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REVIEW ARTICLE

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duction of cortisol by abnormal adrenocortical tissue causes the syndrome and suppresses the secretion of both CRH and corticotropin. Corticotropin-Dependent Cushing’s Syndrome

CUSHING’S SYNDROME DAVID N. ORTH, M.D.

H

ARVEY W. Cushing’s 1932 description1 of the syndrome that results from long-term exposure to glucocorticoids has not been improved upon, but our understanding of its pathophysiologic features and our ability to diagnose and treat the disorder have increased dramatically. NORMAL HYPOTHALAMIC–PITUITARY–ADRENAL PHYSIOLOGY Corticotropin-releasing hormone (CRH)2 is synthesized in the hypothalamus and carried to the anterior pituitary in portal blood (Fig. 1). CRH, whose secretion is regulated by a variety of neurotransmitters,3 is the most potent regulator of corticotropin secretion. Arginine vasopressin and other hypothalamic agents also stimulate corticotropin secretion.4,5 Corticotropin is synthesized as a large precursor, pro-opiomelanocortin (POMC), which is processed post-translationally into several peptides, including corticotropin, b-lipotropin, and b-endorphin, that are secreted together.6 Except for corticotropin, which stimulates the adrenal cortex to produce cortisol (Fig. 1), the physiologic roles of these peptides are unclear. Cortisol is called a glucocorticoid because it stimulates the catabolism of peripheral fat and protein to provide substrates for hepatic glucose production. It also has antiinflammatory effects and modulates the response to stress.7 Cortisol inhibits the biosynthesis and secretion of CRH and corticotropin5,8-11 in a classic example of negative-feedback regulation by hormones (Fig. 1). PATHOPHYSIOLOGIC FEATURES OF CUSHING’S SYNDROME Cushing’s syndrome can be separated into the categories of corticotropin-dependent Cushing’s syndrome, in which inappropriately high plasma corticotropin concentrations stimulate the adrenal cortex to produce excessive amounts of cortisol, and corticotropin-independent Cushing’s syndrome, in which excessive proFrom the Division of Endocrinology, Department of Medicine, Vanderbilt Medical Center North, Nashville. Supported by research grants (DK-33334, DK-46070, and RR-00095) from the National Institutes of Health. Dr. Orth is a principal in the IgG Corporation, Nashville, which produces and markets the IgG–ACTH-1 anticorticotropin serum used to generate the corticotropin radioimmunoassay data reported by his laboratory and that of the National Institute of Child Health and Human Development, National Institutes of Health, in all the articles from those laboratories cited in this review.

Cushing’s Disease

The term “Cushing’s disease” is reserved for Cushing’s syndrome caused by excessive secretion of corticotropin by pituitary corticotroph tumors. It is the most common form of the syndrome (Table 1). The tumors are usually microadenomas (1 cm in diameter).16,17 Macroadenomas are rare, and corticotroph hyperplasia1,17 and carcinomas18-20 are extremely rare. The adenomas arise from a single progenitor cell.21 Chronic CRH hypersecretion causes corticotroph hyperplasia,22,23 but not adenomas.24 Hypersecretion of corticotropin from corticotroph adenomas causes bilateral adrenocortical hyperplasia, and the resulting hypercortisolemia suppresses both CRH secretion25 and the secretion of corticotropin by normal corticotrophs (Fig. 1). In some patients, especially those with chronic Cushing’s disease, macronodular adrenal hyperplasia develops; the plasma cortisol concentrations of such patients do not differ from those of patients with diffuse hyperplasia, but their plasma concentrations of corticotropin may be low.26 Patients with Cushing’s disease usually have exaggerated plasma corticotropin and cortisol responses to CRH stimulation and incompletely suppressed secretion of corticotropin and cortisol by glucocorticoids (e.g., dexamethasone).12,25,27-30 These phenomena suggest that the adenoma cells are relatively resistant to glucocorticoids31 and unusually sensitive to CRH.32 However, whereas the absolute increment in the plasma corticotropin concentration is increased after CRH stimulation, basal secretion of corticotropin is increased as well, and the fractional increase is often normal. The fractional decrease in corticotropin secretion induced by dexamethasone is also often normal. Thus, these phenomena may simply reflect an increased number of corticotropin-secreting cells25,33 rather than abnormal regulation of the secretion of corticotropin in individual cells. About 10 percent of patients with microadenomas do not have substantial increases in plasma corticotropin concentrations in response to CRH, presumably because the clonal adenoma cells lack the necessary receptor or postreceptor mechanism.25,34,35 Ectopic Corticotropin Syndrome

The acute ectopic corticotropin syndrome (i.e., the rapid onset of hypertension, edema, hypokalemia, and glucose intolerance) is most often associated with smallcell lung carcinoma.36,37 Because the syndrome may cause only mild hypokalemia and occurs in patients with rapidly progressive cancer,37 it is the most underdiagnosed form of Cushing’s syndrome. Small-cell lung carcinoma accounts for about three quarters of all cases of ectopic corticotropin secretion. The chronic syn-

