgens, depending on the region. ADRENAL CORTEX Consists of three zones. The zona glomerulosa contains abundant smooth endoplasmic reticulum and is the unique source of the mineralocorticoid aldosterone. The zona fasciculata contains abundant lipid droplets and produces the glucocorticoids, cortisol and corticosterone, and the androgens, DHEA and DHEA sulfate (DHEAS). The zona reticularis develops postnatally and is recognizable at about age 3; it also produces glucocorticoids and androgens. The products of the adrenal cortex can be classified into 3 general categories: glucocorticoids, mineralocorticoids, and androgens SCHEMATIC DIAGRAM OF THE STRUCTURE OF THE HUMAN ADRENAL CORTEX, DEPICTING THE OUTER ZONA GLOMERULOSA AND INNER ZONA FASCICULATA AND ZONA RETICULARIS SPECIFIC EFFECT OF GLUCOCORTICOIDS Cortisol, the main glucocorticoid in humans, enters the cell by passive diffusion and binds to the glucocorticoid receptor . The hormone-receptor complex translocates to the nucleus, where it binds to specific DNA sequences (glucocorticoid response elements) and exerts its physiologic effects by altering transcription of genes. Because virtually all cells express glucocorticoid receptors, the physiologic effects are multisystemic. Glucocorticoids affect intermediary metabolism, stimulate proteolysis and gluconeogenesis, inhibit muscle protein synthesis, and increase fatty acid mobilization. At high levels, glucocorticoids are catabolic and result in loss of lean body mass. Their gluconeogenic effect increases blood glucose concentrations, hence the name "glucocorticoids." Glucocorticoids modulate the immune response by increasing anti-inflammatory cytokine synthesis and decreasing proinflammatory cytokine synthesis. In the central nervous system, they modulate perception and emotion and may produce marked changes in behavior. GLUCOCORTICOID SYNTHESIS AND RELEASE The release of cortisol is pulsatile and is under direct stimulation by ACTH released from the anterior pituitary.. An important feature in the release of cortisol is that in addition to being pulsatile, it follows a circadian rhythm that is exquisitely sensitive to light, sleep, stress, and disea. Release of cortisol is greatest during the early waking hours, with levels declining as the afternoon progresses. The stimulation of cortisol release by ACTH is mediated by its binding to a Gs protein–coupled plasma membrane melanocortin 2 receptor on adrenocortical cells, resulting in activation of adenylate cyclase, an increase in cyclic adenosine monophosphate, and activation of protein kinase A . Protein kinase A phosphorylates the enzyme cholesterol ester hydrolase, increasing enzymatic activity. This enzyme catalyzes the release of cholesterol from cholesterol esters, providing the free cholesterol needed for steroid hormone synthesis. In addition, ACTH activates and increases the synthesis of steroid acute regulatory protein, the enzyme involved in the transport of cholesterol into the inner mitochondrial membrane, where cytochrome P450 converts cholesterol to pregnenolone. Therefore, ACTH stimulates the 2 initial and rate-limiting steps in steroid hormone synthesis. The release of ACTH from the anterior pituitary is regulated by corticotropinreleasing hormone (CRH), produced by the hypothalamus and released in the median eminence. Cortisol inhibits the biosynthesis and secretion of CRH and ACTH in a classic example of negative feedback regulation by hormones METABOLISM OF GLUCOCORTICOIDS Because of their lipophilic nature, free cortisol molecules are mostly insoluble in water. Therefore, cortisol is usually found in biologic fluids either in a conjugated form (eg, as sulfate or glucuronide derivatives) or bound to proteins (noncovalent, reversible binding). In the plasma, unconjugated steroids are usually bound to carrier proteins. The half-life of cortisol is 70–90 minutes. The majority of cortisol is bound to glucocorticoid-binding alpha2-globulin (transcortin or cortisol-binding globulin), a specific carrier of cortisol. Normal levels of transcortin average 3–4 mg/dL and are saturated with cortisol levels of 28 g/dL. The hepatic synthesis of transcortin is stimulated by estrogen and decreased by hepatic disease (cirrhosis). About 20–50% of bound cortisol is bound nonspecifically to plasma albumin. Approximately 1–10% of