The Adrenal Gland - good hormone healthgoodhormonehealth.com/adrenal-cecils.pdfChapter66 The Adrenal Gland Theodore C. Friedman 603 Physiology The adrenal glands lie at the superior

C h a p t e r 66The Adrenal Gland

Theodore C. Friedman

603

PhysiologyThe adrenal glands lie at the superior pole of eachkidney and are composed of two distinct regions: thecortex and the medulla. The adrenal cortex consists ofthree anatomic zones: the outer zona glomerulosa,which secretes the mineralocorticoid aldosterone; theintermediate zona fasciculata, which secretes cortisol;and the inner zona reticularis, which secretes adrenalandrogens. The adrenal medulla, lying in the center of the adrenal gland, is functionally related to the sympathetic nervous system and secretes the cate-cholamines epinephrine and norepinephrine in responseto stress.

The synthesis of all steroid hormones begins withcholesterol and is catalyzed by a series of regulated,enzyme-mediated reactions (Fig. 66–1). Glucocorticoidsaffect metabolism, cardiovascular function, behavior,and the inflammatory/immune response (Table 66–1).Cortisol, the natural human glucocorticoid, is secretedby the adrenal glands in response to ultradian, circa-dian, and stress-induced hormonal stimulation byadrenocorticotropic hormone (ACTH). Plasma cortisolhas marked circadian rhythm; levels are highest in themorning. ACTH, a 39–amino acid neuropeptide, is part of the pro-opiomelanocortin (POMC) precursormolecule, which also contains b-endorphin, b-lipotropin, corticotropin-like intermediate-lobe peptide(CLIP), and various melanocyte-stimulating hormones(MSH). The secretion of ACTH by the pituitary glandis regulated primarily by two hypothalamic polypep-tides: the 41–amino acid corticotropin-releasinghormone (CRH) and the decapeptide vasopressin. Glu-cocorticoids exert negative feedback upon CRH andACTH secretion. The brain-hypothalamic-pituitary-adrenal (HPA) axis (Fig. 66–2) interacts with and influ-ences the function of the reproductive, growth, andthyroid axes at multiple levels, with major participationof glucocorticoids at all levels.

The renin-angiotensin-aldosterone system (Fig. 66–3)is the major regulator of aldosterone secretion. Renaljuxtaglomerular cells secrete renin in response to adecrease in circulating volume and/or a reduction inrenal perfusion pressure. Renin is the rate-limitingenzyme that cleaves the 60-kD angiotensinogen, syn-thesized by the liver, to the bioinactive decapeptideangiotensin I. Angiotensin I is rapidly converted to theoctapeptide angiotensin II by angiotensin-convertingenzyme in the lungs and other tissues. Angiotensin II isa potent vasopressor and stimulates aldosterone pro-duction but does not stimulate cortisol production.

Angiotensin II is the predominant regulator of aldos-terone secretion, but plasma potassium concentration,plasma volume, and ACTH levels also influence aldos-terone secretion. ACTH also mediates the circadianrhythm of aldosterone; as a result, the plasma concen-tration of aldosterone is highest in the morning. Aldos-terone binds to the type I mineralocorticoid receptor. Incontrast, cortisol binds to both the type I mineralocor-ticoid and type II glucocorticoid receptors, although thefunctional binding to the former receptor is limited bythe intracellular enzyme 11b-hydroxysteroid dehydro-genase (11b-HSD) type II, which catabolizes cortisol toinactive cortisone. The availability of cortisol to bind tothe glucocorticoid receptor is modulated by 11b-HSDtype I, which interconverts cortisol and cortisone.Binding of aldosterone to the cytosol mineralocorticoidreceptor leads to Na+ absorption and K+ and H+ secre-tion by the renal tubules. The resultant increase inplasma Na+ and decrease in plasma K+ provide a feed-back mechanism for suppressing renin and, sub-sequently, aldosterone secretion.

Approximately 5% of cortisol and 40% of aldos-terone circulate in the free form; the remainder is boundto corticosteroid-binding globulin and albumin.

Adrenal androgen precursors include dehy-droepiandrosterone (DHEA) and its sulfate andandrostenedione. They are synthesized in the zona retic-ularis under the influence of ACTH and other adrenalandrogen-stimulating factors. Although they haveminimal intrinsic androgenic activity, they contribute toandrogenicity by their peripheral conversion to test-osterone and dihydrotestosterone. In men, excessiveadrenal androgens have no clinical consequences;however in women, peripheral conversion of excessadrenal androgen precursor secretion results in acne,hirsutism, and virilization. Because of gonadal pro-duction of androgens and estrogens and secretion ofnorepinephrine by sympathetic ganglia, deficiencies ofadrenal androgens and catecholamines are not clinicallyrecognized.

Adrenal InsufficiencyGlucocorticoid insufficiency can be either primary,resulting from the destruction or dysfunction of theadrenal cortex, or secondary, resulting from ACTHhyposecretion (Table 66–2). Autoimmune destruction ofthe adrenal glands (Addison’s disease) is the mostcommon cause of primary adrenal insufficiency in theindustrialized world, accounting for about 65% of

XI

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604 SECTION XI—Endocrine Disease

Cholesterol

Pregnenolone Progesterone 11-Deoxy-corticosterone(DOC)

17-Hydroxy-pregnenolone

17-Hydroxy-progesterone

Corticosterone Aldosterone Mineralocorticoids

1

2

7 7

3 4

3 4

5

Glucocorticoids11-Deoxy-cortisol

Cortisol5

Dehydroepian-drosterone (DHEA)

D4-Androstene-dione

7 7

3 9Sex Steroids

Sex Steroids

Estrone

Testosterone

Enzyme Number123456789

Enzyme (Current and Trivial Name)StAR; Steroidogenic acute regulatory proteinCYP11A1; Cholesterol side chain cleavage enzyme/desmolase3b-HSD II; 3b-Hydroxylase dehydrogenaseCYP21A2; 21a-HydroxylaseCYP11B1; 11b-HydroxylaseCYP11B2; Corticosterone MethyloxidaseCYP17; 17a-Hydroxylase/17, 20 lyase17b-HSD; 17b-Hydroxysteroid dehydrogenaseCYP19; Aromatase

8 8

9Estradiol

6

FIGURE 66–1 Pathways of steroid biosynthesis.

Hypothalamus

Pituitary

Adrenal

BrainCatecholamines,cytokines, growth

factors

ACTH

Cortisol

CRH AVP

Site

–

––

–

FIGURE 66–2 The brain-hypothalamic-pituitary-adrenal axis. ACTH =adrenocorticotropic hormone; AVP = arginine vasopressin; CRH = corti-cotropin-releasing hormone.

Angiotensinogen (452 A.A.)

