Adrenal Gland PDF

Adrenal gland.. Adrenal gland is made of two distinct parts: 1. Adrenal cortex: Outer portion, constituting 80% of the gland 2. Adrenal medulla: Central portion, constituting 20% of the gland. HISTOLOGY OF ADRENAL CORTEX Adrenal cortex is formed by three layers of structure. Each layer is distinct...

Adrenal gland.. Adrenal gland is made of two distinct parts: 1. Adrenal cortex: Outer portion, constituting 80% of the gland 2. Adrenal medulla: Central portion, constituting 20% of the gland. HISTOLOGY OF ADRENAL CORTEX Adrenal cortex is formed by three layers of structure. Each layer is distinct from one another. 1. Outer zona glomerulosa 2. Middle zona fasciculata 3. Inner zona reticularis. HORMONES OF ADRENAL CORTEX Adrenocortical hormones are steroids in nature, hence the name ‘corticosteroids’. Based on their functions, corticosteroids are classifed into three groups: 1. Mineralocorticoids 2. Glucocorticoids 3. Sex hormones „ FATE OF CORTICOSTEROIDS Corticosteroids are degraded mainly in the liver and conjugated to form glucuronides and to a lesser extent, form sulfates. About 25% of corticosteroids are excreted in bile and feces and remaining 75%, in the urine. „ MINERALOCORTICOIDS Mineralocorticoids are the corticosteroids that act on the minerals (electrolytes), particularly sodium and potassium. Mineralocorticoids are: 1. Aldosterone 2. 11-deoxycorticosterone. „ SOURCE OF SECRETION Mineralocorticoids are secreted by zona glomerulosa of adrenal cortex. „ FUNCTIONS OF MINERALOCORTICOIDS Ninety (90 %) percent of mineralocorticoid activity is provided by aldosterone. Aldosterone has three important functions. It increases: 1. Reabsorption of sodium from renal tubules 2. Excretion of potassium through renal tubules 3. Secretion of hydrogen into renal tubules. 1. On Sodium Ions Aldosterone acts on the distal convoluted tubule and the collecting duct and increases the reabsorption of sodium. During hypersecretion of aldosterone, the loss of sodium through urine is only few milligram per day. But during hyposecretion of aldosterone, the loss of sodium through urine increases (hypernatriuria) up to about 20 g/day. It proves the importance of aldosterone in regulation of sodium ion concentration and osmolality in the body. 2. On Extracellular Fluid (ECF)Volume When sodium ions are reabsorbed from the renal tubules, simultaneously water is also reabsorbed. Water reabsorption is almost equal to sodium reabsorption; so the net result is the increase in ECF volume. Even though aldosterone increases the sodium reabsorption from renal tubules, the concentration of sodium in the body does not increase very much because water is also reabsorbed simultaneously. But still, there is a possibility for mild increase in concentration of sodium in blood (mild hypernatremia). It induces thirst, leading to intake of water which again increases the ECF volume and blood volume. 3. On Blood Pressure Increase in ECF volume and the blood volume fnally leads to increase in blood pressure. 4. On Sweat Glands and Salivary Glands Aldosterone has almost the similar effect on sweat glands and salivary glands as it shows on renal tubules. Sodium is reabsorbed from sweat glands under the influence of aldosterone, thus the loss of sodium from the body is prevented. Same effect is shown on saliva also. Thus, aldosterone helps in the conservation of sodium in the body. 5. On Intestine Aldosterone increases sodium absorption from the intestine, especially from colon and prevents loss of sodium through feces. Aldosterone defciency leads to diarrhea, with loss of sodium and water. „ GLUCOCORTICOIDS Glucocorticoids act mainly on glucose metabolism. Glucocorticoids are: 1. Cortisol 2. Corticosterone 3. Cortisone. „ SOURCE OF SECRETION Glucocorticoids are secreted mainly by zona fasciculate of adrenal cortex. A small quantity of glucocorticoids is also secreted by zona reticularis. „ FUNCTIONS OF GLUCOCORTICOIDS Cortisol or hydrocortisone is more potent and it has 95% of glucocorticoid activity. Corticosterone is less potent, showing