total plasma cortisol circulates unbound and is referred to as the free fraction. This is considered to represent the biologically active fraction of the hormone that is directly available for action. The major role of plasma-binding proteins is to act as a "buffer" or reservoir for active hormones. Because of the noncovalent nature of the binding, protein-bound steroids are released into the plasma in free form as soon as the free hormone concentration decreases. Plasma-binding proteins also protect the hormone from peripheral metabolism (notably by liver enzymes) and increase the half-life of biologically active forms. Because of their lipophilic nature, steroid hormones diffuse easily through cell membranes and therefore have a large volume of distribution. In their target tissues, steroid hormones are concentrated by an uptake mechanism that relies on their binding to intracellular receptors. Interestingly, high concentrations of steroid hormones are found in adipose tissue even though this tissue is not a target for the physiologic effects of steroid hormones. However, adipose tissue contains enzymatic activity in the form of aromatase (5-reductase), which converts circulating androgens to estrogens METABOLISM OF GLUCOCORTICOIDS Metabolism of glucocorticoids occurs in the liver and, to a lesser extent, in the kidneys. In other words, the liver and kidney are the 2 major sites of hormone inactivation and elimination, or catabolism. Inactive hormones are mainly eliminated as urinary (mostly conjugated) metabolites. Usually, steroids are eliminated once they have been inactivated. Urinary excretion of metabolic products requires conversion from lipophilic to hydrophilic compounds to ensure their solubility in biologic fluids at rather high concentrations. Several pathways are involved in this process, including reduction, oxidation, hydroxylation, and conjugation, to form the sulfate and glucuronide derivatives of the steroid hormones. Inactivation of cortisol to cortisone and to tetrahydrocortisol and tetrahydrocortisone is followed by conjugation and renal excretion. These metabolites are referred to as 17-hydroxycorticosteroids, and their determination in 24-hour urine collections is used to assess the status of adrenal steroid production. THE ANTIINFLAMMATORY ACTION OF GLUCOCORTICOIDS. GLUCOCORTICOID RECEPTOR THROUGH (GR). GLUCOCORTICOIDS CORTISOL BINDS TO THE CYTOPLASMIC MEDIATE THEIR ANTIINFLAMMATORY EFFECTS : A:THE INHIBITORY PROTEIN INDUCED.B 1KB, WHICH THE GR–CORTISOL COMPLEX INFLAMMATORY PROCESS. BINDS AND INACTIVATES NUCLEAR FACTOR KB IS ABLE TO BIND NFKB AND THUS PREVENT (NFKB), IS INITIATION OF AN EFFECT OF MINERALCORTICOIDS The principal physiologic function of aldosterone is to regulate renal sodium reabsorption, hence the name "mineralocorticoid." Aldosterone binds to the mineralocorticoid receptor in the principal cells of the distal tubule and the collecting duct of the nephron, producing an increase in sodium reabsorption and potassium excretion . Aldosterone also diffuses across the plasma membrane and binds to its cytosolic receptor. The receptor-hormone complex is translocated to the nucleus, where it interacts with the promoter region of target genes, activating or repressing their transcriptional activity. Aldosterone-induced activation of preexisting proteins and stimulation of new proteins mediate an increase in transepithelial sodium transport. Aldosterone increases sodium entry at the apical membrane of the cells of the distal nephron through the amiloridesensitive epithelial Na+ channel. The Na+/K+-adenosine triphosphatase (ATPase), located in the basolateral membrane of the cells, maintains the intracellular sodium concentration by extruding the reabsorbed sodium toward the extracellular and blood compartments. The increase in Na+ reabsorption leads to increased water reabsorption, creating an electrochemical gradient that facilitates the transfer of intracellular K+ from tubular cells into the urine. When most of the filtered Na+ is reabsorbed in the proximal tubule, only a small amount of sodium reaches the distal tubule (the site of aldosterone regulation).. The role of aldosterone in regulation of blood pressure is considered central. By regulating sodium transport across the tight epithelia of Na+-reabsorbing tissues such as the distal