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Tumor CRH

CRH

CRH

CRH

CRH

Ectopic CRH Tumor Corticotropin

Cortisol

Corticotropin

Cortisol

Corticotropin

Cortisol

Corticotropin

Cortisol

Tumor

Tumor

Ectopic corticotropin

CRH

CRH

CRH

CRH

CRH

Dexamethasone

Dexamethasone

Dexamethasone

Dexamethasone

Dexamethasone

Corticotropin

Cortisol

Ectopic CRH Corticotropin

Cortisol

Cortisol

Corticotropin

Cortisol

Corticotropin

Cortisol

Corticotropin

Cortisol

Corticotropin

Ectopic corticotropin

Normal

Cushing’s Disease

Ectopic Corticotropin Syndrome

Ectopic CRH Syndrome

Adrenal Cushing’s Syndrome

Figure 1. Physiologic and Pathophysiologic Features of the Hypothalamic–Pituitary–Adrenal Axis in Normal Subjects and Patients with Cushing’s Syndrome (Top Panels) and the Effect of Dexamethasone (Bottom Panels). Stimulation of the hypothalamus by other central nervous system centers, such as the locus caeruleus, regulates the secretion of CRH; corticotropin stimulates adrenal secretion of cortisol; and cortisol inhibits the secretion of both CRH and corticotropin. Adrenal (i.e., corticotropin-independent) Cushing’s syndrome is caused by adrenal tumors and corticotropin-independent bilateral micronodular and macronodular adrenal hyperplasia. Low doses of dexamethasone are shown by thin blue arrows, and high doses by thick blue arrows. Normal hormone secretion is shown by thin purple lines, suppressed secretion by dotted purple lines, and hypersecretion by thick purple lines.

drome, clinically indistinguishable from Cushing’s disease but much less common (Table 1), is associated with indolent tumors. They are generally bronchial carcinoids but can be thymic or pancreatic carcinoids, medullary carcinomas of the thyroid, pheochromocytomas, or other neuroendocrine tumors.37 Corticotropin secreted by the nonpituitary tumor causes bilateral adrenal hyperplasia and hyperfunction, and CRH and pituitary secretion of corticotropin are suppressed (Fig. 1). Tumor secretion of corticotropin is usually not suppressed by glucocorticoids,38 even though most tumor cells presumably contain glucocorticoid receptors. The fact that the secretion of corticotropin cannot be suppressed in these tumors has long been used clinically to differentiate them from pituitary adenomas.24 Unfortunately, secretion of corticotropin from perhaps half of bronchial carcinoids is suppressed by high doses of glucocorticoid.35,39,40 Many normal tissues contain POMC messenger RNA (mRNA) and peptides,41-43 so that corticotropin secretion by tumors could be merely inappropriate.44 POMC mRNA from an ectopic tumor is usually longer than normal POMC mRNA,45,46 however,

suggesting that ectopic secretion of corticotropin does not result from inappropriately high, but otherwise normal, gene expression. Ectopic CRH Syndrome

The ectopic CRH syndrome, a very rare cause of Cushing’s syndrome (Table 1),24,25 is clinically indistinguishable from the ectopic corticotropin syndrome. In patients with the former, plasma CRH concentrations should be elevated47-49 and CRH-stimulated secretion of corticotropin should be suppressible with high doses of dexamethasone (Fig. 1).50-52 In many putative cases of ectopic CRH syndrome, however, these features have not been observed,48,49,52-55 perhaps because most47,48,52,55 of these tumors, but not all,49,53,54 also secrete corticotropin. Most cases of ectopic CRH secretion have been associated with bronchial carcinoid tumors.47,55-57 Pseudo –Cushing’s Syndrome

Patients with certain nonendocrine disorders may have some of the clinical or biochemical manifesta-

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Table 1. Relative Prevalence of Various Types of Cushing’s Syndrome among 630 Patients Studied at Different Times.* PERCENT OF PATIENTS

DIAGNOSIS

Corticotropin-dependent Cushing’s syndrome Cushing’s disease Ectopic corticotropin syndrome Ectopic CRH syndrome Corticotropin-independent Cushing’s syndrome Adrenal adenoma Adrenal carcinoma Micronodular hyperplasia Macronodular hyperplasia Pseudo–Cushing’s syndrome Major depressive disorder Alcoholism

68 12 1 10 8 1 1 1 1

*Data are based on a study of 146 consecutive patients seen at Vanderbilt University Medical Center before 1993 and on published reports describing a total of 484 patients.12-14 Because these and most other published series were reported by major referral centers, the proportion of patients with unusual diagnoses may be exaggerated as compared with that of patients with more common diagnoses. The prevalence of pseudo–Cushing’s syndrome depends largely on the individual physician’s threshold of clinical suspicion. The proportions of children and adolescents with the different causes of Cushing’s syndrome may differ slightly from the proportions of adults15; for example, the ectopic corticotropin syndrome is less common in children.

