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Chapter 66 XI The Adrenal Theodore C. Friedman

Angiotensin II is the predominant regulator of aldos- Physiology terone secretion, but plasma concentration, plasma volume, and ACTH levels also influence aldos- The adrenal lie at the superior pole of each terone secretion. ACTH also mediates the circadian and are composed of two distinct regions: the rhythm of ; as a result, the plasma concen- and the medulla. The consists of tration of aldosterone is highest in the morning. Aldos- three anatomic zones: the outer , terone binds to the type I receptor. In which secretes the mineralocorticoid aldosterone; the contrast, binds to both the type I mineralocor- intermediate , which secretes cortisol; ticoid and type II receptors, although the and the inner , which secretes adrenal functional binding to the former receptor is limited by . The , lying in the center the intracellular 11 -hydroxysteroid dehydro- of the , is functionally related to the b genase (11 -HSD) type II, which catabolizes cortisol to sympathetic and secretes the cate- b inactive . The availability of cortisol to bind to cholamines and in response the glucocorticoid receptor is modulated by 11 -HSD to . b type I, which interconverts cortisol and cortisone. The synthesis of all begins with Binding of aldosterone to the mineralocorticoid and is catalyzed by a series of regulated, receptor leads to Na+ absorption and K+ and H+ secre- enzyme-mediated reactions (Fig. 66–1). tion by the renal tubules. The resultant increase in affect , cardiovascular function, behavior, plasma Na+ and decrease in plasma K+ provide a feed- and the inflammatory/immune response (Table 66–1). back mechanism for suppressing and, sub- Cortisol, the natural human glucocorticoid, is secreted sequently, aldosterone secretion. by the adrenal glands in response to ultradian, circa- Approximately 5% of cortisol and 40% of aldos- dian, and stress-induced hormonal stimulation by terone circulate in the free form; the remainder is bound adrenocorticotropic (ACTH). Plasma cortisol to -binding globulin and albumin. has marked ; levels are highest in the Adrenal precursors include dehy- morning. ACTH, a 39– neuropeptide, is droepiandrosterone (DHEA) and its sulfate and part of the pro-opiomelanocortin (POMC) precursor . They are synthesized in the zona retic- molecule, which also contains -endorphin, - b b ularis under the influence of ACTH and other adrenal , corticotropin-like intermediate-lobe androgen-stimulating factors. Although they have (CLIP), and various melanocyte-stimulating hormones minimal intrinsic androgenic activity, they contribute to (MSH). The secretion of ACTH by the androgenicity by their peripheral conversion to test- is regulated primarily by two hypothalamic polypep- osterone and . In men, excessive tides: the 41–amino acid corticotropin-releasing adrenal androgens have no clinical consequences; hormone (CRH) and the decapeptide . Glu- however in women, peripheral conversion of excess cocorticoids exert negative feedback upon CRH and adrenal androgen precursor secretion results in , ACTH secretion. The brain-hypothalamic-pituitary- , and . Because of gonadal pro- adrenal (HPA) axis (Fig. 66–2) interacts with and influ- duction of androgens and and secretion of ences the function of the reproductive, growth, and norepinephrine by , deficiencies of axes at multiple levels, with major participation adrenal androgens and are not clinically of glucocorticoids at all levels. recognized. The renin--aldosterone system (Fig. 66–3) is the major regulator of aldosterone secretion. Renal juxtaglomerular cells secrete renin in response to a decrease in circulating volume and/or a reduction in renal perfusion pressure. Renin is the rate-limiting enzyme that cleaves the 60-kD angiotensinogen, syn- Glucocorticoid insufficiency can be either primary, thesized by the , to the bioinactive decapeptide resulting from the destruction or dysfunction of the angiotensin I. Angiotensin I is rapidly converted to the adrenal cortex, or secondary, resulting from ACTH octapeptide angiotensin II by angiotensin-converting hyposecretion (Table 66–2). Autoimmune destruction of enzyme in the and other tissues. Angiotensin II is the adrenal glands (Addison’s disease) is the most a potent vasopressor and stimulates aldosterone pro- common cause of primary adrenal insufficiency in the duction but does not stimulate cortisol production. industrialized world, accounting for about 65% of 603 Ch066.qxd 10/8/03 7:07 PM Page 604

604 SECTION XI—

Cholesterol 1

2 3 4 5 6 11-Deoxy- Aldosterone corticosterone (DOC) 7 7

3 4 5 17-Hydroxy- 17-Hydroxy- 11-Deoxy- Cortisol Glucocorticoids pregnenolone progesterone cortisol

7 7

3 9 Dehydroepian- D4-Androstene- Sex drosterone (DHEA) dione

8 8

9 Sex Steroids

Enzyme Number Enzyme (Current and Trivial Name) 1 StAR; Steroidogenic acute regulatory protein 2 CYP11A1; Cholesterol side chain cleavage enzyme/desmolase 3 3b-HSD II; 3b-Hydroxylase dehydrogenase 4 CYP21A2; 21a-Hydroxylase 5 CYP11B1; 11b-Hydroxylase 6 CYP11B2; Corticosterone Methyloxidase 7 CYP17; 17a-Hydroxylase/17, 20 lyase 8 17b-HSD; 17b-Hydroxysteroid dehydrogenase 9 CYP19; Aromatase

FIGURE 66–1 Pathways of steroid biosynthesis.

Site Site Catecholamines, Liver Angiotensinogen (452 A.A.) Brain cytokines, growth – factors Kidney Prorenin Renin

Angiotensin I (10 A.A.) , – CRH AVP – plasma Angiotensin-converting enzyme Angiotensin II (8 A.A.) Pituitary – ACTH

Adrenal, Angiotensin II receptor vascular

Adrenal Cortisol Adrenal Aldosterone

FIGURE 66–2 The brain-hypothalamic-pituitary-adrenal axis. ACTH = FIGURE 66–3 The renin-angiotensin-aldosterone axis. A.A. = amino adrenocorticotropic hormone; AVP = arginine vasopressin; CRH = corti- acids. cotropin-releasing hormone. Ch066.qxd 10/8/03 7:07 PM Page 605

CHAPTER 66—The Adrenal Gland 605

TABLE 66–1 Actions of Glucocorticoids TABLE 66–2 Syndromes of Adrenocortical Hypofunction