only 4% of glucocorticoid activity. Cortisone with 1% activity is secreted in minute quantity. Life-protecting Hormone Like aldosterone, cortisol is also essential for life but in a different way. Aldosterone is a life-saving hormone, whereas cortisol is a life- protecting hormone because, it helps to withstand the stress and trauma in life. Glucocorticoids have metabolic effects on carbohydrates, proteins, fats and water. These hormones also show mild mineralocorticoid effect. Removal of adrenal glands in human beings and animals causes disturbances of metabolism. Exposure to even mild harmful stress after adrenalectomy, leads to collapse and death. 1. On Carbohydrate Metabolism Glucocorticoids increase the blood glucose level by two ways: i. By promoting gluconeogenesis in liver from amino acids: Glucocorticoids enhance the breakdown of proteins in extrahepatic cells, particularly the muscle. It is followed by release of amino acids into circulation. From blood, amino acids enter the liver and get converted into glucose (gluconeogenesis). ii. By inhibiting the uptake and utilization of glucose by peripheral cells: This action is called antiinsulin action of glucocorticoids. Hypersecretion of glucocorticoids increases the blood glucose level, resulting in hyperglycemia, glucosuria and adrenal diabetes. Hyposecretion ofthese hormones causes hypoglycemia and fasting during adrenal insuffciency will be fatal. It decreases blood glucose level to a great extent, resulting in death. 2. On Protein Metabolism Glucocorticoids promote the catabolism of proteins, leading to: i. Decrease in cellular proteins ii. Increase in plasma level of amino acids iii. Increase in protein content in liver. Glucocorticoids cause catabolism of proteins by the following methods: i. By releasing amino acids from body cells (except liver cells), into the blood ii. By increasing the uptake of amino acids by hepatic cells from blood. In hepatic cells, the amino acids are used for the synthesis of proteins and carbohydrates (gluconeogenesis). Thus, glucocorticoids cause mobilization of proteins from tissues other than liver. In hypersecretion of glucocorticoids, there is excess catabolism of proteins, resulting in muscular wasting and negative nitrogen balance. 3. On Fat Metabolism Glucocorticoids cause mobilization and redistribution of fats. Actions on fats are: i. Mobilization of fatty acids from adipose tissue ii. Increasing the concentration of fatty acids in blood iii. Increasing the utilization of fat for energy. Role of Hypothalamus Hypothalamus also plays an important role in the regulation of cortisol secretion by controlling the ACTH secretion through corticotropin-releasing factor (CRF). It is also called corticotropin-releasing hormone. CRF reaches the anterior pituitary through the hypothalamohypophyseal portal vessels. CRF stimulates the corticotropes of anterior pituitary and causes the synthesis and release of ACTH. CRF secretion is induced by several factors such as emotion, stress, trauma and circadian rhythm. CRF in turn, causes release of ACTH, which induces glucocorticoid secretion. Feedback Control Cortisol regulates its own secretion through negative feedback control by inhibiting the release of CRF from hypothalamus and ACTH from anterior pituitary. „ ADRENAL SEX HORMONES Adrenal sex hormones are secreted mainly by zona reticularis. Zona fasciculata secretes small quantities of sex hormones. Adrenal cortex secretes mainly the male sex hormones, which are called androgens. But small quantity of estrogen and progesterone are also secreted by adrenal cortex. Androgens secreted by adrenal cortex: 1. Dehydroepiandrosterone 2. Androstenedione 3. Testosterone. Dehydroepiandrosterone is the most active adrenal androgen. Androgens, in general, are responsible for masculine features of the body. But in normal conditions, the adrenal androgens have insignifcant physiological effects, because of the low amount of secretion both in males and females. In congenital hyperplasia of adrenal cortex or tumor of zona reticularis, an