tions of Cushing’s syndrome, the presence of which may on occasion cause diagnostic confusion (Table 1). As many as 80 percent of patients with major depressive disorder have abnormally regulated cortisol secretion,58-60 but cortisol hypersecretion, when present, is usually minimal. Occasional patients (e.g., middleaged women with obesity, hypertension, diabetes, and severe depression) may be thought to have Cushing’s syndrome with secondary depression. Their hormonal abnormalities, which may be difficult to distinguish from those typical of Cushing’s disease, presumably result from hyperactivity of the hypothalamic–pituitary–adrenal axis60 and disappear with the remission of depression.61 Chronic alcoholism is an even more uncommon cause of pseudo–Cushing’s syndrome (Table 1).62-64 Patients with chronic alcoholism may appear clinically to have Cushing’s syndrome, but they also have liver dysfunction. Their hormonal abnormalities disappear rapidly during abstinence from alcohol as their liver function returns to normal. The mechanism of the hormonal abnormality may involve either increased CRH secretion or impaired hepatic metabolism of cortisol.65 Corticotropin-Independent Cushing’s Syndrome Adrenocortical Tumors

Benign or malignant adrenocortical tumors are the most common cause of corticotropin-independent Cushing’s syndrome (Table 1).24,66,67 There is no evidence that corticotropin-independent adrenocortical tumors arise as a result of chronic hypersecretion of corticotropin.24 Adrenal carcinomas may secrete cortisol in response to agonists not under the inhibitory control of glucocorticoids.68 These tumors are relatively inefficient at synthesizing cortisol, so the overproduction of androgenic precursors and resulting virilization are common.66 Conversely, adrenal adenomas tend to synthesize cortisol efficiently, so the production of precur-

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sors is relatively low and the clinical manifestations are mainly those of cortisol excess.66 Bilateral Micronodular Hyperplasia

About half the cases of bilateral micronodular hyperplasia, a very rare cause of Cushing’s syndrome (Table 1),69 occur sporadically in children and in adults less than 30 years of age,69 whereas the other half occur as autosomal dominant disorders associated with blue nevi; pigmented lentigines; cutaneous, mammary, and atrial myxomas; pituitary somatotroph adenomas; and testicular and other tumors.70 Autoantibodies that stimulate adrenocortical growth and steroidogenesis are said to be involved in the pathogenesis of this disorder.71 Bilateral Macronodular Hyperplasia

Two adults were recently described who had bilateral macronodular hyperplasia, a very rare form of Cushing’s syndrome (Table 1),72 with marked increases in the plasma cortisol concentration in response to meals.73,74 Their abnormal adrenocortical tissue responded to gastric inhibitory polypeptide, an example of the “promiscuous receptor” concept.68 The intermittent nature of the stimulation probably explains the late onset of the hyperplasia. Why the patients had macronodular, rather than diffuse, hyperplasia is unclear, although chronic stimulation seems to be correlated with the formation of nodules.75 DIAGNOSIS The surest way to confirm the clinical diagnosis of Cushing’s syndrome and determine the cause of the hypercortisolemia is to perform a variety of tests of pituitary–adrenal function and to be certain that the results of every test are consistent with the same cause.24 This approach is economically unfeasible for most patients and unnecessary for many of them. Consequently, one must use a rational approach that yields the most accurate diagnostic information at the lowest cost, accepting the fact that one will sometimes reach an incorrect diagnosis and recommend inappropriate therapy. Since there is no consensus on the best approach, the following represents my own attempt to define one. Diagnosis of Cushing’s Syndrome Clinical Diagnosis

The essential first step is to establish that the patient has the symptoms and signs that constitute Cushing’s syndrome. There are no pathognomonic symptoms or signs, so the clinical diagnosis must be based on the more or less simultaneous development of several new symptoms and signs.76 The most common is the relatively sudden onset of weight gain, which is usually central but may be general in distribution, often accompanied by thickening of the facial fat, which rounds the facial contour (moon facies), and a florid complexion due to telangiectasias. An enlarged dorsocervical fat pad, or “buffalo hump,” accompanies major weight gain of any cause, whereas increased fat pads that fill

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and bulge above the supraclavicular fossae are more specific for Cushing’s syndrome. Hypertension, glucose intolerance, oligomenorrhea or amenorrhea in premenopausal women, decreased libido in men, and spontaneous ecchymoses are frequent concomitant findings. Muscle wasting and weakness are manifested by difficulty in climbing stairs or arising from a low chair; most patients cannot rise from a squatting position without assistance. The cessation of linear growth and excessive weight gain in children and young adolescents and the development of multiple violaceous striae wider than 1 cm on the abdomen or proximal extremities in persons of any age are almost unique to Cushing’s syndrome. Depression and insomnia often occur at the same time as other symptoms.77 Patients with Cushing’s disease may have mild hirsutism and acne, but severe hirsutism and especially virilization strongly suggest an adrenal carcinoma. Cutaneous hyperpigmentation is unusual, except in patients with the ectopic corticotropin syndrome in whom plasma corticotropin concentrations are markedly elevated; hyperpigmentation does not occur in patients with adrenal tumors. Thinning of the skin and osteoporosis, with low back pain and vertebral collapse, tend to be more common in older patients and those with chronic Cushing’s syndrome. A history of episodes of depression and the absence of other manifestations of hypercortisolism are helpful in excluding pseudo–Cushing’s syndrome in a patient who is depressed, but there is no clinical finding that reliably distinguishes a patient with depression and abnormal cortisol secretion from one with hypercortisolism and associated depression. Alcoholic pseudo– Cushing’s syndrome can usually be ruled out by history taking and follow-up. Laboratory Confirmation