Maintain Metabolic Primary Adrenal Disorders Regulate blood level, permissive effects on Combined Glucocorticoid and Mineralocorticoid Deficiency , increase glycogen synthesis Autoimmune Raise levels, permissive effects on lipolytic hormones Isolated (Addison’s disease) Increase catabolism, decrease anabolism (except fat), inhibit Polyglandular autoimmune syndrome, type I axis Polyglandular autoimmune syndrome, type II Inhibit reproductive axis Infectious Mineralocorticoid activity of cortisol Affect Connective Tissues Fungal Cytomegalovirus Cause loss of collagen and Human immunodeficiency virus Affect Calcium Homeostasis Vascular Stimulate osteoclasts, inhibit Bilateral adrenal hemorrhage Reduce intestinal calcium absorption, stimulate parathyroid hormone release, increase urinary calcium excretion, Coagulopathy decrease reabsorption of phosphate Thrombosis/embolism Maintain Cardiovascular Function Adrenal infarction Increase cardiac output Infiltration Increase vascular tone Metastatic carcinoma/lymphoma Permissive effects on pressor hormones, increase sodium retention Hemochromatosis Affect Behavior and Cognitive Function Congenital Affect Congenital adrenal Increase intravascular leukocyte concentration 21-hydroxylase deficiency Decrease migration of inflammatory cells to sites of 3b-ol dehydrogenase deficiency Suppress immune system (thymolysis; suppression of cytokines, 20,22-desmolase deficiency prostanoids, kinins, serotonin, histamine, collagenase, and Adrenal unresponsiveness to ACTH plasminogen activator) Congenital adrenal hypoplasia Adrenomyeloneuropathy latrogenic Bilateral cases. Usually both glucocorticoid and mineralocorti- Drugs: , , , coid secretion are diminished in this condition and, if , o,p¢-DDD, RU-486 untreated, it may be fatal. Isolated glucocorticoid or Mineralocorticoid Deficiency without Glucocorticoid mineralocorticoid deficiency may also occur, and it is Deficiency becoming apparent that mild adrenal insufficiency Corticosterone methyloxidase deficiency (similar to subclinical , discussed in Isolated zona glomerulosa defect Chapter 65) should also be diagnosed and treated. Heparin therapy Adrenal medulla function is usually spared. Approxi- Critical illness mately 70% of the patients with Addison’s disease have Converting enzyme inhibitors anti-adrenal . Tuberculosis used to be the most common cause of Secondary Adrenal Disorders adrenal insufficiency. However, its incidence in the Secondary Adrenal Insufficiency industrialized world has decreased since the 1960s, and Hypothalamic/pituitary dysfunction it now accounts for only 15 to 20% of cases of adrenal Exogenous glucocorticoids insufficiency; calcified adrenal glands can be seen in After removal of an ACTH-secreting tumor 50% of these cases. Fungal and cytomegalovirus in- Hyporeninemic fections, metastatic infiltration of the adrenal glands, Diabetic nephropathy sarcoidosis, amyloidosis, hemochromatosis, traumatic Tubulointerstitial diseases injury to both adrenal glands, bilateral adrenal hemor- Obstructive uropathy rhage, and sepsis (usually meningococcemia) are rare Autonomic neuropathy causes of adrenal insufficiency. Many patients with Nonsteroidal anti-inflammatory drugs human immunodeficiency virus have decreased b-Adrenergic drugs adrenal reserve without overt adrenal insufficiency. Congenital causes of adrenal dysfunction include con- ACTH = adrenocorticotropic hormone. genital adrenal hyperplasia (to be discussed), adrenal unresponsiveness to ACTH, congenital adrenal Ch066.qxd 10/8/03 7:07 PM Page 606