Site

Prorenin Renin

Liver

Kidney

Lung,plasma

Adrenal,vascular

Angiotensin-convertingenzyme

Angiotensin I (10 A.A.)

Angiotensin II (8 A.A.)

Angiotensin II receptor

AldosteroneAdrenal

FIGURE 66–3 The renin-angiotensin-aldosterone axis. A.A. = aminoacids.

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cases. Usually both glucocorticoid and mineralocorti-coid secretion are diminished in this condition and, ifuntreated, it may be fatal. Isolated glucocorticoid ormineralocorticoid deficiency may also occur, and it isbecoming apparent that mild adrenal insufficiency(similar to subclinical hypothyroidism, discussed inChapter 65) should also be diagnosed and treated.Adrenal medulla function is usually spared. Approxi-mately 70% of the patients with Addison’s disease haveanti-adrenal antibodies.

Tuberculosis used to be the most common cause ofadrenal insufficiency. However, its incidence in theindustrialized world has decreased since the 1960s, andit now accounts for only 15 to 20% of cases of adrenalinsufficiency; calcified adrenal glands can be seen in50% of these cases. Fungal and cytomegalovirus in-fections, metastatic infiltration of the adrenal glands,sarcoidosis, amyloidosis, hemochromatosis, traumaticinjury to both adrenal glands, bilateral adrenal hemor-rhage, and sepsis (usually meningococcemia) are rarecauses of adrenal insufficiency. Many patients withhuman immunodeficiency virus infection have decreasedadrenal reserve without overt adrenal insufficiency.Congenital causes of adrenal dysfunction include con-genital adrenal hyperplasia (to be discussed), adrenalunresponsiveness to ACTH, congenital adrenal

CHAPTER 66—The Adrenal Gland 605

TABLE 66–1 Actions of Glucocorticoids

Maintain Metabolic HomeostasisRegulate blood glucose level, permissive effects on

gluconeogenesis, increase glycogen synthesisRaise insulin levels, permissive effects on lipolytic hormonesIncrease catabolism, decrease anabolism (except fat), inhibit

growth hormone axisInhibit reproductive axisMineralocorticoid activity of cortisol

Affect Connective TissuesCause loss of collagen and connective tissue

Affect Calcium HomeostasisStimulate osteoclasts, inhibit osteoblastsReduce intestinal calcium absorption, stimulate parathyroid

hormone release, increase urinary calcium excretion,decrease reabsorption of phosphate

Maintain Cardiovascular FunctionIncrease cardiac outputIncrease vascular tonePermissive effects on pressor hormones, increase sodium

retention

Affect Behavior and Cognitive Function

Affect Immune SystemIncrease intravascular leukocyte concentrationDecrease migration of inflammatory cells to sites of injurySuppress immune system (thymolysis; suppression of cytokines,

prostanoids, kinins, serotonin, histamine, collagenase, andplasminogen activator)

TABLE 66–2 Syndromes of Adrenocortical Hypofunction

Primary Adrenal DisordersCombined Glucocorticoid and Mineralocorticoid DeficiencyAutoimmune

Isolated autoimmune disease (Addison’s disease)Polyglandular autoimmune syndrome, type IPolyglandular autoimmune syndrome, type II

InfectiousTuberculosisFungalCytomegalovirusHuman immunodeficiency virus

VascularBilateral adrenal hemorrhageSepsisCoagulopathyThrombosis/embolismAdrenal infarction

InfiltrationMetastatic carcinoma/lymphomaSarcoidosisAmyloidosisHemochromatosis

CongenitalCongenital adrenal hyperplasia

21-hydroxylase deficiency3b-ol dehydrogenase deficiency20,22-desmolase deficiency

Adrenal unresponsiveness to ACTHCongenital adrenal hypoplasiaAdrenoleukodystrophyAdrenomyeloneuropathy

latrogenicBilateral adrenalectomyDrugs: metyrapone, aminoglutethimide, trilostane,

ketoconazole, o,p¢-DDD, RU-486

Mineralocorticoid Deficiency without GlucocorticoidDeficiencyCorticosterone methyloxidase deficiencyIsolated zona glomerulosa defectHeparin therapyCritical illnessConverting enzyme inhibitors

Secondary Adrenal DisordersSecondary Adrenal InsufficiencyHypothalamic/pituitary dysfunctionExogenous glucocorticoidsAfter removal of an ACTH-secreting tumor

Hyporeninemic HypoaldosteronismDiabetic nephropathyTubulointerstitial diseasesObstructive uropathyAutonomic neuropathyNonsteroidal anti-inflammatory drugsb-Adrenergic drugs

ACTH = adrenocorticotropic hormone.

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hypoplasia, and two demyelinating lipid metabolismdisorders: adrenoleukodystrophy and adrenomyeloneu-ropathy. Iatrogenic causes of adrenal insufficiencyinclude bilateral adrenalectomy, agents that inhibit cor-tisol biosynthesis (metyrapone, aminoglutethimide,trilostane, and ketoconazole), adrenolytic drugs(mitotane [o,p¢-DDD]), and the glucocorticoid antago-nist mifepristone (RU-486).

Addison’s disease may be part of two distinct autoim-mune polyglandular syndromes. Type I polyglandularautoimmune syndrome, also termed autoimmune polyendocrine-candidiasis–ectodermal dystrophy orautoimmune polyglandular failure syndrome, is charac-terized by the triad of hypoparathyroidism, adrenalinsufficiency, and mucocutaneous candidiasis. Other,less common manifestations include hypothyroidism,gonadal failure, gastrointestinal malabsorption, insulin-dependent diabetes mellitus, alopecia areata and totalis,pernicious anemia, vitiligo, chronic active hepatitis, keratopathy, hypoplasia of dental enamel and nails,hypophysitis, asplenism, and cholelithiasis. This syn-drome manifests in childhood. Type II polyglandularautoimmune syndrome, also called Schmidt’s syndrome,is characterized by Addison’s disease, autoimmunethyroid disease (Graves’ disease or Hashimoto’s thy-roiditis), and insulin-dependent diabetes mellitus. Otherassociated diseases include pernicious anemia, vitiligo,gonadal failure, hypophysitis, celiac disease, myastheniagravis, primary biliary cirrhosis, Sjögren’s syndrome,lupus erythematosus, and Parkinson’s disease. This syndrome usually manifests in adults.

Adrenal insufficiency commonly manifests as weightloss, increasing fatigue, vomiting, diarrhea or anorexia,and salt craving. Muscle and joint pain, abdominalpain, and postural dizziness may also occur. Signs ofincreased pigmentation (initially most marked on theextensor surfaces, palmar creases, and buccal mucosa)often occur secondarily to the increased production ofACTH and other POMC-related peptides by the pitu-itary gland. Laboratory abnormalities may includehyponatremia, hyperkalemia, mild metabolic acido-sis, azotemia, hypercalcemia, anemia, lymphocytosis,and eosinophilia. Hypoglycemia may also occur, espe-cially in children.