The diagnosis is confirmed by the demonstration of cortisol hypersecretion, a stage referred to as screening. In the past, this was done by documenting the increased excretion of cortisol metabolites in urine, the loss of the normal diurnal rhythm of the plasma cortisol concentration, and the loss of the normal suppressibility of cortisol (i.e., corticotropin) secretion by low doses of dexamethasone.24,31,78 The problem is that the abnormal pituitary–adrenal function in Cushing’s disease, the most common cause of Cushing’s syndrome, blends imperceptibly into normal function. In patients with florid Cushing’s disease there is seldom any clinical or laboratory ambiguity, but in those with mild, early manifestations the diagnosis is less certain. Daily urinary cortisol excretion. The determination of 24-hour excretion of cortisol in urine is now the most direct and reliable practical index of cortisol secretion. The reason is that plasma concentrations of corticotropin and cortisol rise and fall episodically, not only in normal subjects but also in most patients with Cushing’s disease or the ectopic corticotropin syndrome.79-81 The measurement of 24-hour excretion of cortisol in urine integrates the plasma free cortisol concentrations

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during the entire day. The mean (SD) rate of cortisol secretion in normal adults is 9.92.7 mg per 24 hours (277.5 mmol per 24 hours),82 about 12 to 40 mg (33 to 110 nmol) of which is filtered by the kidney and excreted in urine as unmetabolized cortisol (usually called urinary free cortisol).83 In many assays of urinary cortisol, the upper limit of normal is 90 to 100 mg (250 to 275 nmol) per 24 hours, indicating that the assay is not specific. If cortisol excretion is consistently elevated, the patient has increased cortisol secretion associated with Cushing’s syndrome, pseudo–Cushing’s syndrome, or major stress, such as from trauma or infection; cortisol secretion is not usually increased by obesity.84 In a patient thought likely to have Cushing’s syndrome, cortisol should be measured in two, and preferably three, consecutive 24-hour urine specimens collected on an outpatient basis (Fig. 2). Multiple measurements are needed because even intelligent and carefully instructed24 patients can make mistakes (such as not discarding the urine voided when the first day’s collection begins). Cortisol excretion in patients with Cushing’s syndrome may vary from day to day and can be frankly cyclical,85 so multiple values indicate the constancy of cortisol secretion, which is important for interpreting subsequent test results. Excretion of creatinine (a 70-kg person excretes about 1 g per day) should be measured to determine the completeness of the collection: the amount should vary by no more than 10 percent from day to day. The result of an incomplete collection cannot be corrected by expressing cortisol excretion as a function of creatinine excretion, because cortisol is excreted episodically, whereas creatinine excretion is relatively constant. If the creatinine content of two specimens does not agree within 10 percent, at least two more collections should be obtained. Low-dose dexamethasone suppression test. The standard suppression tests designed to identify patients with Cushing’s syndrome are the two-day, low-dose dexamethasone suppression test (0.5 mg every six hours for eight doses)31 and the overnight dexamethasone suppression test (1 mg at 11 p.m. or midnight).86 In the two-day test, urinary cortisol values greater than 10 mg (28 mmol) per 24 hours or urinary 17-hydroxycorticosteroid values greater than 2.5 mg (6.9 mmol) per 24 hours indicate the presence of Cushing’s syndrome, as do 8 a.m. plasma cortisol values greater than 5 mg per deciliter (138 nmol per liter) in the overnight test. Dexamethasone is a substitute for endogenous cortisol in suppressing the secretion of corticotropin; the dosages used are three to four times the normal replacement dosage. If cortisol secretion is normal, dexamethasone suppression is almost always normal; if cortisol secretion is only marginally increased, dexamethasone suppression may be only marginally abnormal; and if cortisol secretion is unequivocally increased, the lack of suppressibility with low-dose dexamethasone adds no useful information. These two tests are useful for confirming a diagnosis of Cushing’s

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Clinical diagnosis of Cushing’s syndrome 2 or 3 24-hr urine collections for measurement of cortisol and creatinine No Cushing’s syndrome

Cushing’s syndrome

Equivocal, possible pseudo – Cushing’s syndrome Low-dose dexamethasone suppression test

Cushing’s syndrome

No Cushing’s syndrome

Possible pseudo – Cushing’s syndrome

Midnight plasma cortisol, CRH– dexamethasone, or naloxone test Cushing’s syndrome

Major depressive disorder

2 or 3 Late-afternoon or midnight plasma corticotropin and cortisol measurements Corticotropin-dependent Cushing’s syndrome

Corticotropin -independent Cushing’s syndrome

High-dose dexamethasone suppression test

Adrenal CT or MRI

No Cushing’s syndrome

Cushing’s disease

Surgery

Cushing’s disease or ectopic corticotropin syndrome Radionuclide imaging, CT, or MRI Metyrapone or CRH test