606 SECTION XI—Endocrine Disease

hypoplasia, and two demyelinating lipid metabolism A normal response is a plasma cortisol concentration disorders: adrenoleukodystrophy and adrenomyeloneu- higher than 20mg/dL at any time during the test. A ropathy. Iatrogenic causes of adrenal insufficiency patient with a basal morning plasma cortisol concen- include bilateral adrenalectomy, agents that inhibit cor- tration of less than 5mg/dL and a stimulated cortisol tisol biosynthesis (metyrapone, aminoglutethimide, concentration below 18mg/dL probably has frank trilostane, and ketoconazole), adrenolytic drugs adrenal insufficiency and should receive treatment. A ( [o,p¢-DDD]), and the glucocorticoid antago- basal morning plasma cortisol concentration between nist (RU-486). 10 and 18mg/dL in association with a stimulated corti- Addison’s disease may be part of two distinct autoim- sol concentration lower than 18mg/dL probably indi- mune polyglandular syndromes. Type I polyglandular cates impaired adrenal reserve and a requirement for autoimmune syndrome, also termed autoimmune receiving cortisol replacement under stress conditions polyendocrine-candidiasis–ectodermal dystrophy or (as described later). Recently a 1-mg cosyntropin test to autoimmune polyglandular failure syndrome, is charac- assess partial adrenal insufficiency has been described. terized by the triad of hypoparathyroidism, adrenal This test may identify more patients who need cortisol insufficiency, and mucocutaneous candidiasis. Other, replacement under stress conditions, but should not be less common manifestations include hypothyroidism, used to determine which patients need daily cortisol gonadal failure, gastrointestinal malabsorption, insulin- replacement. dependent diabetes mellitus, alopecia areata and totalis, Once the diagnosis of adrenal insufficiency is made, pernicious anemia, , chronic active hepatitis, the distinction between primary and secondary adrenal keratopathy, hypoplasia of dental enamel and nails, insufficiency needs to be made. Secondary adrenal in- , asplenism, and cholelithiasis. This syn- sufficiency results from inadequate stimulation of the drome manifests in childhood. Type II polyglandular adrenal cortex by ACTH. This can result from lesions autoimmune syndrome, also called Schmidt’s syndrome, anywhere along the HPA axis or as a sequela of pro- is characterized by Addison’s disease, autoimmune longed suppression of the HPA axis by exogenous glu- (Graves’ disease or Hashimoto’s thy- cocorticoids. Secondary adrenal insufficiency manifests roiditis), and insulin-dependent diabetes mellitus. Other similarly to primary adrenal insufficiency with a few associated diseases include pernicious anemia, vitiligo, important differences: Because ACTH and other gonadal failure, hypophysitis, celiac disease, myasthenia POMC-related are reduced in secondary gravis, primary biliary , Sjögren’s syndrome, adrenal insufficiency, does not occur. lupus erythematosus, and Parkinson’s disease. This In addition, because mineralocorticoid levels are normal syndrome usually manifests in adults. in secondary adrenal insufficiency, symptoms of salt Adrenal insufficiency commonly manifests as weight craving, as well as the laboratory abnormalities of loss, increasing fatigue, , or anorexia, hyperkalemia and metabolic acidosis, are not present. and salt craving. Muscle and pain, abdominal However, is often seen as a result of pain, and postural dizziness may also occur. Signs of increased antidiuretic hormone (ADH) secretion (result- increased pigmentation (initially most marked on the ing from volume depletion and ADH co-secretion with extensor surfaces, palmar creases, and buccal mucosa) CRH), which accompanies glucocorticoid insufficiency, often occur secondarily to the increased production of resulting in impaired water excretion. Because corti- ACTH and other POMC-related peptides by the pitu- cotropin is the most preserved of the pituitary hor- itary gland. Laboratory abnormalities may include mones, a patient with secondary adrenal insufficiency hyponatremia, hyperkalemia, mild metabolic acido- caused by a pituitary lesion usually has symptoms sis, azotemia, hypercalcemia, anemia, lymphocytosis, and/or laboratory abnormalities consistent with and . may also occur, espe- hypothyroidism, , or growth hormone cially in children. deficiency. To distinguish primary from secondary Acute adrenal insufficiency is a medical emergency, adrenal insufficiency, a basal morning plasma ACTH and treatment should not be delayed pending laboratory value and a standing (upright for at least 2 hours) serum results. In a critically ill patient with , a aldosterone level and should be plasma sample for cortisol, ACTH, aldosterone, and measured. A plasma ACTH value of more than renin should be obtained, and then treatment with an 20pg/mL (normal 5 to 30pg/mL) is consistent with intravenous bolus of 100mg of and primary adrenal insufficiency, whereas a value less than parenteral saline administration should be initiated. A 20pg/mL probably represents secondary adrenal insuf- plasma cortisol concentration of more than 34mg/dL ficiency. An upright plasma renin activity of more than rules out the diagnosis of , whereas a value 3ng/mL/hr in the setting of a suppressed aldosterone of less than 20mg/dL in the setting of is con- level is consistent with primary adrenal insufficiency, sistent with adrenal insufficiency. A plasma cortisol whereas a value less than 3ng/mL/hr probably re- value between 20mg/dL and 34mg/dL in the setting presents secondary adrenal insufficiency. The 1-hour of a severely ill patient may indicate partial adrenal cosyntropin test is suppressed in both secondary and insufficiency. primary adrenal insufficiency. In a patient with chronic symptoms, a 1-hour cosyn- Secondary adrenal insufficiency occurs commonly tropin test should be performed. In this test, 0.25mg after discontinuation of glucocorticoids. Alternate-day ACTH (1–24) (cosyntropin) is given intravenously, and glucocorticoid treatment, if feasible, results in less sup- plasma cortisol is measured 0, 30, and 60 minutes later. pression of the HPA axis than does daily glucocorticoid Ch066.qxd 10/8/03 7:07 PM Page 607

CHAPTER 66—The Adrenal Gland 607

therapy. The natural history of recovery from adrenal nism is caused by autonomic insufficiency and is a suppression is first a gradual increase in ACTH levels, frequent cause of orthostatic . Stimuli followed by the normalization of plasma cortisol levels such as upright posture or volume depletion, mediated and then normalization of the cortisol response to by baroreceptors, do not cause a normal renin response. ACTH. Complete recovery of the HPA axis can take up Administration of pharmacologic agents such as nons- to 1 year, and the rate-limiting step appears to be re- teroidal anti-inflammatory agents, angiotensin-convert- covery of the CRH neurons. ing enzyme inhibitors, and b-adrenergic antagonists can also produce conditions of hypoaldosteronism. Fludro- TREATMENT cortisone and/or the alpha1-agonist midodrine are effec- tive in correcting the and After stabilization of acute adrenal insufficiency, abnormalities caused by hypoaldosteronism. patients with Addison’s disease require lifelong replace- ment therapy with both glucocorticoids and mineralo- corticoids. Unfortunately, most physicians overtreat patients with glucocorticoids and undertreat them with Congenital Adrenal mineralocorticoids. Because overtreatment with gluco- Hyperplasia corticoids results in insidious weight gain and osteo- porosis, the minimal cortisol dose tolerated without Congenital adrenal hyperplasia (CAH) refers to disor- symptoms of glucocorticoid insufficiency (usually joint ders of biosynthesis that result in gluco- pain) is recommended. An initial regimen of 15 to corticoid and mineralocorticoid deficiencies. Because of 20mg of hydrocortisone first thing in the morning and deficient cortisol biosynthesis, a compensatory increase 5mg of hydrocortisone at around 4:00 pm mimics the in ACTH occurs, inducing adrenal hyperplasia and physiologic dose and is recommended. Whereas gluco- overproduction of the steroids that precede blockage corticoid replacement is fairly uniform in most patients, of enzyme production (see Fig. 66–1). There are five mineralocorticoid replacement varies greatly. The initial major types of CAH, and the clinical manifestations of dose of the synthetic mineralocorticoid fludrocortisone each type depend on which steroids are in excess and should be 100mg/day, and dosage should be adjusted to which are deficient. All these syndromes are transmitted keep the standing plasma renin activity between 1 and in an autosomal recessive pattern. 21-Hydroxylase 3ng/mL/hour. A standing plasma renin activity higher (CYP21) deficiency is the most common of these than 3ng/mL/hour, while the patient is taking the disorders and accounts for about 95% of cases of CAH. correct glucocorticoid dosage, is suggestive of under- In this condition, there is a failure of 21-hydroxylation treatment with fludrocortisone. of 17-hydroxyprogesterone and progesterone to 11- Under the stress of a minor illness (, vomiting, deoxycortisol and 11-deoxycortisone, respectively, with or fever greater than 100.5°F), the hydrocortisone dose deficient cortisol and aldosterone production. Cortisol should be doubled for as short a period of time as pos- deficiency leads to increased ACTH release, causing sible. The inability to ingest hydrocortisone pills may overproduction of 17-hydroxyprogesterone and proges- necessitate parenteral hydrocortisone administration. terone. Increased ACTH production also leads to Patients undergoing a major stressful event (i.e., surgery increased biosynthesis of androstenedione and DHEA, necessitating general anesthesia, or major trauma) which can be converted to testosterone. Patients should receive 150 to 300mg of parenteral hydrocorti- with 21-hydroxylase deficiency can be divided into sone daily (in three divided doses) with a rapid taper to two clinical phenotypes: classic 21-hydroxylase defi- normal replacement during recovery. All patients should ciency, usually diagnosed at birth or during childhood, wear a medical information bracelet and should be and late-onset 21-hydroxylase deficiency, which instructed in the use of intramuscular emergency manifests during or after . Two thirds of patients hydrocortisone injections. with classic 21-hydroxylase deficiency have various degrees of mineralocorticoid deficiency (salt-losing form); the remaining third are not salt losing (simple vir- ilizing form). Both decreased aldosterone production Hyporeninemic and increased concentrations of precursors that are Hypoaldosteronism mineralocorticoid antagonists (progesterone and 17- hydroxyprogesterone) contribute to salt loss in the salt- Mineralocorticoid deficiency can result from decreased losing form, in which the enzymatic block is more renin secretion by the kidneys. Resultant hypoan- severe. giotensinemia leads to hypoaldosteronism with hyper- The most useful measurement for the diagnosis of kalemia and hyperchloremic metabolic acidosis. Plasma classic 21-hydroxylase deficiency is that of plasma 17- sodium concentration is usually normal, but total hydroxyprogesterone. A value greater than 200ng/dL is plasma volume is often deficient. Plasma renin and consistent with the diagnosis. Late-onset 21-hydroxy- aldosterone levels are low and unresponsive to stimuli. lase deficiency represents an allelic variant of classic 21- Diabetes mellitus and chronic tubulointerstitial diseases hydroxylase deficiency and is characterized by a mild of the kidney are the most common underlying condi- enzymatic defect. This is the most frequent autosomal tions leading to impairment of the juxtaglomerular recessive disorder in humans and is present especially in apparatus. A subset of hyporeninemic hypoaldostero- Ashkenazi Jews. The syndrome usually manifests Ch066.qxd 10/8/03 7:07 PM Page 608