Acute adrenal insufficiency is a medical emergency,and treatment should not be delayed pending laboratoryresults. In a critically ill patient with hypovolemia, aplasma sample for cortisol, ACTH, aldosterone, andrenin should be obtained, and then treatment with anintravenous bolus of 100mg of hydrocortisone and parenteral saline administration should be initiated. Aplasma cortisol concentration of more than 34mg/dLrules out the diagnosis of adrenal crisis, whereas a valueof less than 20mg/dL in the setting of shock is con-sistent with adrenal insufficiency. A plasma cortisolvalue between 20mg/dL and 34mg/dL in the setting of a severely ill patient may indicate partial adrenalinsufficiency.

In a patient with chronic symptoms, a 1-hour cosyn-tropin test should be performed. In this test, 0.25mgACTH (1–24) (cosyntropin) is given intravenously, andplasma cortisol is measured 0, 30, and 60 minutes later.

A normal response is a plasma cortisol concentrationhigher than 20mg/dL at any time during the test. Apatient with a basal morning plasma cortisol concen-tration of less than 5mg/dL and a stimulated cortisolconcentration below 18mg/dL probably has frankadrenal insufficiency and should receive treatment. Abasal morning plasma cortisol concentration between10 and 18mg/dL in association with a stimulated corti-sol concentration lower than 18mg/dL probably indi-cates impaired adrenal reserve and a requirement forreceiving cortisol replacement under stress conditions(as described later). Recently a 1-mg cosyntropin test toassess partial adrenal insufficiency has been described.This test may identify more patients who need cortisolreplacement under stress conditions, but should not beused to determine which patients need daily cortisol replacement.

Once the diagnosis of adrenal insufficiency is made,the distinction between primary and secondary adrenalinsufficiency needs to be made. Secondary adrenal in-sufficiency results from inadequate stimulation of theadrenal cortex by ACTH. This can result from lesionsanywhere along the HPA axis or as a sequela of pro-longed suppression of the HPA axis by exogenous glu-cocorticoids. Secondary adrenal insufficiency manifestssimilarly to primary adrenal insufficiency with a fewimportant differences: Because ACTH and otherPOMC-related peptides are reduced in secondaryadrenal insufficiency, hyperpigmentation does not occur.In addition, because mineralocorticoid levels are normalin secondary adrenal insufficiency, symptoms of saltcraving, as well as the laboratory abnormalities ofhyperkalemia and metabolic acidosis, are not present.However, hyponatremia is often seen as a result ofincreased antidiuretic hormone (ADH) secretion (result-ing from volume depletion and ADH co-secretion withCRH), which accompanies glucocorticoid insufficiency,resulting in impaired water excretion. Because corti-cotropin is the most preserved of the pituitary hor-mones, a patient with secondary adrenal insufficiencycaused by a pituitary lesion usually has symptomsand/or laboratory abnormalities consistent withhypothyroidism, hypogonadism, or growth hormonedeficiency. To distinguish primary from secondaryadrenal insufficiency, a basal morning plasma ACTHvalue and a standing (upright for at least 2 hours) serumaldosterone level and plasma renin activity should bemeasured. A plasma ACTH value of more than 20pg/mL (normal 5 to 30pg/mL) is consistent withprimary adrenal insufficiency, whereas a value less than20pg/mL probably represents secondary adrenal insuf-ficiency. An upright plasma renin activity of more than3ng/mL/hr in the setting of a suppressed aldosteronelevel is consistent with primary adrenal insufficiency,whereas a value less than 3ng/mL/hr probably re-presents secondary adrenal insufficiency. The 1-hourcosyntropin test is suppressed in both secondary andprimary adrenal insufficiency.

Secondary adrenal insufficiency occurs commonlyafter discontinuation of glucocorticoids. Alternate-dayglucocorticoid treatment, if feasible, results in less sup-pression of the HPA axis than does daily glucocorticoid

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therapy. The natural history of recovery from adrenalsuppression is first a gradual increase in ACTH levels,followed by the normalization of plasma cortisol levelsand then normalization of the cortisol response toACTH. Complete recovery of the HPA axis can take upto 1 year, and the rate-limiting step appears to be re-covery of the CRH neurons.

TREATMENTAfter stabilization of acute adrenal insufficiency,patients with Addison’s disease require lifelong replace-ment therapy with both glucocorticoids and mineralo-corticoids. Unfortunately, most physicians overtreatpatients with glucocorticoids and undertreat them withmineralocorticoids. Because overtreatment with gluco-corticoids results in insidious weight gain and osteo-porosis, the minimal cortisol dose tolerated withoutsymptoms of glucocorticoid insufficiency (usually jointpain) is recommended. An initial regimen of 15 to 20mg of hydrocortisone first thing in the morning and5mg of hydrocortisone at around 4:00 pm mimics thephysiologic dose and is recommended. Whereas gluco-corticoid replacement is fairly uniform in most patients,mineralocorticoid replacement varies greatly. The initialdose of the synthetic mineralocorticoid fludrocortisoneshould be 100mg/day, and dosage should be adjusted tokeep the standing plasma renin activity between 1 and3ng/mL/hour. A standing plasma renin activity higherthan 3ng/mL/hour, while the patient is taking thecorrect glucocorticoid dosage, is suggestive of under-treatment with fludrocortisone.

Under the stress of a minor illness (nausea, vomiting,or fever greater than 100.5°F), the hydrocortisone doseshould be doubled for as short a period of time as pos-sible. The inability to ingest hydrocortisone pills maynecessitate parenteral hydrocortisone administration.Patients undergoing a major stressful event (i.e., surgerynecessitating general anesthesia, or major trauma)should receive 150 to 300mg of parenteral hydrocorti-sone daily (in three divided doses) with a rapid taper tonormal replacement during recovery. All patients shouldwear a medical information bracelet and should beinstructed in the use of intramuscular emergency hydrocortisone injections.

HyporeninemicHypoaldosteronismMineralocorticoid deficiency can result from decreasedrenin secretion by the kidneys. Resultant hypoan-giotensinemia leads to hypoaldosteronism with hyper-kalemia and hyperchloremic metabolic acidosis. Plasmasodium concentration is usually normal, but totalplasma volume is often deficient. Plasma renin andaldosterone levels are low and unresponsive to stimuli.Diabetes mellitus and chronic tubulointerstitial diseasesof the kidney are the most common underlying condi-tions leading to impairment of the juxtaglomerularapparatus. A subset of hyporeninemic hypoaldostero-

nism is caused by autonomic insufficiency and is a frequent cause of orthostatic hypotension. Stimuli such as upright posture or volume depletion, mediatedby baroreceptors, do not cause a normal renin response.Administration of pharmacologic agents such as nons-teroidal anti-inflammatory agents, angiotensin-convert-ing enzyme inhibitors, and b-adrenergic antagonists canalso produce conditions of hypoaldosteronism. Fludro-cortisone and/or the alpha1-agonist midodrine are effec-tive in correcting the orthostatic hypotension andelectrolyte abnormalities caused by hypoaldosteronism.