Cushing’s disease

Cushing’s disease or ectopic corticotropin syndrome

Operable tumor Surgery

Inferior-petrosal-sinus sampling Cushing’s disease

Ectopic corticotropin syndrome

Pituitary CT or MRI

Abdominal CT or MRI

Surgery

Surgery

Figure 2. An Approach to the Diagnosis of Cushing’s Syndrome and Its Cause. The heavy line indicates the diagnostic path for the majority of patients, who have Cushing’s disease. CT denotes computed tomography, and MRI magnetic resonance imaging.

syndrome, but they should be reserved primarily for patients with mildly increased urinary cortisol excretion and those thought to have pseudo–Cushing’s syndrome (Fig. 2). Measuring plasma dexamethasone at the conclusion of the test can clarify otherwise confusing results87,88 caused by noncompliance, individual variability in dexamethasone metabolism, or the effects of drugs on steroid metabolism.89-92 Patients who are acutely ill may have decreased suppressibility of plasma cortisol. However, a normal result of either of these two tests excludes the possibility of Cushing’s syndrome. Other tests to identify patients with pseudo–Cushing’s

syndrome. Four tests may be useful in identifying patients with pseudo–Cushing’s syndrome due to major depressive disorder. First, the evening nadir in the plasma cortisol concentration is preserved in depressed patients but not in patients with Cushing’s syndrome. Consequently, a midnight plasma cortisol value greater than 7.5 mg per deciliter (207 nmol per liter) indicates the presence of Cushing’s syndrome, whereas a value less than 5 mg per deciliter (138 nmol per liter) virtually rules it out. A second, newly described test involves the administration of CRH and dexamethasone in sequence to exploit the greater sensitivity of corticotropin secre-

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tion to dexamethasone suppression in depressed patients and the greater plasma cortisol response to exogenous CRH in patients with Cushing’s disease.93 In patients with pseudo–Cushing’s syndrome, plasma cortisol concentrations were low after the administration of dexamethasone and remained low when CRH was given soon after dexamethasone, whereas in patients with Cushing’s syndrome, plasma cortisol concentrations were not as low after the administration of dexamethasone and were increased after CRH had been given. A third test is based on the ability of the opioid antagonist naloxone to stimulate the release of CRH.94 Because endogenous CRH secretion is suppressed in patients with Cushing’s disease, naloxone releases less CRH (and hence less corticotropin and cortisol) in them than in depressed patients95 (and unpublished data). The fourth test makes use of the fact that in depression hypercortisolism is usually mild and transient, so that suppression of the hypothalamic–pituitary axis is incomplete and can be overcome by the stimulatory effect of hypoglycemia on CRH secretion. Therefore, plasma cortisol concentrations increase in response to insulin-induced hypoglycemia in depressed patients with pseudo–Cushing’s syndrome, but not in patients with chronic Cushing’s syndrome.96 Distinguishing between Corticotropin-Dependent and Corticotropin-Independent Cushing’s Syndrome

Determining whether a patient’s hypercortisolism is corticotropin-dependent or corticotropin-independent requires reliable measurements of plasma corticotropin, which are now best made by a two-site immunoradiometric assay.97 The ideal time to measure plasma corticotropin and cortisol in order to diagnose Cushing’s syndrome, as well as to determine whether it is corticotropin-dependent, is between midnight and about 2 a.m., when the concentrations of these hormones are normally at their lowest.98,99 However, measurements made during the late afternoon (i.e., at 4 p.m. or later) are usually satisfactory. Because the secretion of corticotropin and cortisol in patients with Cushing’s syndrome is episodic, it is wise to measure the two hormones on at least two, and preferably three, separate days (Fig. 2). If there is a strong suspicion of Cushing’s syndrome, the plasma measurements should be performed on the same days that urinary cortisol is measured, to shorten the time required for diagnosis and to corroborate the results of the urinary cortisol tests. If the plasma cortisol concentration is greater than 15 mg per deciliter (415 nmol per liter) and the corticotropin concentration is less than 5 pg per milliliter (1.1 pmol per liter), cortisol secretion is corticotropin-independent (i.e., the patient has primary adrenal Cushing’s syndrome). If the plasma corticotropin concentration is greater than 15 pg per milliliter (3.3 pmol per liter), the cortisol secretion is corticotropin-dependent (i.e., the patient has Cushing’s disease or the ectopic corticotropin or CRH syn-

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drome). Intermediate plasma corticotropin values are less definitive but usually indicate that cortisol secretion is corticotropin-dependent. Determining the Source of Excess Corticotropin Secretion

Because most patients with corticotropin-dependent Cushing’s syndrome have Cushing’s disease (Table 1), the objective is to identify the few who have the ectopic corticotropin syndrome. High-Dose Dexamethasone Suppression Tests