608 SECTION XI—Endocrine Disease

around the time of puberty with signs of virilization (hirsutism and acne) and amenorrhea or oligomenor- TABLE 66–3 Syndromes of Adrenocortical Hyperfunction rhea. It should be considered in women with un- explained hirsutism and menstrual abnormalities or States of Glucocorticoid Excess . The diagnosis is made from the finding of Physiologic States an elevated plasma 17-hydroxyprogesterone level Stress (>1500ng/dL) 30 minutes after administration of Strenuous exercise 0.25mg of synthetic ACTH (1–24). Last trimester of pregnancy The aim of treatment for classic 21-hydroxylase defi- Pathologic States ciency is to replace glucocorticoids and mineralocorti- Psychiatric conditions (pseudo-Cushing’s disorders) coids, suppress ACTH and androgen overproduction, Depression and allow for normal growth and sexual maturation Alcoholism in children. A proposed approach to treating classic Anorexia nervosa 21-hydroxylase deficiency recommends physiologic Panic disorders replacement with hydrocortisone and fludrocortisone in Alcohol/drug withdrawal all affected patients, including those with the simple vir- ACTH-dependent states ilizing form. The deleterious effects of excess androgens Pituitary (Cushing’s disease) can then be prevented by the use of an Ectopic ACTH syndrome agent (flutamide) and an (test- Bronchial carcinoid olactone) that blocks the conversion of testosterone to Thymic carcinoid . Islet cell tumor Although the traditional treatment for late-onset 21- Small cell lung carcinoma hydroxylase deficiency is (0.5mg/day), Ectopic CRH secretion the use of an antiandrogen such as (100 ACTH-independent states to 200mg/day) is probably more effective and has fewer Adrenal adenoma side effects. Mineralocorticoid replacement is not Adrenal carcinoma needed in late-onset 21-hydroxylase deficiency. Micronodular adrenal disease 11b-Hydroxylase (CYP11B1) deficiency accounts for about 5% of the cases of CAH. In this syndrome, the Exogenous Sources conversions of 11-deoxycortisol to cortisol and 11- Glucocorticoid intake deoxycorticosterone to corticosterone (the precursor to ACTH intake aldosterone) are blocked. Affected patients usually have States of Mineralocorticoid Excess and because of increased amounts of precursors with mineralocorticoid activity. Aldosterone-secreting adenoma Virilization occurs, as with 21-hydroxylase deficiency, Bilateral adrenal hyperplasia and a late-onset form manifesting as androgen excess Aldosterone-secreting carcinoma also occurs. The diagnosis is made from the finding of Glucocorticoid-suppressible elevated plasma 11-deoxycortisol levels, either basally Adrenal Enzyme Deficiencies or after ACTH stimulation. 11 -hydroxylase deficiency Rare forms of CAH are 3b-HSD type II, 17a-hydrox- b ylase (CYP17), and steroidogenic acute regulatory 17a-hydroxylase deficiency protein deficiencies. 11b-hydroxysteroid dehydrogenase, type II Exogenous Mineralocorticoids Licorice Syndromes of Carbenoxolone Adrenocorticoid Secondary Hyperaldosteronism Hyperfunction Associated with hypertension Accelerated hypertension Hypersecretion of the glucocorticoid hormone cortisol Renovascular hypertension results in Cushing’s syndrome, a metabolic disorder Estrogen administration affecting carbohydrate, protein, and lipid metabolism. Renin-secreting tumors Hypersecretion of mineralocorticoids such as ald- Without hypertension osterone results in a syndrome of hypertension and Bartter’s syndrome electrolyte disturbances. Sodium-wasting nephropathy Renal tubular acidosis CUSHING’S SYNDROME Diuretic/laxative abuse Edematous states (cirrhosis, nephrosis, congestive Pathophysiology failure)

Increased production of cortisol is seen in both physio- ACTH = adrenocorticotropin hormone; CRH = corticotropin-releasing hormone. logic and pathologic states (Table 66–3). Physiologic Ch066.qxd 10/8/03 7:08 PM Page 609