excess quantity of androgens is secreted. In males, it does not produce any special effect because, large quantity of androgens are produced by testes also. But in females, the androgens produce masculine features. Some of the androgens are converted into testosterone. Testosterone is responsible for the androgenic activity in adrenogenital syndrome or congenital adrenal hyperplasia. „ HYPERACTIVITY OF ADRENAL CORTEX Hypersecretion of adrenocortical hormones leads to the following conditions: 1. Cushing syndrome 2. Hyperaldosteronism 3. Adrenogenital syndrome. „ CUSHING SYNDROME Cushing syndrome is a disorder characterized by obesity. Causes Cushing syndrome is due to the hypersecretion of glucocorticoids, particularly cortisol. It may be either due to pituitary origin or adrenal origin. If it is due to pituitary origin, it is known as Cushing disease. If it is due to adrenal origin it is called Cushing syndrome. Generally, these two terms are used interchangeably. Pituitary Origin Increased secretion of ACTH causes hyperplasia of adrenal cortex, leading to hypersecretion of glucocorticoid. ACTH secretion is increased by: i. Tumor in pituitary cells, particularly in basophilic cells which secrete ACTH. „ ADDISON DISEASE OR CHRONIC ADRENAL INSUFFICIENCY” Addison disease is the failure of adrenal cortex to secrete corticosteroids. Types of Addison Disease i. Primary Addison disease due to adrenal cause ii. Secondary Addison disease due to failure of anterior pituitary to secrete ACTH iii. Tertiary Addison disease due failure of hypothalamus to secrete corticotropin- releasing factor (CRF). Causes for Primary Addison Disease i. Atrophy of adrenal cortex due to autoimmune diseases iii. Destruction of hormone-secreting cells in adrenal cortex by malignant tissues iv. Congenital failure to secrete cortisol v. Adrenalectomy and failure to take hormone therapy. Signs and Symptoms Signs and symptoms develop in Addison disease because of defciency of both cortisol and aldosterone. Common signs and symptom are: i. Pigmentation of skin and mucous membrane due to excess ACTH secretion, induced by cortisol defciency. ACTH causes pigmentation by its melanocyte-stimulating action ii. Muscular weakness iii. Dehydration with loss of sodium iv. Hypotension v. Decreased cardiac output and decreased workload of the heart, leading to decrease in size of the heart vi. Hypoglycemia vii. Nausea, vomiting and diarrhea. Prolonged vomiting and diarrhea cause dehydration and loss of body weight viii. Susceptibility to any type of infection ix. Inability to withstand any stress, resulting in Addisonian crisis. Tests for Addison Disease i. Measurement of blood level of cortisol and aldosterone ii. Measurement of amount of steroids excreted in urine. Addisonian Crisis or Adrenal Crisis or Acute Adrenal Insuffciency Adrenal crisis is a common symptom of Addison disease, characterized by sudden collapse associated with an increase in need for large quantities of glucocorticoids. The condition becomes fatal if not treated in time. Causes i. Exposure to even mild stress ii. Hypoglycemia due to fasting iii. Trauma iv. Surgical operation v. Sudden withdrawal of glucocorticoid treatment. „ CONGENITAL ADRENAL HYPERPLASIA Congenital adrenal hyperplasia is a congenital disorder, characterized by increase in size of adrenal cortex. Size increases due to abnormal increase in the number of steroid-secreting cortical cells. Causes Even though the size of the gland increases, cortisol secretion decreases. It is because of the congenital defciency of the enzymes necessary for the synthesis of cortisol, particularly, 21-hydroxylase. Lack of this enzyme reduces the synthesis of cortisol, resulting in ACTH secretion from pituitary by feedback mechanism. ACTH stimulates the adrenal cortex causing hyperplasia, with accumulation of lipid droplets. Hence, it is also called congenital lipid adrenal hyperplasia. Cortisol cannot be synthesized because of lack of 21-hydroxylase. Therefore, due to the constant simulation of adrenal cortex by ACTH, the secretion of