The standard two-day, high-dose dexamethasone suppression test (2 mg every six hours for eight doses), with measurement of urinary cortisol or cortisol metabolites,31 distinguishes Cushing’s disease, in which there is only relative resistance to glucocorticoid negative feedback, from the ectopic corticotropin syndrome, in which there is usually complete resistance (Fig. 1 and 2). The efficacy of this test as compared with other diagnostic tests has been repeatedly reviewed.29,35,100-102 In a retrospective analysis of 94 patients with confirmed Cushing’s disease, 10 with chronic ectopic corticotropin secretion, and 14 with primary adrenal disease, 24-hour urinary cortisol excretion was suppressed by more than 90 percent on the second day of dexamethasone administration in 69 percent of the patients with Cushing’s disease but in none of those with the ectopic corticotropin syndrome or primary adrenal disease (Fig. 3).103 That is, 69 percent of the patients with Cushing’s disease were correctly identified and required no further endocrine diagnostic tests (69 percent sensitivity and 100 percent specificity for Cushing’s disease). In practice, patients with primary adrenal disease would already have been identified as having corticotropin-independent Cushing’s syndrome and would not be subjected to the test (Fig. 2). However, in a more recent report from the same investigators,104 describing 186 patients, approximately half of whom were subjects of previous reports,12,103 urinary cortisol excretion was suppressed in 59 percent of the 170 patients with Cushing’s disease but not in any of the 15 patients with the ectopic corticotropin syndrome or the 1 patient with primary adrenal disease (i.e., there was only 59 percent sensitivity and 100 percent specificity for Cushing’s disease). Greater sensitivity was achieved in both series (83 percent in the former and 72 percent in the latter) with the use of combined criteria: either more than 90 percent suppression of basal urinary cortisol excretion or more than 64 percent suppression of basal urinary 17-hydroxycorticosteroid excretion.103,104 In a meta-analysis, Miller and Crapo105 estimated the sensitivity to be 72 percent and the specificity to be 94 percent when a decrease of more than 64 percent in urinary excretion of 17-hydroxycorticosteroids was used as the criterion. Greater sensitivity (90 percent and 100 percent) and similar specificity (92 percent and 100 percent) have been reported for an overnight high-dose dexamethasone suppression test (8 mg given at 11 p.m. to midnight)106 and an intravenous test (1 mg per hour

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Suppression from Base Line (%)

Urinary Cortisol

797 Urinary 17-Hydroxycorticosteroids

–300

–300

–200

–200

–100

–100

0

0

10

10

20

20

30

30

40

40

50

50

60

60

70

70

80

80

64%

90

90%

100

90 100

Cushing’s Disease

Ectopic Adrenal Cortico- Cushing’s tropin Syndrome Syndrome

Cushing’s Disease

Ectopic Corticotropin Syndrome

Adrenal Cushing’s Syndrome

Figure 3. Percent Suppression from Mean Base-Line Values for 24-Hour Urinary Excretion of Cortisol and 17-Hydroxycorticosteroid on the Second Day of Treatment with High-Dose Dexamethasone (2 mg Every 6 Hours for Eight Doses) in Patients with Cushing’s Syndrome. Presumably, the high values (negative percentages) after the administration of dexamethasone in some patients with the ectopic corticotropin syndrome or primary adrenal disease reflect variable day-to-day secretion of hormone by the tumor. Dashed lines show the lower limit of the values considered to indicate the presence of the ectopic corticotropin syndrome. Adapted from Flack et al.103 with the permission of the publisher.

for seven hours),107 respectively. A direct comparison of the overnight test and the standard two-day highdose test was made in a subgroup of 41 patients (34 with Cushing’s disease and 7 with the ectopic corticotropin syndrome). Even when slightly modified sampling times and a more stringent criterion for suppression were used to improve sensitivity while retaining 100 percent specificity, the sensitivity was 71 percent for the overnight test, as compared with 65 percent for the standard test.102 Thus, any of these high-dose dexamethasone tests appears to be satisfactory, but none of them correctly categorizes every patient with corticotropin-dependent Cushing’s syndrome. Consequently, results that fall near the published exclusion limits should be interpreted with caution. Metyrapone Stimulation Test

Metyrapone blocks the conversion of 11-deoxycortisol to cortisol. The plasma cortisol concentration falls, the pituitary secretes more corticotropin, the plasma

11-deoxycortisol concentration increases, and the urinary 17-hydroxycorticosteroid concentration, which includes metabolites of both 11-deoxycortisol and cortisol, increases as a consequence.108 Conceived as a test of pituitary insufficiency, the metyrapone stimulation test (750 mg every four hours for six doses) has been used to differentiate Cushing’s disease from the ectopic corticotropin syndrome. Patients with Cushing’s disease have a normal or supranormal increase in the plasma 11-deoxycortisol concentration or in urinary excretion of 17-hydroxycorticosteroids, whereas most patients with ectopic corticotropin-secreting tumors have little or no increase in either value, because their pituitary secretion of corticotropin is suppressed (Fig. 1 and 2).24 When the criterion was either an increase of 400 times or more in the basal plasma 11-deoxycortisol concentration (measured at 8 a.m., 4 hours after the last dose of metyrapone) or an increase of more than 70 percent over the basal 24-hour urinary excretion of 17-hydroxycorticosteroids (on the