Congenital AdrenalHyperplasiaCongenital adrenal hyperplasia (CAH) refers to disor-ders of adrenal steroid biosynthesis that result in gluco-corticoid and mineralocorticoid deficiencies. Because ofdeficient cortisol biosynthesis, a compensatory increasein ACTH occurs, inducing adrenal hyperplasia andoverproduction of the steroids that precede blockage of enzyme production (see Fig. 66–1). There are fivemajor types of CAH, and the clinical manifestations ofeach type depend on which steroids are in excess andwhich are deficient. All these syndromes are transmittedin an autosomal recessive pattern. 21-Hydroxylase(CYP21) deficiency is the most common of these disorders and accounts for about 95% of cases of CAH.In this condition, there is a failure of 21-hydroxylationof 17-hydroxyprogesterone and progesterone to 11-deoxycortisol and 11-deoxycortisone, respectively, withdeficient cortisol and aldosterone production. Cortisoldeficiency leads to increased ACTH release, causingoverproduction of 17-hydroxyprogesterone and proges-terone. Increased ACTH production also leads toincreased biosynthesis of androstenedione and DHEA,which can be converted to testosterone. Patients with 21-hydroxylase deficiency can be divided into two clinical phenotypes: classic 21-hydroxylase defi-ciency, usually diagnosed at birth or during childhood,and late-onset 21-hydroxylase deficiency, which manifests during or after puberty. Two thirds of patientswith classic 21-hydroxylase deficiency have variousdegrees of mineralocorticoid deficiency (salt-losingform); the remaining third are not salt losing (simple vir-ilizing form). Both decreased aldosterone productionand increased concentrations of precursors that are mineralocorticoid antagonists (progesterone and 17-hydroxyprogesterone) contribute to salt loss in the salt-losing form, in which the enzymatic block is moresevere.

The most useful measurement for the diagnosis ofclassic 21-hydroxylase deficiency is that of plasma 17-hydroxyprogesterone. A value greater than 200ng/dL isconsistent with the diagnosis. Late-onset 21-hydroxy-lase deficiency represents an allelic variant of classic 21-hydroxylase deficiency and is characterized by a mildenzymatic defect. This is the most frequent autosomalrecessive disorder in humans and is present especially inAshkenazi Jews. The syndrome usually manifests


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around the time of puberty with signs of virilization(hirsutism and acne) and amenorrhea or oligomenor-rhea. It should be considered in women with un-explained hirsutism and menstrual abnormalities orinfertility. The diagnosis is made from the finding of an elevated plasma 17-hydroxyprogesterone level(>1500ng/dL) 30 minutes after administration of 0.25mg of synthetic ACTH (1–24).

The aim of treatment for classic 21-hydroxylase defi-ciency is to replace glucocorticoids and mineralocorti-coids, suppress ACTH and androgen overproduction,and allow for normal growth and sexual maturation in children. A proposed approach to treating classic 21-hydroxylase deficiency recommends physiologicreplacement with hydrocortisone and fludrocortisone inall affected patients, including those with the simple vir-ilizing form. The deleterious effects of excess androgenscan then be prevented by the use of an antiandrogenagent (flutamide) and an aromatase inhibitor (test-olactone) that blocks the conversion of testosterone toestrogen.

Although the traditional treatment for late-onset 21-hydroxylase deficiency is dexamethasone (0.5mg/day),the use of an antiandrogen such as spironolactone (100to 200mg/day) is probably more effective and has fewerside effects. Mineralocorticoid replacement is notneeded in late-onset 21-hydroxylase deficiency.

11b-Hydroxylase (CYP11B1) deficiency accounts forabout 5% of the cases of CAH. In this syndrome, theconversions of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone (the precursor toaldosterone) are blocked. Affected patients usually havehypertension and hypokalemia because of increasedamounts of precursors with mineralocorticoid activity.Virilization occurs, as with 21-hydroxylase deficiency,and a late-onset form manifesting as androgen excessalso occurs. The diagnosis is made from the finding ofelevated plasma 11-deoxycortisol levels, either basallyor after ACTH stimulation.

Rare forms of CAH are 3b-HSD type II, 17a-hydrox-ylase (CYP17), and steroidogenic acute regulatoryprotein deficiencies.

Syndromes ofAdrenocorticoidHyperfunctionHypersecretion of the glucocorticoid hormone cortisolresults in Cushing’s syndrome, a metabolic disorderaffecting carbohydrate, protein, and lipid metabolism.Hypersecretion of mineralocorticoids such as ald-osterone results in a syndrome of hypertension and electrolyte disturbances.

CUSHING’S SYNDROME

PathophysiologyIncreased production of cortisol is seen in both physio-logic and pathologic states (Table 66–3). Physiologic

TABLE 66–3 Syndromes of Adrenocortical Hyperfunction

States of Glucocorticoid ExcessPhysiologic StatesStressStrenuous exerciseLast trimester of pregnancy

Pathologic StatesPsychiatric conditions (pseudo-Cushing’s disorders)

DepressionAlcoholismAnorexia nervosaPanic disordersAlcohol/drug withdrawal

ACTH-dependent statesPituitary adenoma (Cushing’s disease)Ectopic ACTH syndrome

Bronchial carcinoidThymic carcinoidIslet cell tumorSmall cell lung carcinoma

Ectopic CRH secretionACTH-independent states

Adrenal adenomaAdrenal carcinomaMicronodular adrenal disease

Exogenous SourcesGlucocorticoid intakeACTH intake

States of Mineralocorticoid ExcessPrimary AldosteronismAldosterone-secreting adenomaBilateral adrenal hyperplasiaAldosterone-secreting carcinomaGlucocorticoid-suppressible hyperaldosteronism

Adrenal Enzyme Deficiencies11b-hydroxylase deficiency17a-hydroxylase deficiency11b-hydroxysteroid dehydrogenase, type II

Exogenous MineralocorticoidsLicoriceCarbenoxoloneFludrocortisone

Secondary HyperaldosteronismAssociated with hypertension

Accelerated hypertensionRenovascular hypertensionEstrogen administrationRenin-secreting tumors

Without hypertensionBartter’s syndromeSodium-wasting nephropathyRenal tubular acidosisDiuretic/laxative abuseEdematous states (cirrhosis, nephrosis, congestive heart

failure)

ACTH = adrenocorticotropin hormone; CRH = corticotropin-releasing hormone.