androgens increases. It results in sexual abnormalities such as virilism. Symptoms In boys Adrenal hyperplasia produces a condition known as macrogenitosomia praecox. Features of macrogenitosomia praecox: i. Precocious body growth, causing stocky appearance called infant Hercules ii. Precocious sexual development with enlarged penis even at the age of 4 years. In girls In girls, adrenal hyperplasia produces masculinization. It is otherwise called virilism. In some cases of genetic disorders, the female child is born with external geni talia of male type. This condition is called pseudohermaphroditism. Adrenal medulla. „ INTRODUCTION Medulla is the inner part of adrenal gland and it forms 20% of the mass of adrenal gland. It is made up of interlacing cords of cells known as chromaffn cells. Chromaffn cells are also called pheochrome cells or chromophil cells. These cells contain fne granules which are stained brown by potassium dichromate. Types of chromaffn cells Adrenal medulla is formed by two types of chromaffn cells: 1. Adrenaline-secreting cells (90%) 2. Noradrenaline-secreting cells (10%). „ HORMONES OF ADRENAL MEDULLA Adrenal medullary hormones are the amines derived from catechol and so these hormones are called catecholamines. Catecholamines secreted by adrenal medulla 1. Adrenaline or epinephrine 2. Noradrenaline or norepinephrine 3. Dopamine. „ PLASMA LEVEL OF CATECHOLAMINES 1. Adrenaline : 3 µg/dL 2. Noradrenaline : 30 µg/dL 3. Dopamine : 3.5 µg/dL „ HALF-LIFE OF CATECHOLAMINES Half-life of catecholamines is about 2 minutes. „ SYNTHESIS OF CATECHOLAMINES Catecholamines are synthesized from the amino acid tyrosine in the chromaffn cells of adrenal medulla. These hormones are formed from phenylalanine also. But phenylalanine has to be converted into tyrosine. Stages of Synthesis of Catecholamines 1. Formation of tyrosine from phenylalanine in the presence of enzyme phenylalanine hydroxylase 2. Uptake of tyrosine from blood into the chromaffn cells of adrenal medulla by active transport 3. Conversion of tyrosine into dihydroxyphenylalanine (DOPA) by hydroxylation in the presence of tyrosine hydroxylase 4. Decarboxylation of DOPA into dopamine by DOPA decarboxylase 5. Entry of dopamine into granules of chromaffn cells 6. Hydroxylation of dopamine into noradrenaline by the enzyme dopamine beta- hydroxylase 7. Release of noradrenaline from granules into the cytoplasm 8. Methylation of noradrenaline into adrenaline by the most important enzyme called phenylethanolamineN-methyltransferase (PNMT). PNMT is present in chromaffn cells. „ METABOLISM OF CATECHOLAMINES Eighty fve percent of noradrenaline is taken up by the sympathetic adrenergic neurons. Remaining 15% of noradrenaline and adrenaline are degraded : Metabolism of catecholamines. COMT = Catechol-O-methyltransferase, MAO = Monoamine oxidase. Stages of Metabolism of Catecholamines 1. Methoxylation of adrenaline into meta-adrenaline and noradrenaline into metanoradrenaline in the presence of ‘catechol-O-methyltransferase’ (COMT). Meta-adrenaline and meta-noradrenaline are toget her called metanephrines 2. Oxidation of metanephrines into vanillylmandelic acid (VMA) by monoamine oxidase (MAO) Removal of Catecholamines Catecholamines are removed from body through urine in three forms: i. 15% as free adrenaline and free noradrenaline ii. 50% as free or conjugated meta-adrenaline and meta-noradrenaline iii. 35% as vanillylmandelic acid (VMA). „ ACTIONS OF ADRENALINE AND NORADRENALINE Adrenaline and noradrenaline stimulate the nervous system. Adrenaline has signifcant effects on metabolic functions and both adrenaline and noradrenaline have signifcant effects on cardiovascular system. „ MODE OF ACTION OF ADRENALINE AND NORADRENALINE – ADRENERGIC RECEPTORS Actions of adrenaline and noradrenaline are executed by binding with receptors called adrenergic receptors, which are present in the target organs. 