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day of metyrapone administration), the sensitivity (71 percent) was better than with the two-day, high-dose dexamethasone suppression test; using a positive result in either the metyrapone test or the high-dose dexamethasone test increased the sensitivity to 88 percent while maintaining 100 percent specificity.104 The limitations of the metyrapone test are the fact that it requires access to a reliable assay of urinary 17-hydroxycorticosteroid (the assay of the plasma 11deoxycortisol concentration alone gave only 38 percent sensitivity; that of urinary 17-hydroxycorticosteroid excretion alone gave 60 percent) and the fact that the test must be performed in the hospital for reasons of compliance and safety (nausea and hypotension may develop in patients who do not respond to metyrapone). Petrosal Venous Sinus Catheterization

The most direct way to demonstrate pituitary hypersecretion of corticotropin is to document a centralto-peripheral-vein corticotropin gradient in blood draining the tumor. Indeed, some12,13,109,110 have advocated routine catheterization of the inferior petrosal venous sinuses, which drain the pituitary through the cavernous sinuses,111-113 with measurements of corticotropin in petrosal and peripheral venous plasma before and after stimulation with CRH (described in the next section) in all patients with corticotropin-dependent Cushing’s syndrome. This is an invasive procedure in which the success and complications depend on the operator’s skill and experience. Besides failure to place both catheters properly, the complications range from inguinal hematomas to permanent damage to the brain stem.114 The incidence of complications ranges from 0.2 percent114 to 23 percent (unpublished data). Furthermore, the cost of the procedure ranges from about $2,500 to more than $5,000. Thus, it cannot be recommended as a routine procedure. Determining the Source of Corticotropin in Patients Whose Hypersecretion Cannot Be Suppressed with Dexamethasone

In patients whose cortisol secretion cannot be suppressed adequately with a high dose of dexamethasone, the source of corticotropin must be determined. Sixty to 70 percent of such patients have Cushing’s disease, and the remainder have nonpituitary tumors. Although frequently referred to as occult tumors, they are occult only in the sense that the presenting manifestations are those of Cushing’s syndrome, not those of the tumor. The great majority of such tumors arise in the lungs or mediastinum (as small-cell lung carcinomas or bronchial or thymic carcinoid tumors) and can be detected by radionuclide imaging115-117 using an analogue of octreotide labeled with indium-111 or by computed tomography (CT) or magnetic resonance imaging (MRI) (Fig. 2).118 Radionuclide imaging detects up to 86 percent of carcinoid tumors, a sensitivity at least comparable to that of CT or MRI,116 and may also demonstrate occult metastatic lesions, but it is not specific for tumors,

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since it detects some granulomas and autoimmune inflammatory lesions. This imaging procedure should be performed before petrosal-sinus sampling is done. If plasma or urinary cortisol is not suppressed with a high dose of dexamethasone and there is no detectable nonpituitary mass that is resectable or accessible to biopsy, simultaneous bilateral inferior-petrosal-sinus sampling before and after the administration of CRH should be performed (Fig. 2).12 CRH is not currently available for clinical use except with an Investigational New Drug exemption. After a catheter is positioned in each inferior petrosal sinus,12,111 blood samples are withdrawn simultaneously from each sinus and from a peripheral vein: twice immediately before the peripheral venous injection of 1 mg of ovine CRH per kilogram of body weight and twice more, two to three minutes and five to six minutes after the injection.12 Among 203 patients with Cushing’s disease and 17 patients with the chronic ectopic corticotropin syndrome, if the sinus-to-peripheral-vein plasma corticotropin ratio for either sinus was 2.0 or higher in either of the two basal sets of samples or 3.0 or higher in either of the two sets of samples obtained after the CRH injection, the diagnostic accuracy, sensitivity, and specificity of the procedure were all 100 percent (Fig. 4).12 The test is less reliable when the maximal corticotropin concentration in the inferior petrosal sinus is less than 20 pg per milliliter (4.4 pmol per liter).12 This is not a useful procedure for determining on which side the corticotropin-secreting adenoma is located.110,119 Imaging Procedures

The diagnosis of Cushing’s syndrome and its cause lies in the domain of the endocrine laboratory. Imaging procedures provide no information about function and are useful only for determining the location of a tumor. If the patient has corticotropin-independent Cushing’s syndrome, thin-section CT or MRI of the adrenal glands is usually the next and final procedure (Fig. 2). MRI may provide more information about the benign or malignant nature of the tumor,120 as may measurement of the urinary excretion of 17-ketosteroids or other cortisol precursors (e.g., dehydroepiandrosterone), concentrations of which tend to be disproportionately elevated in patients with adrenal carcinomas. If a patient with corticotropin-dependent Cushing’s syndrome has corticotropin secretion that cannot be suppressed with dexamethasone, chest CT or MRI (the latter of which may detect mediastinal tumors) should be performed before petrosal-sinus sampling. Only in rare cases does abdominal imaging detect occult ectopic corticotropin-secreting tumors (Fig. 2). Neither CT nor MRI of the sella turcica has any diagnostic value,121 and neither study should be used to decide whether to proceed with pituitary surgery. If the patient has Cushing’s disease, the neurosurgeon will probably require both unenhanced and gadoliniumenhanced high-resolution MRI of the sella turcica. MRI is more sensitive than CT in detecting corticotroph ad-