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hypercortisolism occurs in stress, during the last trimester of pregnancy, and in persons who regularly TABLE 66–4 Signs, Symptoms, and Laboratory perform strenuous exercise. Pathologic conditions of Abnormalities of Hypercortisolism elevated cortisol levels include exogenous or endoge- nous Cushing’s syndrome and several psychiatric states, Fat redistribution (dorsocervical and supraclavicular fat pads, including depression, alcoholism, anorexia nervosa, temporal wasting, centripetal obesity, weight gain) (95%) panic disorder, and alcohol or narcotic withdrawal. Menstrual irregularities (80% of affected women) Cushing’s syndrome may be caused by exogenous Thin skin/plethora (80%) ACTH or glucocorticoid administration or by endoge- Moon facies (75%) nous overproduction of these hormones. Endogenous Increased appetite (75%) Cushing’s syndrome is either ACTH dependent or Sleep disturbances (75%) ACTH independent. ACTH dependency accounts for Hypertension (75%) 85% of cases and includes pituitary sources of ACTH Hypercholesterolemia/hypertrigliceridemia (70%) (Cushing’s disease), ectopic sources of ACTH, and, in Altered mentation (poor concentration, decreased memory, rare instances, ectopic sources of CRH. Pituitary euphoria) (70%) Cushing’s disease accounts for 80% of cases of ACTH- Diabetes mellitus/glucose intolerance (65%) dependent Cushing’s syndrome. Ectopic secretion of Striae (65%) ACTH occurs most commonly in patients with small Hirsutism (65%) cell lung carcinoma. These patients are older, usually Proximal muscle weakness (60%) have a history of smoking, and present primarily with Psychological disturbances (emotional lability, depression, signs and symptoms of lung rather than of mania, psychosis) (50%) Cushing’s syndrome. Patients with the clinically appar- Decreased libido/impotence (50%) ent ectopic ACTH syndrome, in contrast, have mostly Acne (45%) intrathoracic (lung and thymic) carcinoids. The remain- /pathologic fractures (40%) ing patients have pancreatic, adrenal, or thyroid tumors Virilization (in women) (40%) that secrete ACTH. ACTH-independent causes account Easy bruisability (40%) for 15% of cases of Cushing’s syndrome and include Poor wound (40%) adrenal , adrenal carcinomas, micronodular Edema (20%) adrenal disease, and autonomous macronodular adrenal Increased (10%) disease. The female-to-male ratio for noncancerous Cataracts (5%) forms of Cushing’s syndrome is 4:1.

Clinical Manifestations The clinical signs, symptoms, and common laboratory findings of hypercortisolism seen in patients with levels, granulocytosis, thrombocytosis, hypercholes- Cushing’s syndrome are listed in Table 66–4. Typically terolemia, hypertriglyceridemia, and glucose intoler- the obesity is centripetal, with a wasting of the arms and ance/diabetes mellitus. Hypokalemic alkalosis legs; this is distinct from the generalized weight gain is an infrequent finding in patients with Cushing’s seen in idiopathic obesity. Rounding of the face (so- syndrome and usually occurs in patients with severe called moon facies) and a dorsocervical fat pad hypercortisolism as a result of the ectopic ACTH (“buffalo hump”) may occur in obesity that is not syndrome. related to Cushing’s syndrome, whereas facial plethora and supraclavicular filling are more specific for Diagnosis (Fig. 66–4) Cushing’s syndrome. Patients with Cushing’s syndrome may have proximal muscle weakness, so the physical If the history and physical examination findings are sug- finding of inability to stand up from a squat can be quite gestive of hypercortisolism, the diagnosis of Cushing’s revealing. Menstrual irregularities often precede other syndrome can usually be established by collecting cushingoid symptoms in affected women, whereas for 24 hours and measuring urinary free cortisol (UFC). affected men frequently complain of poor libido and UFC excretion reflects plasma unbound cortisol that is impotence. Adult-onset acne or hirsutism in women filtered and excreted by the kidney. This test is extremely should also raise the suspicion of Cushing’s syndrome. sensitive for the diagnosis of Cushing’s syndrome The skin striae seen in cushingoid patients are because, in 90% of affected patients, the initial UFC violaceous (purple or dark red), with a width of at level is greater than 50mg/24 hours when measured by least 1cm. Thinning of the skin on the top of the hands HPLC or mass spectroscopy cortisol assays. Patients is a very specific sign in younger adults with Cushing’s with Cushing’s disease usually have UFC levels between syndrome and should always be examined. Old pictures 100 and 500mg/24 hours, whereas patients with the of patients are extremely helpful for evaluating the ectopic ACTH syndrome and cortisol-secreting adrenal progression of the physical stigmata of Cushing’s adenomas or carcinomas frequently have UFC levels syndrome. greater than 500mg/24 hours. Associated laboratory findings in Cushing’s Cortisol normally is secreted in a diurnal manner; the syndrome include elevated plasma alkaline phosphatase plasma concentration is highest in the early morning Ch066.qxd 10/8/03 7:08 PM Page 610

610 SECTION XI—Endocrine Disease

Diagnosis History and physical consistent with hypercortisolism

Urinary free cortisol (UFC) Low-dose dexamethasone test

UFC normal UFC elevated Suppression to low-dose No suppression to low- dexamethasone dose dexamethasone

Cushing syndrome Cushing syndrome likely; unlikely proceed to differential diagnosis

Measure plasma ACTH Differential diagnosis

ACTH suppressed ACTH normal or elevated

Adrenal tumor likely Cushing disease () or ectopic ACTH syndrome

Unilateral Adrenalectomy

oCRH-stimulation test and/or high-dose dexamethasone test and/or bilateral inferior petrosal sinus sampling (BIPSS) with oCRH

Negative results Increase in cortisol/ACTH after oCRH Suppression during the high-dose dexamethasone test Ectopic ACTH syndrome Central to peripheral ACTH gradient after oCRH administration in BIPSS

If Tumor is Localized, Surgical Removal of Tumor Cushing disease

Transsphenoidal Surgery

FIGURE 66–4 Flow chart for evaluating a patient with suspected Cushing’s syndrome. ACTH = adrenocorticotropic hormone; oCRH = ovine corticotropin–releasing hormone.