3. On Heart (via Beta Receptors) Adrenaline has stronger effects on heart than noradrenaline. It increases overall activity of the heart, i.e. i. Heart rate (chronotropic effect) ii. Force of contraction (inotropic effect) iii. Excitability of heart muscle (bathmotropic effect) iv. Conductivity in heart muscle (dromotropic effect). 4. On Blood Vessels (via Alpha and Beta-2 Receptors) Noradrenaline has strong effects on blood vessels. It causes constriction of blood vessels throughout the body via alpha receptors. So it is called ‘general vasoconstrictor’. Vasoconstrictor effect of noradrenaline increases total peripheral resistance. Adrenaline also causes constriction of blood vessels. However, it causes dilatation of blood vessels in skeletal muscle, liver and heart through beta-2 receptors. So, the total peripheral resistance is decreased by adrenaline. Catecholamines need the presence of glucocorticoids, for these vascular effects. 5. On Blood Pressure (via Alpha and Beta Receptors) Adrenaline increases systolic blood pressure by increasing the force of contraction of the heart and cardiac output. But, it decreases diastolic blood pressure by reducing the total peripheral resistance. Noradrenaline increases diastolic pressure due to general vasoconstrictor effect by increasing the total peripheral resistance. It also increases the systolic blood pressure to a slight extent by its actions on heart. The action of catecholamines on blood pressure needs the presence of glucocorticoids. Adrenergic receptors are of two types: 1. Alpha-adrenergic receptors, which are subdivided into alpha-1 and alpha-2 receptors 2. Beta-adrenergic receptors, which are subdivided into beta-1 and beta-2 receptors. „ ACTIONS Circulating adrenaline and noradrenaline have similar effect of sympathetic stimulation. But, the effect of adrenal hormones is prolonged 10 times more than that of sympathetic stimulation. It is because of the slow inactivation, slow degradation and slow removal of these hormones. Effects of adrenaline and noradrenaline on various target organs depend upon the type of receptors present in the cells of the organs. Adrenaline acts through both alpha and beta receptors equally. Noradrenaline acts mainly through alpha receptors and occasionally through beta receptors. 1. On Metabolism (via Alpha and Beta Receptors) Adrenaline influences the metabolic functions more than noradrenaline. i. General metabolism: Adrenaline increases oxygen consumption and carbon dioxide removal. It increases basal metabolic rate. So, it is said to be a calorigenic hormone ii. Carbohydrate metabolism: Adrenaline increases the blood glucose level by increasing the glycogenolysis in liver and muscle. So, a large quantity of glucose enters the circulation iii. Fat metabolism: Adrenaline causes mobilization of free fatty acids from adipose tissues. Catecholamines need the presence of glucocorticoids for this action. 2. On Blood (via Beta Receptors) Adrenaline decreases blood coagulation time. It increases RBC count in blood by contracting smoothThus, hypersecretion of catecholamines leads to hypertension. 3. On Respiration (via Beta-2 Receptors) Adrenaline increases rate and force of respiration. Adrenaline injection produces apnea, which is known as adrenaline apnea. It also causes bronchodilation. 4. On Skin (via Alpha and Beta-2 Receptors) Adrenaline causes contraction of arrector pili. It also increases the secretion of sweat. 5. On Skeletal Muscle (via Alpha and Beta-2 Receptors) Adrenaline causes severe contraction and quick fatigue of skeletal muscle. It increases glycogenolysis and release of glucose from muscle into blood. It also causes vasodilatation in skeletal muscles. 6. On Smooth Muscle (via Alpha and Beta Receptors) Catecholamines cause contraction of smooth muscles in the following organs: i. Splenic capsule ii. Sphincters of gastrointestinal (GI) tract iii. Arrector pili of skin iv. Gallbladder v. Uterus vi. Dilator pupillae of iris vii. Nictitating membrane of cat. Catecholamines cause relaxation of smooth muscles in the following organs: i. Non-sphincteric part of GI tract (esophagus, stomach and intestine) ii. Bronchioles iii. Urinary bladder. 