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hypercortisolism occurs in stress, during the lasttrimester of pregnancy, and in persons who regularlyperform strenuous exercise. Pathologic conditions ofelevated cortisol levels include exogenous or endoge-nous Cushing’s syndrome and several psychiatric states,including depression, alcoholism, anorexia nervosa,panic disorder, and alcohol or narcotic withdrawal.

Cushing’s syndrome may be caused by exogenousACTH or glucocorticoid administration or by endoge-nous overproduction of these hormones. EndogenousCushing’s syndrome is either ACTH dependent orACTH independent. ACTH dependency accounts for85% of cases and includes pituitary sources of ACTH(Cushing’s disease), ectopic sources of ACTH, and, inrare instances, ectopic sources of CRH. PituitaryCushing’s disease accounts for 80% of cases of ACTH-dependent Cushing’s syndrome. Ectopic secretion ofACTH occurs most commonly in patients with smallcell lung carcinoma. These patients are older, usuallyhave a history of smoking, and present primarily withsigns and symptoms of lung cancer rather than ofCushing’s syndrome. Patients with the clinically appar-ent ectopic ACTH syndrome, in contrast, have mostlyintrathoracic (lung and thymic) carcinoids. The remain-ing patients have pancreatic, adrenal, or thyroid tumorsthat secrete ACTH. ACTH-independent causes accountfor 15% of cases of Cushing’s syndrome and includeadrenal adenomas, adrenal carcinomas, micronodularadrenal disease, and autonomous macronodular adrenaldisease. The female-to-male ratio for noncancerousforms of Cushing’s syndrome is 4 :1.

Clinical ManifestationsThe clinical signs, symptoms, and common laboratoryfindings of hypercortisolism seen in patients withCushing’s syndrome are listed in Table 66–4. Typicallythe obesity is centripetal, with a wasting of the arms andlegs; this is distinct from the generalized weight gainseen in idiopathic obesity. Rounding of the face (so-called moon facies) and a dorsocervical fat pad(“buffalo hump”) may occur in obesity that is notrelated to Cushing’s syndrome, whereas facial plethoraand supraclavicular filling are more specific forCushing’s syndrome. Patients with Cushing’s syndromemay have proximal muscle weakness, so the physicalfinding of inability to stand up from a squat can be quiterevealing. Menstrual irregularities often precede othercushingoid symptoms in affected women, whereasaffected men frequently complain of poor libido andimpotence. Adult-onset acne or hirsutism in womenshould also raise the suspicion of Cushing’s syndrome.The skin striae seen in cushingoid patients are violaceous (purple or dark red), with a width of at least 1cm. Thinning of the skin on the top of the handsis a very specific sign in younger adults with Cushing’ssyndrome and should always be examined. Old picturesof patients are extremely helpful for evaluating the progression of the physical stigmata of Cushing’s syndrome.

Associated laboratory findings in Cushing’s syndrome include elevated plasma alkaline phosphatase

levels, granulocytosis, thrombocytosis, hypercholes-terolemia, hypertriglyceridemia, and glucose intoler-ance/diabetes mellitus. Hypokalemic alkalosis is an infrequent finding in patients with Cushing’s syndrome and usually occurs in patients with severe hypercortisolism as a result of the ectopic ACTH syndrome.

Diagnosis (Fig. 66–4)

If the history and physical examination findings are sug-gestive of hypercortisolism, the diagnosis of Cushing’ssyndrome can usually be established by collecting urinefor 24 hours and measuring urinary free cortisol (UFC).UFC excretion reflects plasma unbound cortisol that isfiltered and excreted by the kidney. This test is extremelysensitive for the diagnosis of Cushing’s syndromebecause, in 90% of affected patients, the initial UFClevel is greater than 50mg/24 hours when measured byHPLC or mass spectroscopy cortisol assays. Patientswith Cushing’s disease usually have UFC levels between100 and 500mg/24 hours, whereas patients with theectopic ACTH syndrome and cortisol-secreting adrenaladenomas or carcinomas frequently have UFC levelsgreater than 500mg/24 hours.

Cortisol normally is secreted in a diurnal manner; theplasma concentration is highest in the early morning


TABLE 66–4 Signs, Symptoms, and Laboratory Abnormalities of Hypercortisolism

Fat redistribution (dorsocervical and supraclavicular fat pads,temporal wasting, centripetal obesity, weight gain) (95%)

Menstrual irregularities (80% of affected women)Thin skin/plethora (80%)Moon facies (75%)Increased appetite (75%)Sleep disturbances (75%)Hypertension (75%)Hypercholesterolemia/hypertrigliceridemia (70%)Altered mentation (poor concentration, decreased memory,

euphoria) (70%)Diabetes mellitus/glucose intolerance (65%)Striae (65%)Hirsutism (65%)Proximal muscle weakness (60%)Psychological disturbances (emotional lability, depression,

mania, psychosis) (50%)Decreased libido/impotence (50%)Acne (45%)Osteoporosis/pathologic fractures (40%)Virilization (in women) (40%)Easy bruisability (40%)Poor wound healing (40%)Edema (20%)Increased infections (10%)Cataracts (5%)

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History and physical consistentwith hypercortisolism

Urinary free cortisol (UFC)Low-dose dexamethasone test

UFC normalSuppression to low-dose

dexamethasone

UFC elevatedNo suppression to low-

dose dexamethasone

Cushing syndromeunlikely

Cushing syndrome likely;proceed to differential

diagnosis

ACTH suppressed ACTH normal or elevated

Adrenal tumor likely

UnilateralAdrenalectomy

Cushing disease (pituitaryadenoma) or ectopic ACTH

syndrome

Negative results

Ectopic ACTH syndrome

If Tumor is Localized,Surgical Removal of Tumor

Increase in cortisol/ACTH after oCRH

Suppression during the high-dosedexamethasone test

Central to peripheral ACTH gradient afteroCRH administration in BIPSS

Cushing disease

Transsphenoidal Surgery

Differentialdiagnosis

Diagnosis

Measure plasma ACTH

oCRH-stimulation test and/orhigh-dose dexamethasone test and/or

bilateral inferior petrosal sinussampling (BIPSS) with oCRH

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-night. The normal 8:00 am plasma cortisol level rangesbetween 8 and 25mg/dL and declines throughout theday. By 11:00 pm, the values are usually less than 5mg/dL. Most patients with Cushing’s syndrome lackthis diurnal variation. Thus, although their morningcortisol levels may be normal, their afternoon or evening

concentrations are markedly higher. Late afternoon ornight values greater than 50% of the morning values areconsistent with Cushing’s syndrome. Measurement ofrandom morning cortisol levels is not particularlyhelpful.