nephron and colon, aldosterone is a major factor determining total-body Na+ levels and thus long-term blood pressure regulation. MINERALOCORTICOID HORMONE ACTION. The much higher concentrations of cortisol are inactivated by the type 2 isozyme of 11ß-hydroxysteroid dehydrogenase (11ß-HSD2) to cortisone, permitting the endogenous ligand, aldosterone, to bind to the mineralocorticoid receptor (MR). Relatively few mineralocorticoid target genes have been identified, but these include serum and glucocorticoid-induced kinase (SGK), subunits of the epithelial sodium channel (ENaC), and basolateral Na+,K+-adenosine triphosphatase MINERALOCORTICOID SYNTHESIS AND RELEASE aldosterone synthesis and release in the adrenal zona glomerulosa are predominantly regulated by angiotensin II and extracellular K+ and, to a lesser extent, by ACTH. Aldosterone is part of the reninangiotensin-aldosterone system, which is responsible for preserving circulatory homeostasis in response to a loss of salt and water (eg, with intense and prolonged sweating, vomiting, or diarrhea). The components of the renin-angiotensin-aldosterone system respond quickly to reductions in intravascular volume and renal perfusion. Angiotensin II is the principal stimulator of aldosterone production when intravascular volume is reduced. RENIN –ANGIOTENSIN ALDOSTERONE SYSTEM CONTROL OF ALDOSTERONE SYNTHESIS The main physiologic stimulus for aldosterone release is a decrease in the effective intravascular blood volume . A decline in blood volume leads to decreased renal perfusion pressure, which is sensed by the juxtaglomerular apparatus (baroreceptor) and triggers the release of renin. Renin release is also regulated by NaCl concentration in the macula densa, plasma electrolyte concentrations, angiotensin II levels, and sympathetic tone. Renin catalyzes the conversion of angiotensinogen, a liver-derived protein, to angiotensin I. Circulating angiotensin I is converted to angiotensin II by endothelial cells, primarily in the lung. The increase in circulating angiotensin II produces direct arteriolar vasoconstriction, but it also binds to the angiotensin II receptor in the adrenocortical cells of the zona glomerulosa, stimulating phospholipase C. This results in an increase in intracellular Ca2+, leading to stimulation of aldosterone synthesis and release OTHER FORMS OF MINERALOCORTICOID EXCESS OR EFFECT Hyperdeoxycorticosteronism(Congenital adrenal hyperplasia (CAH)) is caused by enzymatic defects in adrenal steroidogenesis that result in deficient secretion of cortisol, A deficiency of both 11ß-hydroxylase (CYP11B) and 17a-hydroxylase (CYP17)causes hypertension and hypokalemia. Deoxycorticosterone-Producing Tumor; Primary Cortisol Resistance Increased cortisol secretion and plasma cortisol concentrations without evidence of Cushing's syndrome are found in patients with primary cortisol resistance (or glucocorticoid resistance), a rare familial syndrome ANDROGENS DHEA is a crucial precursor of human sex steroid biosynthesis and exerts androgenic or estrogenic activity following conversion by the activities of 3ßHSD, a superfamily of ß-HSD isozymes and aromatase, expressed in peripheral target tisswhich is of clinical importance in many diseases. Only desulfated DHEA is converted downstream and biologically active. Serum DHEAS was previously thought to represent a circulating storage pool for DHEA regeneration. However, recent work has suggested that conversion of DHEAS to DHEA by steroid sulfatase plays a minor role in adult physiology and that the equilibrium between serum DHEA and DHEAS is mainly regulated by DHEA sulfotransferase The physiologic effects of DHEA and DHEAS are not completely understood. Current knowledge indicates that low levels of DHEA are associated with cardiovascular disease in men and with an increased risk of premenopausal breast and ovarian cancer in women. In contrast, high levels of DHEA might increase the risk of postmenopausal breast cancer. Exogenous administration of DHEA to the elderly increases several hormone levels, including insulin-like growth factor-1, testosterone, dihydrotestosterone, and estradiol. However, the clinical benefit of these changes and the side effects of long-term use remain to be clearly defined. Furthermore, the specific mechanisms through which DHEA exerts its actions