7. On Central Nervous System (via Beta Receptors) Adrenaline increases the activity of brain. Adrenaline secretion increases during ‘fght or flight reactions’ after exposure to stress. It enhances the cortical arousal and other facilitatory functions of central nervous system. 8. Other Effects of Catecholamines i. On salivary glands (via alpha and beta-2 receptors): Cause vasoconstriction in salivary gland, leading to mild increase in salivary secretion ii. On sweat glands (via beta-2 receptors): Increase the secretion of apocrine sweat glands iii. On lacrimal glands (via alpha receptors): Increase the secretion of tears iv. On ACTH secretion (via alpha receptors): Adrenaline increases ACTH secretion v. On nerve fbers (via alpha receptors): Adrenaline decreases the latency of action potential in the nerve fbers, i.e. electrical activity is accelerated vi. On renin secretion (via beta receptors): Increase the rennin secretion from juxtaglomerular apparatus of the kidney. „ REGULATION OF SECRETION OF ADRENALINE AND NORADRENALINE Adrenaline and noradrenaline are secreted from adrenal medulla in small quantities even during rest. During stress conditions, due to sympathoadrenal discharge, a large quantity of catecholamines is secreted. These hormones prepare the body for fght or flight reactions. Catecholamine secretion increases during exposure to cold and hypoglycemia also. „ DOPAMINE Dopamine is secreted by adrenal medulla. Type of cells secreting this hormone is not known. Dopamine is also secreted by dopaminergic neurons in some areas of brain, particularly basal ganglia. In brain, this hormone acts as a neurotransmitter. Injected dopamine produces the following effects: 1. Vasoconstriction by releasing norepinephrine 2. Vasodilatation in mesentery 3. Increase in heart rate via beta receptors 4. Increase in systolic blood pressure. Dopamine does not affect diastolic blood pressure. Defciency of dopamine in basal ganglia produces nervous disorder called parkinsonism). „ APPLIED PHYSIOLOGY –PHEOCHROMOCYTOMA Pheochromocytoma is a condition characterized by hypersecretion of catecholamines. Cause Pheochromocytoma is caused by tumor of chromophil cells in adrenal medulla. It is also caused rarely by tumor of sympathetic ganglia (extra-adrenal pheochromocytoma). Signs and Symptoms Characteristic feature of pheochromocytoma is hypertension. This type of hypertension is known as endocrine or secondary hypertension. Other features: 1. Anxiety 2. Chest pain 3. Fever 4. Headache 5. Hyperglycemia 6. Metabolic disorders 7. Nausea and vomiting 8. Palpitation 9. Polyuria and glucosuria 10. Sweating and flushing 11. Tachycardia 12. Weight loss. Tests for Pheochromocytoma Pheochromocytoma is detected by measuring metanephrines and vanillylmandelic acid in urine and catecholamines in plasma. Adrenal Cortical Insufficiency Deficient production of adrenal cortical hormones can result from (1) adrenal gland destruction, (2) pituitary or hypothalamic dysfunction with decreased ACTH production or (3) chronic corticosteroid therapy. Primary Chronic Adrenal Insufficiency (Addison Disease) Often Reflects an Autoimmune Destruction of the Adrenal Addison disease is a fatal wasting disorder caused by failure of the adrenal glands to produce glucocorticoids, mineralocorticoids and androgens. It causes weakness, weight loss, gastrointestinal symptoms, hypotension, electrolyte imbalance and hyperpigmentation. PATHOLOGY: Over 90% of the adrenal gland must be destroyed before chronic adrenal insufficiency is symptomatic. If specific infectious, neoplastic or metabolic disorders are involved, there is corresponding evidence of the underlying disorder in the adrenals. Autoimmune adrenalitis leads to pale, irregular, shrunken glands, weighing 2 to 3 g or less. The medulla is intact but surrounded by fibrous tissue containing small islands of atrophic cortical cells. Depending on the stage of the disease, lymphoid infiltrates, predominantly T cells, of varying density are encountered. CLINICAL FEATURES:Addison’s original description of the clinical features of chronic adrenal