The overnight dexamethasone suppression test canalso be used as a screening test to evaluate patients sus-

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pected of having hypercortisolism. Dexamethasone, 1mg, is given orally at 11:00 pm, and plasma cortisol ismeasured the following morning at 8:00 am. A morningplasma cortisol level greater than 3mg/dL suggestshypercortisolism. This test is easy and can be performedin an outpatient setting. The test is fairly sensitive,although some pituitary adenomas are very sensitive todexamethasone and can suppress cortisol productionreadily in this test. However, the test produces a signif-icant number of false-positive results, especially in obeseand depressed patients, the two patient populations inwhom the differentiation from mild Cushing’s syndromemay be difficult. For these reasons, collection of urinefor measurement of 24-hour UFC excretion is a betterscreening test.

Differential DiagnosisOnce the diagnosis of Cushing’s syndrome is estab-lished, the etiology of the hypercortisolism needs to beascertained. This is accomplished by biochemicalstudies, which evaluate the feedback regulation of theHPA axis; by venous sampling techniques; and byimaging procedures. Basal ACTH levels are normal orelevated in Cushing’s disease and the ectopic ACTH syndrome and are suppressed in primary adrenalCushing’s syndrome.

In the dexamethasone suppression test (Liddle test),0.5mg of dexamethasone is given orally every 6 hoursfor 2 days, followed by 2mg of dexamethasone every 6hours for another 2 days. On the second day of the highdosage of dexamethasone, UFC is suppressed to lessthan 10% of that of the baseline collection in patientswith pituitary adenomas but not in patients with theectopic ACTH syndrome or adrenal cortisol-secretedtumors. Although the Liddle test is often helpful inestablishing the etiology of Cushing’s syndrome, it hassome disadvantages. The test requires accurate meas-urement of urine collections, often necessitating inpa-tient hospitalization. In approximately 50% of patientswith bronchial carcinoids causing ectopic ACTH pro-duction, cortisol secretion is suppressible by high-dosedexamethasone, which yields a false-positive result. Inaddition, because patients with Cushing’s syndrome areoften episodic secretors of corticosteroids, considerablevariation in daily UFC excretion can occur and falseresults can be obtained. Therefore, the Liddle testshould be interpreted cautiously and other confirmatorytests should be performed before a patient is sent tosurgery.

An overnight high-dose dexamethasone suppressiontest is helpful in establishing the etiology of Cushing’ssyndrome. In this test, a baseline 8:00 am cortisol levelis measured, and then 8mg of dexamethasone is givenorally at 11:00 pm. At 8:00 am the following morning,a plasma cortisol measurement is obtained. Suppression,which would occur in patients with pituitary Cushing’sdisease, is defined as a decrease in plasma cortisol to lessthan 50% of the baseline level. Few patients withbronchial carcinoid have been examined, so the suppressibility of these tumors by high-dose overnightdexamethasone is not well established.


The ovine CRH (oCRH) test and bilateral simulta-neous inferior petrosal sinus sampling are also used toestablish the etiology of Cushing’s syndrome. Pituitarycorticotrophs of normal persons and of patients withpituitary Cushing’s disease respond to oCRH by increas-ing the secretion of ACTH and, therefore, cortisol. Thusthe oCRH test cannot be used to distinguish normalpersons from patients with pituitary Cushing’s disease.Patients with cortisol-secreting adrenal tumors have lowor undetectable concentrations of ACTH that do notrespond to oCRH. Patients with ectopic ACTH secre-tion have high basal ACTH levels that do not increasewith oCRH. In patients with both the ectopic ACTHsyndrome and primary adrenal hypercortisolism, cortisol levels do not change in response to oCRH. Dis-crepancies between the oCRH and dexamethasone tests necessitate further work-up for ascertainment ofthe diagnosis.

Bilateral inferior petrosal sinus sampling (BIPSS) isan accurate and safe procedure for distinguishing pituitary Cushing’s disease from the ectopic ACTH syndrome. Venous blood from the anterior lobe of thepituitary gland empties into the cavernous sinuses andthen into the superior and inferior petrosal sinuses.Venous plasma samples for ACTH determination areobtained from both inferior petrosal sinuses, along witha simultaneous peripheral sample, both before and afterintravenous bolus administration of CRH. In baselinemeasurements, an ACTH concentration gradient of 1.6or more between a sample from either of the petrosalsinuses and the peripheral sample is strongly suggestiveof pituitary Cushing’s disease, whereas patients withectopic ACTH syndrome or adrenal adenomas have noACTH gradient between their petrosal and peripheralsamples. After CRH administration, a central-to-peripheral gradient of more than 3.2 is consistent withpituitary Cushing’s disease. The use of CRH has enabledcomplete distinction of pituitary Cushing’s disease fromnonpituitary Cushing’s syndrome. An ACTH gradientipsilateral to the side of the tumor is found in 70 to 80%of patients sampled. Although BIPSS requires a radiol-ogist experienced in petrosal sinus sampling, it is cur-rently available at many tertiary care facilities.

Imaging of the pituitary gland by magnetic resonanceimaging (MRI) with gadolinium is the preferred proce-dure for localizing a pituitary adenoma. This test detectsapproximately 50 to 60% of pituitary ACTH-secretingtumors and can detect many pituitary tumors as smallas 3mm in diameter. About 10% of normal individualsmay have a nonfunctioning pituitary adenoma found on pituitary MRI. It is therefore recommended that pituitary imaging not be the sole criterion for the diag-nosis of pituitary Cushing’s disease.

TreatmentThe preferred treatment for all forms of Cushing’s syn-drome is appropriate surgery. Pituitary Cushing’sdisease is best treated by transsphenoidal surgery. Whenthe operation is performed by an experienced neuro-surgeon, the cure rate is higher than 90%. Transsphe-noidal surgery carries very low rates of morbidity and

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mortality. Complications (e.g., meningitis, cerebrospinalfluid leakage, optic nerve damage, isolated thyrotropinor growth hormone deficiency) are rare. In patients withthe ectopic ACTH syndrome, it is hoped that the tumoris localized by appropriate scans and then removed sur-gically. A unilateral adrenalectomy is the treatment ofchoice in patients with a cortisol-secreting adrenaladenoma. Patients with cortisol-secreting adrenal carci-nomas should also be managed surgically; however, theyhave a poor prognosis, with only 20% surviving morethan 1 year after diagnosis.