(between 6:00 and 8:00 am) and lowest around mid- concentrations are markedly higher. Late afternoon or night. The normal 8:00 am plasma cortisol level ranges night values greater than 50% of the morning values are between 8 and 25mg/dL and declines throughout the consistent with Cushing’s syndrome. Measurement of day. By 11:00 pm, the values are usually less than random morning cortisol levels is not particularly 5mg/dL. Most patients with Cushing’s syndrome lack helpful. this diurnal variation. Thus, although their morning The overnight dexamethasone suppression test can cortisol levels may be normal, their afternoon or evening also be used as a screening test to evaluate patients sus- Ch066.qxd 10/8/03 7:08 PM Page 611

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pected of having hypercortisolism. Dexamethasone, The ovine CRH (oCRH) test and bilateral simulta- 1mg, is given orally at 11:00 pm, and plasma cortisol is neous inferior petrosal sinus sampling are also used to measured the following morning at 8:00 am. A morning establish the etiology of Cushing’s syndrome. Pituitary plasma cortisol level greater than 3mg/dL suggests corticotrophs of normal persons and of patients with hypercortisolism. This test is easy and can be performed pituitary Cushing’s disease respond to oCRH by increas- in an outpatient setting. The test is fairly sensitive, ing the secretion of ACTH and, therefore, cortisol. Thus although some pituitary adenomas are very sensitive to the oCRH test cannot be used to distinguish normal dexamethasone and can suppress cortisol production persons from patients with pituitary Cushing’s disease. readily in this test. However, the test produces a signif- Patients with cortisol-secreting adrenal tumors have low icant number of false-positive results, especially in obese or undetectable concentrations of ACTH that do not and depressed patients, the two patient populations in respond to oCRH. Patients with ectopic ACTH secre- whom the differentiation from mild Cushing’s syndrome tion have high basal ACTH levels that do not increase may be difficult. For these reasons, collection of urine with oCRH. In patients with both the ectopic ACTH for measurement of 24-hour UFC excretion is a better syndrome and primary adrenal hypercortisolism, screening test. cortisol levels do not change in response to oCRH. Dis- crepancies between the oCRH and dexamethasone Differential Diagnosis tests necessitate further work-up for ascertainment of the diagnosis. Once the diagnosis of Cushing’s syndrome is estab- Bilateral inferior petrosal sinus sampling (BIPSS) is lished, the etiology of the hypercortisolism needs to be an accurate and safe procedure for distinguishing ascertained. This is accomplished by biochemical pituitary Cushing’s disease from the ectopic ACTH studies, which evaluate the feedback regulation of the syndrome. Venous blood from the anterior lobe of the HPA axis; by venous sampling techniques; and by pituitary gland empties into the cavernous sinuses and imaging procedures. Basal ACTH levels are normal or then into the superior and inferior petrosal sinuses. elevated in Cushing’s disease and the ectopic ACTH Venous plasma samples for ACTH determination are syndrome and are suppressed in primary adrenal obtained from both inferior petrosal sinuses, along with Cushing’s syndrome. a simultaneous peripheral sample, both before and after In the dexamethasone suppression test (Liddle test), intravenous bolus administration of CRH. In baseline 0.5mg of dexamethasone is given orally every 6 hours measurements, an ACTH concentration gradient of 1.6 for 2 days, followed by 2mg of dexamethasone every 6 or more between a sample from either of the petrosal hours for another 2 days. On the second day of the high sinuses and the peripheral sample is strongly suggestive dosage of dexamethasone, UFC is suppressed to less of pituitary Cushing’s disease, whereas patients with than 10% of that of the baseline collection in patients ectopic ACTH syndrome or adrenal adenomas have no with pituitary adenomas but not in patients with the ACTH gradient between their petrosal and peripheral ectopic ACTH syndrome or adrenal cortisol-secreted samples. After CRH administration, a central-to- tumors. Although the Liddle test is often helpful in peripheral gradient of more than 3.2 is consistent with establishing the etiology of Cushing’s syndrome, it has pituitary Cushing’s disease. The use of CRH has enabled some disadvantages. The test requires accurate meas- complete distinction of pituitary Cushing’s disease from urement of urine collections, often necessitating inpa- nonpituitary Cushing’s syndrome. An ACTH gradient tient hospitalization. In approximately 50% of patients ipsilateral to the side of the tumor is found in 70 to 80% with bronchial carcinoids causing ectopic ACTH pro- of patients sampled. Although BIPSS requires a radiol- duction, cortisol secretion is suppressible by high-dose ogist experienced in petrosal sinus sampling, it is cur- dexamethasone, which yields a false-positive result. In rently available at many tertiary care facilities. addition, because patients with Cushing’s syndrome are Imaging of the pituitary gland by magnetic resonance often episodic secretors of , considerable imaging (MRI) with gadolinium is the preferred proce- variation in daily UFC excretion can occur and false dure for localizing a pituitary adenoma. This test detects results can be obtained. Therefore, the Liddle test approximately 50 to 60% of pituitary ACTH-secreting should be interpreted cautiously and other confirmatory tumors and can detect many pituitary tumors as small tests should be performed before a patient is sent to as 3mm in diameter. About 10% of normal individuals surgery. may have a nonfunctioning pituitary adenoma found An overnight high-dose dexamethasone suppression on pituitary MRI. It is therefore recommended that test is helpful in establishing the etiology of Cushing’s pituitary imaging not be the sole criterion for the diag- syndrome. In this test, a baseline 8:00 am cortisol level nosis of pituitary Cushing’s disease. is measured, and then 8mg of dexamethasone is given orally at 11:00 pm. At 8:00 am the following morning, Treatment a plasma cortisol measurement is obtained. Suppression, which would occur in patients with pituitary Cushing’s The preferred treatment for all forms of Cushing’s syn- disease, is defined as a decrease in plasma cortisol to less drome is appropriate surgery. Pituitary Cushing’s than 50% of the baseline level. Few patients with disease is best treated by . When bronchial carcinoid have been examined, so the the operation is performed by an experienced neuro- suppressibility of these tumors by high-dose overnight surgeon, the cure rate is higher than 90%. Transsphe- dexamethasone is not well established. noidal surgery carries very low rates of morbidity and Ch066.qxd 10/8/03 7:08 PM Page 612