are not completely understood GLUCOCORTICOIDS EXCESS Glucocorticoid excess can be due to overproduction by an adrenal tumor or to overstimulation of adrenal glucocorticoid synthesis and release by ACTH produced by a pituitary tumor or an ectopic tumor. Glucocorticoid excess, or Cushing syndrome, can be separated into 2 categories depending on its etiology, In corticotropin-dependent Cushing syndrome, elevated glucocorticoid levels are due to excess stimulation by ACTH. The chronic elevation of ACTH causes bilateral enlargement (hyperplasia) of the adrenal cortex. Corticotropin production may also be ectopic (derived from extrapituitary tissue), most frequently because of small cell lung carcinoma. Tumor secretion of corticotropin is usually not suppressed by glucocorticoids, and this feature is helpful in distinguishing the source of corticotropin. The name "Cushing disease" is reserved for Cushing syndrome caused by excess secretion of corticotropin by pituitary corticotroph tumors and is the most common form of the syndrome. In corticotropin-independent Cushing syndrome, excess cortisol production is due to abnormal adrenocortical tissue regardless of ACTH stimulation. In fact, the elevated circulating cortisol levels suppress CRH and ACTH levels in plasma. GLUCOCORTICOID DEFECIENCY Glucocorticoid deficiency is less common than diseases due to excess production of glucocorticoids. Glucocorticoid deficiency can result from lack of ACTH stimulation of adrenal glucocorticoid production (secondary deficiency) or from adrenal dysfunction (primary deficiency). Exogenous administration of synthetic analogs of glucocorticoids in the chronic treatment of some diseases will also suppress CRH and ACTH. Therefore, the sudden discontinuation of treatment may be manifested as an acute case of adrenal insufficiency. It is important to carefully taper the withdrawal of steroid treatment from patients. Most cases of ACTH deficiency involve deficiencies of other pituitary hormones. Because aldosterone is mainly under the regulation of angiotensin II and K+, individuals may not necessarily have simultaneous mineralocorticoid deficiency when impaired ACTH release is the causative factor. Glucocorticoid deficiency due to adrenal hypofunction is known as Addison disease, which can be the result of autoimmune destruction of the adrenal gland or inborn errors of steroid hormone synthesis PRIMARY ALDOSTERONISM Hypertension, suppressed plasma renin activity (PRA), and increased aldosterone excretion characterize the syndrome of primary aldosteronism, first described in 1955. Aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism (IHA) are the most common subtypes of primary aldosteronism CLASSIFICATION AND PATHOPHYSIOLOGY OF CUSHING'S SYNDROME ACTH-DEPENDENT Cushing's disease (pituitarydependent) Ectopic ACTH syndrome Ectopic CRH syndrome Macronodular adrenal hyperplasia Iatrogenic (treatment with ACTH 1-24) ACTH-INDEPENDENT Adrenal adenoma and carcinoma Primary pigmented nodular adrenal hyperplasia and Carney's syndrome. McCune-Albright syndrome Aberrant receptor expression (gastric inhibitory polypeptide,interleukin1ß). Iatrogenic (e.g., pharmacologic doses of prednisolone, dexamethasone PSEUDOCUSHING'S SYNDROMES Alcoholism Depression Obesity ACTH DEPENDENT CASES. When iatrogenic causes are excluded, the commonest cause of Cushing's syndrome is Cushing's disease, accounting for approximately 70 percent of cases. The adrenal glands in these patients show bilateral adrenocortical hyperplasia with widening of the zona fasciculata and reticularis. Etiology Cushing himself raised the question as to whether this disease was a primary pituitary condition or secondary to an abnormality in the hypothalamus, and there has been an ongoing debate on this issue. The hypothalamic theory states that ACTH-secreting adenomas arise because of dysfunctional regulation of corticotrophs through chronic stimulation by CRF (or arginine vasopressin), whereas other studies provide data to support a primary pituitary defect as the cause of the condition ECTOPIC ACTH SYNDROME In 15% of cases, Cushing's syndrome may be associated with nonpituitary tumors secreting ACTH—the ectopic ACTH syndrome. On clinical grounds, this can be divided into two entities, cases occurring in the setting of highly malignant tumors such as