Patients who have failed initial pituitary surgery orhave recurrent Cushing’s disease may be treated witheither pituitary irradiation or bilateral adrenalectomy.Irradiation has more long-term complications than doestranssphenoidal surgery, and results in cure in about60% of patients, but it may take up to 5 years to rendera person eucortisolemic. Panhypopituitarism eventuallydevelops in almost all these patients, and so growthhormone, thyroid, gonadal, and even steroid replace-ment may be needed. A more appealing option forpatients with Cushing’s disease who remain hypercor-tisolemic after pituitary surgery is bilateral adrena-lectomy, followed by lifelong glucocorticoid andmineralocorticoid replacement therapy. About 10% ofpatients with Cushing’s disease who undergo bilateraladrenalectomy develop Nelson’s syndrome (hyperpig-mentation and an ACTH-secreting macroadenoma thatoften causes visual field deficits). The incidence ofNelson’s syndrome is reduced if patients have under-gone pituitary irradiation. Patients who undergo bilat-eral adrenalectomy may, on rare occasions, developadrenal rest tissue leading to recurrence of Cushing’ssyndrome.

Medical treatment for hypercortisolism may beneeded to prepare patients for surgery, in patients whoare undergoing or have undergone pituitary irradiationand are awaiting its effects, or in patients who are notsurgical candidates or who elect not to have surgery.Ketoconazole, o,p¢-DDD, metyrapone, aminog-lutethimide, RU-486, and trilostane are the most commonly used agents for adrenal blockade and can beused alone or in combination.

PRIMARY MINERALOCORTICOID EXCESS

PathophysiologyIncreased mineralocorticoid activity is manifested bysalt retention, hypertension, hypokalemia, and meta-bolic alkalosis. The causes of primary aldosteronism(see Table 66–3) are aldosterone-producing adenoma(75%), bilateral adrenal hyperplasia (25%), adrenalcarcinoma (1%), and glucocorticoid-remediable hyper-aldosteronism (<1%). The adrenal enzyme defects—11b-HSD type II, 11b-hydroxylase, and 17a-hydroxylase deficiencies—and apparent mineralocorti-coid excess (from licorice or carbenoxolone ingestion,which inhibits 11b-HSD type II, or from a congenitaldefect in this enzyme) are also states of functional min-eralocorticoid overactivity. Secondary aldosteronism(see Table 66–3) results from overactivation of therenin-angiotensin system.

Primary aldosteronism is usually recognized duringevaluation of hypertension or hypokalemia and repre-sents a potentially curable form of hypertension. Up to5% of patients with hypertension have primary aldos-teronism. The patients are usually between 30 and 50years of age, and the female-to-male ratio is 2 :1.

Clinical ManifestationsHypertension, hypokalemia, and metabolic alkalosis arethe main clinical manifestations of hyperaldosteronism;most of the presenting symptoms are related tohypokalemia. Symptoms in mildly hypokalemic patientsare fatigue, muscle weakness, nocturia, lassitude, andheadaches. If more severe hypokalemia exists, poly-dipsia, polyuria, paresthesias, and even intermittentparalysis and tetany can occur. Blood pressure can rangefrom being minimally elevated to very high. Retinopa-thy is mild, and hemorrhages are rarely present. A pos-itive Trousseau or Chvostek sign may occur as a resultof metabolic alkalosis.

Diagnosis and TreatmentInitially, hypokalemia in the presence of hypertensionmust be documented (Fig. 66–5). The patient must havean adequate salt intake and discontinue diuretics beforepotassium measurement. If hypokalemia is found underthese conditions, spironolactone should be stopped (ifthe patient is taking it) and a morning plasma aldos-terone level and a plasma renin activity (PRA) shouldbe measured. A serum aldosterone/PRA ratio >20ng/dLper ng/mL/hr and a serum aldosterone level >15ng/dLsuggest the diagnosis of hyperaldosteronism.

Once the diagnosis of primary aldosteronism hasbeen demonstrated, it is important to distinguishbetween an aldosterone-producing adenoma and bilat-eral hyperplasia, because the former is treated withsurgery and the latter is treated medically. In the initialtest (a postural challenge), an 8:00 am supine bloodsample is drawn for plasma aldosterone, 18-hydrocor-ticosterone, renin, and cortisol measurement. Thepatient then stands for 2 hours, and an upright sampleis drawn for measurement of the same hormones. Abasal plasma aldosterone level of less than 20ng/dL isusually found in patients with bilateral hyperplasia, anda value greater than 20ng/dL suggests the diagnosis ofadrenal adenoma. In bilateral hyperplasia, plasmaaldosterone often increases as a result of the increase inrenin in response to the upright position, whereas, inadenoma, plasma aldosterone levels usually fall as aresult of decreased stimulation by ACTH at 10:00 am,in comparison with 8:00 am. An 8:00 am plasma 18-hydroxycorticosterone level of greater than 50ng/dLthat falls with upright posture occurs in most patientswith an adenoma, whereas an 8:00 am level less than 50ng/dL that rises with upright posture occursin most patients with bilateral hyperplasia.

A computed tomography (CT) scan of the adrenalglands should be performed to localize the tumor. If adiscrete adenoma is seen in one adrenal gland, the con-tralateral gland is normal, and biochemical test resultsare consistent with an adenoma, the patient should

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undergo unilateral adrenalectomy. Patients in whombiochemical study findings are consistent with anadenoma but CT results are consistent with bilateraldisease should undergo adrenal venous sampling foraldosterone and cortisol measurement. Patients inwhom biochemical and localization study findings areconsistent with bilateral hyperplasia should be treatedmedically, usually with spironolactone. Those in whombiochemical study results are consistent with bilateralhyperplasia should also be evaluated for dexametha-sone-suppressible hyperaldosteronism by receiving atrial of dexamethasone, which reverses the hyperaldos-teronism in this rare autosomal dominant disorder.

Hyperaldosteronism and hypertension secondary to activation of the renin-angiotensin system can occur in patients with accelerated hypertension, thosewith renovascular hypertension, those receiving estrogen therapy, and, rarely, patients with renin-secreting tumors. Hyperaldosteronism without hyper-tension occurs in patients with Bartter’s syndrome, thosewith sodium-wasting nephropathy, those with renaltubular acidosis, and those who abuse diuretics or laxatives.

Adrenal MedullaryHyperfunctionThe adrenal medulla synthesizes the catecholaminesnorepinephrine, epinephrine, and dopamine from theamino acid tyrosine. Norepinephrine, the major cate-cholamine produced by the adrenal medulla, has pre-dominantly a-agonist actions, causing vasoconstriction.Epinephrine acts primarily on the b-receptors, havingpositive inotropic and chronotropic effects on the heart,causing peripheral vasodilation, and increasing plasmaglucose concentrations in response to hypoglycemia.The action of circulating dopamine is unclear. Whereasnorepinephrine is synthesized in the central nervoussystem and sympathetic postganglionic neurons, epi-nephrine is synthesized almost entirely in the adrenalmedulla. The adrenal medullary contribution to norep-inephrine secretion is relatively small. Bilateral adrena-lectomy results in only minimal changes in circulatingnorepinephrine levels, although epinephrine levels aredramatically reduced. Thus hypofunction of the adrenalmedulla has little physiologic impact, whereas hyper-secretion of catecholamines produces the clinical syndrome of pheochromocytoma.