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mortality. Complications (e.g., , cerebrospinal Primary aldosteronism is usually recognized during fluid leakage, optic damage, isolated thyrotropin evaluation of hypertension or hypokalemia and repre- or growth hormone deficiency) are rare. In patients with sents a potentially curable form of hypertension. Up to the ectopic ACTH syndrome, it is hoped that the tumor 5% of patients with hypertension have primary aldos- is localized by appropriate scans and then removed sur- teronism. The patients are usually between 30 and 50 gically. A unilateral adrenalectomy is the treatment of years of age, and the female-to-male ratio is 2:1. choice in patients with a cortisol-secreting adrenal adenoma. Patients with cortisol-secreting adrenal carci- Clinical Manifestations nomas should also be managed surgically; however, they have a poor prognosis, with only 20% surviving more Hypertension, hypokalemia, and metabolic alkalosis are than 1 year after diagnosis. the main clinical manifestations of hyperaldosteronism; Patients who have failed initial pituitary surgery or most of the presenting symptoms are related to have recurrent Cushing’s disease may be treated with hypokalemia. Symptoms in mildly hypokalemic patients either pituitary irradiation or bilateral adrenalectomy. are fatigue, muscle weakness, nocturia, lassitude, and Irradiation has more long-term complications than does headaches. If more severe hypokalemia exists, poly- transsphenoidal surgery, and results in cure in about dipsia, polyuria, paresthesias, and even intermittent 60% of patients, but it may take up to 5 years to render paralysis and tetany can occur. can range a person eucortisolemic. Panhypopituitarism eventually from being minimally elevated to very high. Retinopa- develops in almost all these patients, and so growth thy is mild, and hemorrhages are rarely present. A pos- hormone, thyroid, gonadal, and even steroid replace- itive Trousseau or Chvostek sign may occur as a result ment may be needed. A more appealing option for of metabolic alkalosis. patients with Cushing’s disease who remain hypercor- tisolemic after pituitary surgery is bilateral adrena- Diagnosis and Treatment lectomy, followed by lifelong glucocorticoid and mineralocorticoid replacement therapy. About 10% of Initially, hypokalemia in the presence of hypertension patients with Cushing’s disease who undergo bilateral must be documented (Fig. 66–5). The patient must have adrenalectomy develop Nelson’s syndrome (hyperpig- an adequate salt intake and discontinue diuretics before mentation and an ACTH-secreting macroadenoma that potassium measurement. If hypokalemia is found under often causes visual field deficits). The incidence of these conditions, spironolactone should be stopped (if Nelson’s syndrome is reduced if patients have under- the patient is taking it) and a morning plasma aldos- gone pituitary irradiation. Patients who undergo bilat- terone level and a plasma renin activity (PRA) should eral adrenalectomy may, on rare occasions, develop be measured. A serum aldosterone/PRA ratio >20ng/dL adrenal rest tissue leading to recurrence of Cushing’s per ng/mL/hr and a serum aldosterone level >15ng/dL syndrome. suggest the diagnosis of hyperaldosteronism. Medical treatment for hypercortisolism may be Once the diagnosis of primary aldosteronism has needed to prepare patients for surgery, in patients who been demonstrated, it is important to distinguish are undergoing or have undergone pituitary irradiation between an aldosterone-producing adenoma and bilat- and are awaiting its effects, or in patients who are not eral hyperplasia, because the former is treated with surgical candidates or who elect not to have surgery. surgery and the latter is treated medically. In the initial Ketoconazole, o,p¢-DDD, metyrapone, aminog- test (a postural challenge), an 8:00 am supine blood lutethimide, RU-486, and trilostane are the most sample is drawn for plasma aldosterone, 18-hydrocor- commonly used agents for adrenal blockade and can be ticosterone, renin, and cortisol measurement. The used alone or in combination. patient then stands for 2 hours, and an upright sample is drawn for measurement of the same hormones. A PRIMARY MINERALOCORTICOID EXCESS basal plasma aldosterone level of less than 20ng/dL is usually found in patients with bilateral hyperplasia, and Pathophysiology a value greater than 20ng/dL suggests the diagnosis of adrenal adenoma. In bilateral hyperplasia, plasma Increased mineralocorticoid activity is manifested by aldosterone often increases as a result of the increase in salt retention, hypertension, hypokalemia, and meta- renin in response to the upright position, whereas, in bolic alkalosis. The causes of primary aldosteronism adenoma, plasma aldosterone levels usually fall as a (see Table 66–3) are aldosterone-producing adenoma result of decreased stimulation by ACTH at 10:00 am, (75%), bilateral adrenal hyperplasia (25%), adrenal in comparison with 8:00 am. An 8:00 am plasma 18- carcinoma (1%), and glucocorticoid-remediable hyper- hydroxycorticosterone level of greater than 50ng/dL aldosteronism (<1%). The adrenal enzyme defects— that falls with upright posture occurs in most patients 11b-HSD type II, 11b-hydroxylase, and 17a- with an adenoma, whereas an 8:00 am level hydroxylase deficiencies—and apparent mineralocorti- less than 50ng/dL that rises with upright posture occurs coid excess (from licorice or carbenoxolone ingestion, in most patients with bilateral hyperplasia. which inhibits 11b-HSD type II, or from a congenital A computed tomography (CT) scan of the adrenal defect in this enzyme) are also states of functional min- glands should be performed to localize the tumor. If a eralocorticoid overactivity. Secondary aldosteronism discrete adenoma is seen in one adrenal gland, the con- (see Table 66–3) results from overactivation of the tralateral gland is normal, and biochemical test results renin-angiotensin system. are consistent with an adenoma, the patient should Ch066.qxd 10/8/03 7:08 PM Page 613

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Hypertension Adrenal Medullary Measure plasma K+ Hyperfunction Low The adrenal medulla synthesizes the catecholamines norepinephrine, epinephrine, and from the amino acid . Norepinephrine, the major cate- Suspect hyperaldosteronism cholamine produced by the adrenal medulla, has pre- Plasma aldosterone/ dominantly a-agonist actions, causing vasoconstriction. plasma renin activity Epinephrine acts primarily on the b-receptors, having 20 ng/dL positive inotropic and chronotropic effects on the heart, Aldosterone/plasma renin activity > ng/mL/hr causing peripheral , and increasing plasma and serum aldosterone > 15 ng/dL glucose concentrations in response to hypoglycemia. The action of circulating dopamine is unclear. Whereas norepinephrine is synthesized in the central nervous Primary aldosteronism system and sympathetic postganglionic neurons, epi- nephrine is synthesized almost entirely in the adrenal Supine and upright plasma aldosterone and medulla. The adrenal medullary contribution to norep- 18-hydroxycorticosterone inephrine secretion is relatively small. Bilateral adrena- lectomy results in only minimal changes in circulating norepinephrine levels, although epinephrine levels are Mildly elevated plasma Substantially elevated plasma aldosterone and aldosterone and dramatically reduced. Thus hypofunction of the adrenal 18-hydroxycorticosterone, 18-hydroxycorticosterone, medulla has little physiologic impact, whereas hyper- which increase on standing which decrease on standing secretion of catecholamines produces the clinical syndrome of .