small cell carcinoma of bronchus and more indolent cases occurring in patients with underlying neuroendocrine tumors such as bronchial carcinoids. Circulating ACTH concentrations and cortisol secretion rates can be extremely high. As a result, duration of symptoms from onset to presentation is short (<3 months); patients are commonly pigmented and the metabolic manifestations of glucocorticoid excess are often rapid and progressive. Weight loss, myopathy, and glucose intolerance are prominent symptoms and signs PSEUDO-CUSHING'S SYNDROMES A pseudo-Cushing's state can be defined as some or all of the clinical features of Cushing's syndrome together with some evidence for hypercortisolism. Resolution of the underlying cause results in disappearance of the Cushingoid state. Several causes are described. Alcoholism:In the original description of this syndrome, urinary and plasma cortisol levels were elevated and failed to suppress with dexamethasone. Plasma ACTH has been found to be normal or suppressed. The condition is rare but should be suspected in a patient with an ongoing history of heavy alcohol intake and biochemical/clinical evidence of chronic liver disease Depression:Although the cause is unknown, it is recognized that patients with depression may exhibit the hormonal abnormalities of patients with Cushing's syndrome.These abnormalities are reversible on correction of the psychiatric condition. Obesity: As one of the symptoms of this disease is extreme waight gain. The most commont referrals to a clinical endocrinologist is to exclude an underlying endocrine cause in a patient with obesity, the diagnosis of Cushing's syndrome in such patients should not cause difficulties. Patients with obesity have mildly increased cortisol secretion rates. TREATMENT OF CUSHING'S DISEASE. Surgical removal of the Adrenal adenomas by unilateral adrenalectomy, with a 100% cure rate. Pituitary-Dependent Cushing's Syndrome The treatment of Cushing's disease has been significantly enhanced through transsphenoidal surgery conducted by an experienced surgeon. Medical Treatment of Cushing's syndromeSeveral drugs have been used in the treatment of Cushing's syndrome. Metyrapone inhibits 11ßhydroxylase and has been most commonly given. 1. Aminoglutethimide is a more toxic drug, which in high dose blocks earlier enzymes in the steroidogenic pathway and thus affects the secretion of steroids other than cortisol 2. Trilostane, a 3ß-hydroxysteroid dehydrogenase inhibitor, is ineffective in Cushing's disease. 3. Ketoconazole is an imidazole that has been widely used as an antifungal agent but causes abnormal liver function tests in about 15% of patients. Ketoconazole blocks a variety of steroidogenic cytochrome P450–dependent enzymes and thus lowers plasma cortisol levels HORMONES OF THE ADRENAL MEDULLA The medulla is the central part of the adrenal gland . It is extremely vascular and consists of large chromaphil cells arranged in a network. It is made of 2 cell types called pheochromocytes— norepinephrine-producing and (more numerous) epinephrine-producing cells—and synthesizes and secretes the catecholamines norepinephrineand epinephrine and, to a lesser extent, dopamine. Epinephrine is secreted in greater amounts than norepinephrine; . 1. 2. 3. 4. Hydroxylation of tyrosine to L-dihydrophenylalanine (L-Dopa) by the enzyme tyrosine hydroxylase. This enzyme is found in the cytosol of catecholamine-producing cells and is the main control point for catecholamine synthesis. The activity of this enzyme is inhibited by noradrenaline, providing feedback control of catecholamine synthesis. Decarboxylation of L-Dopa to dopamine by the enzyme dopa decarboxylase in a reaction that requires pyridoxal phosphate as a cofactor. This end product is packaged into secretory vesicles. Hydroxylation of dopamine to norepinephrine by the enzyme dopamine -hydroxylase, a membrane-bound enzyme found in synaptic vesicles that uses vitamin C as a cofactor. This reaction occurs inside the secretory vesicles. Methylation of norepinephrine to epinephrine by the enzyme phenylethanolamine N-methyltransferase. The activity of this adrenal medullary enzyme is modulated by adjacent adrenal steroid production, underscoring the importance of arterial flow from the cortex to the medulla RELEASE OF CATECHOLAMINE Stressful stimuli (e.g., myocardial infarction, anesthesia, hypoglycemia) trigger adrenal medullary catecholamine release. The release is a direct response to sympathetic nerve stimulation of the adrenal medulla. Acetylcholine released from the preganglionic sympathetic nerve terminals binds to nicotinic cholinergic receptors in the plasma membrane of the chromaffin cells, depolarizing the cells. Depolarization of the cells leads to activation of voltage-gated Ca2+ channels, producing an influx of Ca2+. The synaptic vesicles containing the preformed catecholamines are docked beneath the synaptic membrane and are closely associated with voltagegated Ca2+ channels. The influx of Ca2+ triggers the exocytosis of secretory granules, which release their contents (catecholamines, chromogranins, ATP, adrenomedullin, proopiomelanocortin products, and other peptides) into the interstitial space, from where they are transported in the circulation to their target organs CATECHOLAMINE PHYSIOLOGIC EFFECTS Catecholamines are released as part of the stress response to a physical or psychological insult such as severe blood loss, decrease in blood glucose concentration, traumatic injury, surgical intervention, or a fearful experience. Because catecholamines are part of the "fight or flight" response, their physiologic effects include arousal, alerting, papillary dilation, piloerection, sweating, bronchial dilation, tachycardia, inhibition of smooth muscle activity in the gastrointestinal tract, constriction of the sphincters, and relaxation of the uterine muscles. Most of the events involved in coping with a stressful situation require the expenditure of energy. Catecholamines ensure substrate mobilization from the liver, muscle, and fat by stimulating the breakdown of glycogen (glycogenolysis) and fat (lipolysis). Thus, an increase in circulating catecholamines is associated with elevations in plasma glucose and free fatty acid levels. Some of the most important effects of catecholamines are exerted in the cardiovascular system, where they increase heart rate (tachycardia), produce peripheral vasoconstriction, and elevate vascular resistance. CATECHOLAMINE TRANSPORT & METABOLISM The half-life of circulating catecholamines is short and is estimated to range from 10 seconds to 1.7 minutes. A fraction of the catecholamines released circulate bound to albumin with low affinity. Their elimination rate varies depending on the site of release. Catecholamine metabolism occurs mainly in the cytoplasm of the same cells where they are synthesized following leakage from cytoplasmic vesicles. In humans, vanilmandelic acid (VMA) is the major end product of norepinephrine and epinephrine metabolism. Monoamine oxidase (MAO) catalyzes the first step of oxidative deamination of catecholamines, followed by reduction to dihydroxyphenylglycol (DHPG) by aldehyde reductase in sympathetic nerves. Catechol-o-methyl transferase (COMT) catalyzes conversion of norepinephrine to normetanephrine and of DHPG to 3-methoxy-4-hydroxyphenylglycol (MHPG) in extraneuronal tissues. Catecholamines of neuronal or glandular origin are degraded by COMT at their target cells. Circulating catecholamines can undergo reuptake by extraneuronal sites and degradation by COMT or MAO, especially in the liver (>94%), producing the metabolites metanephrine and normetanephrine. The joint action of MAO and COMT on norepinephrine and epinephrine produces the metabolite vanillylmandelic acid, which is then excreted in the urine; dopamine metabolized through this pathway yields homovanillic acid. Because these metabolites are water soluble and have high levels of urinary excretion, they play an important role in the clinical detection of tumors that produce excess catecholamines. Circulating catecholamines can also undergo direct filtration into urine, ADRENERGIC RECEPTOR AND SIGNALLING PATHWAYS The adrenergic receptors are classified as predominantly stimulatory receptors (α) or predominantly inhibitory receptors (β). For many of these receptors, their precise physiologic functions and their therapeutic potential have not been fully elucidated. Only for the -adrenergic receptors have subtype-selective ligands been developed that have helped to identify the physiologic significance of β1, β2, andβ 3 receptors, some of which are now used in clinical medicine. Selective