insufficiency still applies to untreated cases. Patients had “general languor and debility, remarkable feebleness of the heart’s action, irritability of the stomach and a peculiar change of the colour of the skin.” Typically, the first symptom is insidious onset of weakness, which may lead to a patient being bedridden. Anorexia and weight loss are invariably present. Diffuse, tan skin pigmentation usually develops, and dark patches may appear on mucous membranes. This hyperpigmentation is related to pituitary proopiomelanocortin (POMC) stimulation of skin melanocytes. Hypotension, with blood pressures in the range of 80/50 mm Hg, is the rule. Most patients have gastrointestinal complaints, including vomiting, diarrhea and abdominal pain. Addison disease often causes marked personality changes and even organic brain syndromes. Impaired mineralocorticoid secretion, plus the other metabolic derangements, lowers serum sodium and raises serum potassium. Lack of glucocorticoids leads to lymphocytosis and mild eosinophilia. The diagnosis is made by testing corticosteroid blood levels after ACTH injection. Glucocorticoid and mineralocorticoid replacement allows patients to live normal lives. Acute Adrenal Insufficiency Is a Life-Threatening Emergency Acute adrenal insufficiency, or adrenal crisis, reflects a sudden loss of adrenal cortical function. Symptoms are related more to mineralocorticoid deficiency than to inadequate glucocorticoids. Adrenal crisis occurs in three settings: Abrupt withdrawal of corticosteroid therapy in patients with adrenal atrophy that is due to long-term use of these steroids. This is the most common cause of acute adrena insufficiency. Sudden, devastating deterioration of chronic adrenal insufficiency may be precipitated by the stress of infection or surgery. Waterhouse-Friderichsen syndrome is acute, bilateral, hemorrhagic infarction of the adrenal cortex, most often due to meningococcus or Pseudomonas septicemia. Adrenal hemorrhage in these circumstances is thought to be a local manifestation of a generalized Shwartzman reaction with disseminated intravascular coagulation. Acute adrenal insufficiency due to adrenal hemorrhage is also seen in newborns subjected to birth trauma. CLINICAL FEATURES: The initial manifestations of adrenal crisis are usually hypotension and shock. Nonspecific symptoms commonly include weakness, vomiting, abdominal pain and lethargy, which may progress to coma. Typically in Waterhouse-Friderichsen syndrome, a young person suddenly develops hypotension and shock, together with abdominal or back pain, fever and purpura. Adrenal crisis is almost invariably fatal unless the patient is treated promptly and aggressively with corticosteroids and supportive measures. Secondary Adrenal Insufficiency Reflects a Lack of Adrenocorticotropic Hormone Destruction of the pituitary and consequent panhypopituitarism result in secondary adrenal insufficiency. Causes include pituitary tumors, craniopharyngioma, empty sella syndrome and pituitary infarction. Trauma, surgery and radiation therapy also may result in loss of pituitary function. Isolated ACTH deficiency is often associated with autoimmune endocrinopathies. Any disorder that interferes with secretion of corticotropin (ACTH)-releasing hormone (CRH) by the hypothalamus (e.g., tumors, sarcoidosis) can cause inadequate production of ACTH. Glucocorticoid response to ACTH distinguishes secondary from primary adrenal insufficiency. Pigmentary and electrolyte abnormalities are unusual in secondary adrenal insufficiency since these processes are not regulated by ACTH. Adrenal Hyperfunction Excess corticosteroid secretion occurs in adrenal hyperplasia or neoplasia, and may entail either hypercortisolism (Cushing syndrome) or hyperaldosteronism (Conn syndrome), which reflect the two major classes of adrenal steroid hormones. Early in the 20th century, the neurosurgeon Harvey Cushing associated “painful obesity, hypertrichosis and amenorrhea” with the presence of a pituitary tumor. The combination of pituitary hyperfunction and