PHEOCHROMOCYTOMA

PathophysiologyAlthough pheochromocytomas can occur in any sym-pathetic ganglion in the body, more than 90% ofpheochromocytomas arise from the adrenal medulla.The majority of extra-adrenal tumors occur in the medi-astinum or abdomen. Bilateral adrenal pheochromocy-tomas occur in about 5% of the cases and may occuras part of familial syndromes. Pheochromocytomaoccurs as part of multiple endocrine neoplasia type IIAor IIB. The former (Sipple’s syndrome) is marked bymedullary carcinoma of the thyroid, hyperparathy-roidism, and pheochromocytoma; the latter is charac-terized by medullary carcinoma of the thyroid, mucosalneuromas, intestinal ganglioneuromas, marfanoidhabitus, and pheochromocytoma. Pheochromocytomasare also associated with neurofibromatosis, cere-belloretinal hemangioblastosis (von Hippel-Lindaudisease), and tuberous sclerosis.

Clinical ManifestationsBecause the majority of pheochromocytomas secretenorepinephrine as the principal catecholamine, hyper-tension (often paroxysmal) is the most common finding.Other symptoms include the triad of headache, palpita-tions, and sweating, as well as flushing, anxiety, nausea,fatigue, weight loss, and abdominal and chest pain.These symptoms may be precipitated by emotionalstress, exercise, anesthesia, abdominal pressure, orintake of tyramine-containing foods. Orthostatichypotension can also occur. Wide fluctuations in bloodpressure are characteristic, and the hypertension associated with pheochromocytoma usually does not


Hypertension

Measure plasma K+

Plasma aldosterone/plasma renin activity

Supine and upright plasmaaldosterone and

18-hydroxycorticosterone

Mildly elevated plasmaaldosterone and

18-hydroxycorticosterone,which increase on standing

Substantially elevated plasmaaldosterone and

18-hydroxycorticosterone,which decrease on standing

Bilateral adrenal hyperplasia Adrenal adenoma

Medical Treatment(Spironolactone)

UnilateralAdrenalectomy

Low

Suspect hyperaldosteronism

Aldosterone/plasma renin activity > 20 ng/dL

Primary aldosteronism

ng/mL/hrand serum aldosterone > 15 ng/dL

FIGURE 66–5 Flow chart for evaluating a patient with suspectedprimary hyperaldosteronism.

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respond to standard antihypertensive medicines.Cardiac abnormalities, as well as idiosyncratic reactionsto medications, may also occur.

Diagnosis and TreatmentPlasma free metanephrine and normetanephrine levelsare the best test for confirming or excluding pheochro-mocytoma because the metabolism of catecholamines to free metanephrines is independent of catechola-mine release and can be performed in the absence of hypertension and other symptoms. A plasma freemetanephrine level greater than 0.61nmol/L and aplasma free normetanephrine level greater than 0.31nmol/L are consistent with the diagnosis of apheochromocytoma. 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, andplasma catecholamines (including free metanephrineand normetanephrine) are measured before and 3 hoursafter administration. In normal persons, catecholaminelevels decrease into the normal range, whereas, inpatients with a pheochromocytoma, levels areunchanged or increase. Once the diagnosis ofpheochromocytoma is made, a CT scan of the adrenalglands should be performed. Most intra-adrenalpheochromocytomas are readily visible on this scan. Ifthe CT scan is negative, extra-adrenal pheochromocy-tomas can often be localized by iodine-131–labeledmetaiodobenzylguanidine (131I-MIBG), positron emis-sion tomography, octreotide scan, or abdominal MRI.

The treatment of pheochromocytoma is surgical ifthe lesion can be localized. Patients should undergo pre-operative a-blockade with phenoxybenzamine 1 to 2weeks before surgery. b-Adrenergic antagonists shouldbe used prior to or during surgery. Approximately 5 to10% of pheochromocytomas are malignant. 131I-MIBGor chemotherapy may be useful, but the prognosis ispoor. a-Methyl-p-tyrosine (an inhibitor of tyrosinehydroxylase, the rate-limiting enzyme in catecholaminebiosynthesis) may be used to decrease catecholaminesecretion from the tumor.

INCIDENTAL ADRENAL MASSClinically inapparent adrenal masses are discoveredinadvertently in the course of diagnostic testing or

treatment for other clinical conditions that are notrelated to suspicion of adrenal disease and, thus, arecommonly known as “incidentalomas.” All patientswith an incidentaloma should have a 1-mg dexametha-sone suppression test and measurement of urine orplasma free metanephrines. Patients with hypertensionshould also undergo measurement of serum potassiumlevel and plasma aldosterone concentration/plasmarenin activity ratio. Surgery should be considered in allpatients with functional adrenal cortical tumors that arehormonally active or greater than 5cm. Tumors notassociated with hormonal secretion or less than 5cmcan be followed with repeat imaging and hormonalassessment.

PROSPECTUS FOR THE FUTURE• An appreciation of the role of tissue-specific, intracellular glu-

cocorticoid excess in common diseases such as osteoporosis,depression, cardiovascular disease, diabetes, and hyperten-sion

• Selective adrenal adenomectomy sparing normal adrenaltissue

• An appreciation of the importance of mild (subclinical) adrenalinsufficiency and excess

REFERENCESFindling JW, Raff H: Diagnosis and differential diagnosis of Cushing’s

syndrome. Endocrinol Metab Clin North Am 2001;30:729–747.Merke DP, Bornstein SR, Avila NA, Chrousos GP: NIH conference:

Future directions in the study and management of congenitaladrenal hyperplasia due to 21-hydroxylase deficiency. Ann InternMed 2002;136:320–334.

Newell-Price J, Trainer P, Besser M, Grossman A: The diagnosis anddifferential diagnosis of Cushing’s syndrome and pseudo-Cushing’sstates. Endocr Rev 1998;19:647–672.

Pacak K, Linehan WM, Eisenhofer G, et al: Recent advances in genet-ics, diagnosis, localization, and treatment of pheochromocytoma.Ann Intern Med 2001;134:315–329.

Ten S, New M, Maclaren N: Clinical review 130: Addison’s disease2001. J Clin Endocrinol Metab 2001;86:2909–2922.

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The Adrenal Gland - good hormone healthgoodhormonehealth.com/adrenal-cecils.pdfChapter66 The Adrenal Gland Theodore C. Friedman 603 Physiology The adrenal glands lie at the superior