Bilateral adrenal hyperplasia Adrenal adenoma PHEOCHROMOCYTOMA Pathophysiology Medical Treatment Unilateral (Spironolactone) Adrenalectomy Although can occur in any sym- pathetic ganglion in the body, more than 90% of pheochromocytomas arise from the adrenal medulla. FIGURE 66–5 Flow chart for evaluating a patient with suspected The majority of extra-adrenal tumors occur in the medi- primary hyperaldosteronism. astinum or . Bilateral adrenal pheochromocy- tomas occur in about 5% of the cases and may occur as part of familial syndromes. Pheochromocytoma occurs as part of multiple endocrine neoplasia type IIA or IIB. The former (Sipple’s syndrome) is marked by undergo unilateral adrenalectomy. Patients in whom medullary carcinoma of the thyroid, hyperparathy- biochemical study findings are consistent with an roidism, and pheochromocytoma; the latter is charac- adenoma but CT results are consistent with bilateral terized by medullary carcinoma of the thyroid, mucosal disease should undergo adrenal venous sampling for neuromas, intestinal , marfanoid aldosterone and cortisol measurement. Patients in habitus, and pheochromocytoma. Pheochromocytomas whom biochemical and localization study findings are are also associated with neurofibromatosis, cere- consistent with bilateral hyperplasia should be treated belloretinal hemangioblastosis (von Hippel-Lindau medically, usually with spironolactone. Those in whom disease), and tuberous sclerosis. biochemical study results are consistent with bilateral hyperplasia should also be evaluated for dexametha- Clinical Manifestations sone-suppressible hyperaldosteronism by receiving a trial of dexamethasone, which reverses the hyperaldos- Because the majority of pheochromocytomas secrete teronism in this rare autosomal dominant disorder. norepinephrine as the principal , hyper- Hyperaldosteronism and hypertension secondary tension (often paroxysmal) is the most common finding. to activation of the renin-angiotensin system can Other symptoms include the triad of headache, palpita- occur in patients with accelerated hypertension, those tions, and sweating, as well as flushing, anxiety, nausea, with renovascular hypertension, those receiving fatigue, , and abdominal and chest pain. estrogen therapy, and, rarely, patients with renin- These symptoms may be precipitated by emotional secreting tumors. Hyperaldosteronism without hyper- stress, exercise, anesthesia, abdominal pressure, or tension occurs in patients with Bartter’s syndrome, those intake of tyramine-containing foods. Orthostatic with sodium-wasting nephropathy, those with renal hypotension can also occur. Wide fluctuations in blood tubular acidosis, and those who abuse diuretics or pressure are characteristic, and the hypertension laxatives. associated with pheochromocytoma usually does not Ch066.qxd 10/8/03 7:08 PM Page 614

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respond to standard antihypertensive medicines. treatment for other clinical conditions that are not Cardiac abnormalities, as well as idiosyncratic reactions related to suspicion of adrenal disease and, thus, are to medications, may also occur. commonly known as “incidentalomas.” All patients with an incidentaloma should have a 1-mg dexametha- Diagnosis and Treatment sone suppression test and measurement of urine or plasma free metanephrines. Patients with hypertension Plasma free metanephrine and normetanephrine levels should also undergo measurement of serum potassium are the best test for confirming or excluding pheochro- level and plasma aldosterone concentration/plasma mocytoma because the metabolism of catecholamines renin activity ratio. Surgery should be considered in all to free metanephrines is independent of catechola- patients with functional adrenal cortical tumors that are mine release and can be performed in the absence hormonally active or greater than 5cm. Tumors not of hypertension and other symptoms. A plasma free associated with hormonal secretion or less than 5cm metanephrine level greater than 0.61nmol/L and a can be followed with repeat imaging and hormonal plasma free normetanephrine level greater than assessment. 0.31nmol/L are consistent with the diagnosis of a pheochromocytoma. If the values are only mildly ele- vated, a clonidine suppression test could be performed; in this test, clonidine (0.3mg/kg) is given orally, and plasma catecholamines (including free metanephrine and normetanephrine) are measured before and 3 hours PROSPECTUS FOR THE FUTURE after administration. In normal persons, catecholamine levels decrease into the normal range, whereas, in • An appreciation of the role of tissue-specific, intracellular glu- patients with a pheochromocytoma, levels are cocorticoid excess in common diseases such as osteoporosis, unchanged or increase. Once the diagnosis of depression, cardiovascular disease, diabetes, and hyperten- pheochromocytoma is made, a CT scan of the adrenal sion glands should be performed. Most intra-adrenal • Selective adrenal adenomectomy sparing normal adrenal pheochromocytomas are readily visible on this scan. If tissue the CT scan is negative, extra-adrenal pheochromocy- • An appreciation of the importance of mild (subclinical) adrenal tomas can often be localized by iodine-131–labeled insufficiency and excess metaiodobenzylguanidine (131I-MIBG), positron emis- sion tomography, octreotide scan, or abdominal MRI. The treatment of pheochromocytoma is surgical if the lesion can be localized. Patients should undergo pre- operative a-blockade with phenoxybenzamine 1 to 2 weeks before surgery. b-Adrenergic antagonists should REFERENCES be used prior to or during surgery. Approximately 5 to 131 Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing’s 10% of pheochromocytomas are malignant. I-MIBG syndrome. Endocrinol Metab Clin North Am 2001;30:729–747. or chemotherapy may be useful, but the prognosis is Merke DP, Bornstein SR, Avila NA, Chrousos GP: NIH conference: poor. a-Methyl-p-tyrosine (an inhibitor of tyrosine Future directions in the study and management of congenital hydroxylase, the rate-limiting enzyme in catecholamine adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med 2002;136:320–334. biosynthesis) may be used to decrease catecholamine Newell-Price J, Trainer P, Besser M, Grossman A: The diagnosis and secretion from the tumor. differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev 1998;19:647–672. Pacak K, Linehan WM, Eisenhofer G, et al: Recent advances in genet- INCIDENTAL ADRENAL MASS ics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001;134:315–329. Clinically inapparent adrenal masses are discovered Ten S, New M, Maclaren N: Clinical review 130: Addison’s disease inadvertently in the course of diagnostic testing or 2001. J Clin Endocrinol Metab 2001;86:2909–2922.