the signs and symptoms produced by chronic glucocorticoid excess was termed Cushing disease. These clinical features are caused by high glucocorticoid levels of any origin (i.e., from an adrenal adenoma or carcinoma, ectopic production of ACTH or CRH by a tumor or exogenous administration of corticosteroids). Thus, hypercortisolism from any cause is now called Cushing syndrome; the term Cushing disease is reserved for excessive secretion of ACTH by pituitary corticotrope tumors. PRIMARY HYPERSECRETION OF ADRENOCORTICOTROPIC HORMONE: Pituitary-derived Cushing disease usually results from corticotrope microadenomas of the pituitary, but is occasionally due to a macroadenoma or, in a few patients, diffuse corticotrope hyperplasia. Adenomas are monoclonal, arising from a single progenitor cell, but corticotrope hyperplasia is caused by chronic CRH hypersecretion. ECTOPIC CORTICOTROPIN-RELEASING HORMONE PRODUCTION: Ectopic CRH syndrome is similar to ectopic ACTH syndrome, except that a malignant tumor secretes CRH. In turn, CRH stimulates pituitary ACTH secretion, leading to adrenal hyperplasia. ADRENAL MEDULLA AND PARAGANGLIA Anatomy and Function The adrenal medulla is entirely surrounded by the cortex and accounts for 10% of the weight of the gland. It consists of neuroendocrine cells, chromaffin cells, derived from primitive pheochromoblasts of the developing sympathetic nervous system. Chromaffin cells, so named because catecholamines in their cytoplasmic granules bind chromium salts and darken on oxidation by potassium dichromate, are also present at such extra-adrenal sympathetic nervous system sites as the preaortic sympathetic plexuses and paravertebral sympathetic chain. Chromaffin cells appear as nests of small polyhedral cells with pale amphophilic cytoplasm and vesicular nuclei. These cells have many electron-dense 100- to 300-nm chromaffin(catecholamine-containing) granules, like those of sympathetic nerve endings. Epinephrine accounts for 85% of the content of these granules, the remainder being norepinephrine and other noncatecholamine hormones. Interspersed among the chromaffin cells are postganglionic neurons and small autonomic nerve fibers. Stored catecholamines are secreted upon sympathetic stimulation in response to stress (exercise, cold, fasting, trauma) or excitement (e.g., fear, anger). The adrenal medulla is supplied by arterial and portal venous circulations that originate in the zona reticularis of the cortex. Most of the blood to the hormonally active cells of the medulla is from the portal system. The medulla is innervated from the splanchnic nerves by cholinergic preganglionic sympathetic neurons. Pheochromocytoma Pheochromocytomas Are Rare CatecholamineSecreting Tumors of Chromaffin Cells of the Adrenal Medulla If pheochromocytomas arise in extra-adrenal sites, they are called aragangliomas. Other catecholamine-producing tumors (e.g., chemodectoma, ganglioneuroma) may also cause a syndrome similar to that associated with pheochromocytoma. Pheochromocytomas are rare tumors, somewhat more frequent in women than in men. They occur at any age, including infancy, but are uncommon after 60 years of age. Hypertension, sustained or episodic, is the key symptom. Other symptoms include pallor, anxiety and cardiac arrhythmias. Pheochromocytomas account for fewer than 0.1% of cases of hypertension, but should be considered in evaluating any hypertensive patient. If detected early, they are amenable to surgical resection, but untreated patients can die of the complications of prolonged hypertension. Most pheochromocytomas are unexpected findings at autopsy, indicating that some curable cases of hypertension escaped clinical detection. Imaging using iodine-metaiodobenzylguanidine (I-MIBG), an analog of guanethidine, may help to localize these and other neuroendocrine tumors. Pheochromocytomas are mostly sporadic. A minority are inherited, either alone or as part of hereditary syndromes, such as MEN types 2A and 2B, von Hippel- Lindau disease, neurofibromatosis type 1 and McCune-Albright syndrome.