agonists for theβ 2adrenergic receptor play an important role in asthma therapy, whereas β1-receptor antagonists are first-line medication for patients with hypertension, coronary heart disease, or chronic heart failure. ALPHA-ADRENERGIC RECEPTORS Alpha-adrenergic receptors have greater affinity for epinephrine than for norepinephrine or for isoproterenol, a synthetic agonist. They are subdivided into α 1- and α 2receptors. Alpha1-adrenergic receptors are further subdivided into α 1A, α 1B, and α 1D. These are G protein–coupled receptors (Gq/11) that activate phospholipase C, resulting in activation of protein kinase C via diacylglycerol . This reaction produces an increase in intracellular Ca2+ (via inositol 1,4,5-trisphosphate) and phospholipase A2. The increase in intracellular Ca2+ calmodulin kinase–mediated phosphorylation of myosin light-chain kinase in smooth muscle produces contraction in vascular, bronchial, and uterine smooth muscle. Alpha1-adrenergic receptors play important roles in the regulation of several physiologic processes, including myocardial contractility and chronotropy and hepatic glucose metabolism BETA-ADRENERGIC RECEPTORS Beta-adrenergic receptors have been subclassified as 1, 2, and 3 receptors. They have greater affinity for isoproterenol than for epinephrine or norepinephrine. All 3 receptor subtypes are associated with Gs proteins, and their stimulation leads to an increase in cyclic adenosine monophosphate . Theβ 1-adrenergic receptor plays an important role in regulating contraction and relaxation of cardiac myocytes . Several mechanisms are thought to be involved, including the phosphorylation of L-type Ca2+ channels in the sarcolemma, ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum, troponin I, and phospholamban. The overall physiologic effect is an increase in contractility. β2-adrenergic receptor mediates several physiologic responses, including vasodilatation, bronchial smooth muscle relaxation, and lipolysis, in various tissues. Abnormalities in the function of this adrenergic receptor may lead to hypertension. The β3-adrenergic receptor plays an important role in mediating catecholamine-stimulated thermogenesis and lipolysis. PHEOCHROMOCYTOMA AND PARAGANGLIOMA Catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic ganglia are pheochromocytomas and extraadrenal catecholamine-secreting paragangliomas (extraadrenal pheochromocytomas), respectively.[Because the tumors have similar clinical presentations and are treated with similar approaches, many clinicians use the term pheochromocytoma to refer to both adrenal pheochromocytomas and extra adrenal catecholamine-secreting paragangliomas. However, the distinction between pheochromocytoma and paraganglioma is an important one because of implications for neoplasms, risk for malignancy, and genetic testing. Catecholamine-secreting tumors are rare, with an annual incidence cases per million people. SYMTEMS OF PHEOCHROMOCYTOMA Pheochromocytomas produce catecholamines, and patients present with signs of excess catecholamine effects, such as sustained or paroxysmal hypertension associated with headache, sweating, or palpitations. Weight Loss High blood pressor Anxiety Skin sensation GENETIC AND SYNDROMIC FORMS OF PHEOCHROMOCYTOMA AND PARAGANGLIOMA Approximately 15% to 20% of patients with catecholamine-secreting tumors have germline mutations (inherited mutations all cells of the body) in genes associated with genetic disease . Hereditary catecholamine-secreting tumors typically present at a younger age than sporadic neoplasms AUTOSOMAL DOMINANT SYNDROMES ASSOCIATED WITH PHEOCHROMOCYTOMA syndrome Gene Protein product Protein function SDHD (familial paraganglioma type 1 SDHD SDHD subunit ATP production Familial paraganglioma type 2 unknown unknown ATP production SDHC (familial paraganglioma type 3) SDHC SDHC-subunit ATP production SDHB (familial paraganglioma type 4) SDHB SDHB-subunit MEN-1 MENIN menin Transcriptional regulation MEN-2A and -2B RET RET Tyrosine kinase Receptor Neurofibromatosi s type 1 NF1 neurofibromin GTP -hydrolysis von HippelLindau disease VHL VHL Transcription elongation suppression ORALLY ADMINISTERED DRUGS USED TO TREAT PHEOCHROMOCYTOMA a-ADRENERGIC BLOCKING AGENTS COMBINED a- AND ß-ADRENERGIC BLOCKING AGENT CALCIUM CHANNEL BLOCKERS CATECHOLAMINE SYNTHESIS INHIBITOR