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Before CRH

799

Before or after CRH

1000

Maximal IPS:P Ratio

100

10

3.0 2.0

1

*

* 0.1 Cushing’s Disease

Ectopic Corticotropin Syndrome

Adrenal Cushing’s Syndrome

Cushing’s Disease

Ectopic Corticotropin Syndrome

Adrenal Cushing’s Syndrome

Figure 4. Ratio of Plasma Corticotropin Concentrations in Either the Left or the Right Inferior Petrosal Sinus (IPS) to Those in a Peripheral Vein (P) in Samples Drawn Simultaneously Either before (Left-Hand Panel) or before or after (Right-Hand Panel) the Peripheral Intravenous Injection of Ovine CRH (1 mg per Kilogram of Body Weight) in Patients with Cushing’s Syndrome. Dashed lines indicate the lower limit of the values considered to indicate the presence of Cushing’s disease. Adapted from Oldfield et al.12 with the permission of the publisher.

enomas but still detects only about half the microadenomas that cause Cushing’s disease.121 When positive, MRI images are useful in determining the location of microadenomas, and high-resolution CT images are useful in locating bony landmarks for the transsphenoidal approach. Role of the CRH Stimulation Test

CRH stimulation tests in which only peripheral-plasma corticotropin and cortisol concentrations are measured have proved to be of little value when used alone in the diagnosis of Cushing’s syndrome,122 because there is too much overlap of peripheral-plasma corticotropin responses among patient groups.25 TREATMENT Cushing’s Disease

The treatment of choice for patients with Cushing’s disease is transsphenoidal microadenomectomy, if a clearly circumscribed microadenoma can be identified and resected. Otherwise, patients should undergo 85 to 90 percent resection of the anterior pituitary, unless they wish to have children, in which case they should be treated with pituitary irradiation and, if that fails,

bilateral total adrenalectomy (Fig. 5). Among experienced neurosurgeons, the cure rate is about 80 percent after the initial surgery; second operations tend to be less successful. The criteria for a cure should be an undetectable plasma cortisol concentration in the morning (1 mg per milliliter [28 nmol per liter]) and a corticotropin concentration of less than 5 pg per milliliter (1.1 pmol per liter) 24 hours after the last 10-to-15-mg dose of hydrocortisone, four to seven days after surgery. Less strict criteria result in higher rates of apparent cure but higher rates of recurrence. Patients require daily glucocorticoid-replacement therapy from the time of surgery until their hypothalamic–pituitary–adrenal function recovers, which usually occurs 6 to 12 months after surgery. For adult patients not cured by transsphenoidal surgery, pituitary irradiation is the most appropriate choice for the next treatment. A conventional-megavoltage linear accelerator or irradiation with cobalt-60 (4200 to 4500 cGy in all) will correct the hypercortisolism in about 45 percent of adults.123 Because 85 percent of children are cured by radiation,124 this treatment may be considered as the initial therapy (Fig. 5). Newer forms of stereotactic radiotherapy — a computer-

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Cushing’s disease Transsphenoidal surgery 20% Not cured

80% Cured

Pituitary irradiation 45 to 85% Cured

15 to 55% Not cured Total bilateral adrenalectomy 100% Cured

Adrenal tumor Surgical resection of tumor Adenomas cured

Carcinomas not cured Immediate mitotane therapy Recurrent carcinoma Surgical resection of recurrent tumor

Some in remission

Majority progressive Adrenal enzyme inhibitors Cushing’s syndrome controlled

Ectopic corticotropin syndrome Surgical resection of tumor Benign (10%) cured

Malignant (90%) not cured Adrenal enzyme inhibitors

Cushing’s syndrome controlled

Indolent tumor Medical or surgical adrenalectomy Cushing’s syndrome cured

Figure 5. Therapeutic Approaches to Patients with the Three Major Causes of Cushing’s Syndrome, and Approximate Rates of Success. The treatment of patients with the ectopic CRH syndrome is identical to that of patients with the ectopic corticotropin syndrome; total bilateral adrenalectomy is needed to cure corticotropin-independent micronodular or macronodular hyperplasia.

assisted linear accelerator (the “photon knife”)125 or cobalt-60 (the “gamma knife”)126 — may be more effective, but experience with them is limited. They are oneday procedures that expose the surrounding neuronal tissues to less irradiation than conventional radiotherapy. During the 3 to 12 months required to achieve the maximal benefit from irradiation, hypercortisolism can be controlled with adrenal enzyme inhibitors, such as ketoconazole, metyrapone, or aminoglutethimide, given

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alone or in combination.24,123 These drugs are useful only as adjunctive therapy in patients with mild disease or after irradiation, since they alone do not cure the disorder.24,127-131 Pituitary irradiation also reduces the incidence of Nelson’s syndrome (enlarged, locally invasive, corticotropin-secreting pituitary tumors),123,132 should adrenalectomy subsequently prove necessary. Bilateral total adrenalectomy with lifelong daily glucocorticoid- and mineralocorticoid-replacement therapy provides the definitive cure (Fig. 5). Ectopic Corticotropin and CRH Syndromes

Resection of nonpituitary tumors cures the hypercortisolism, but most such tumors are nonresectable (Fig. 5). The hypercortisolism can be controlled with adrenal enzyme inhibitors, alone or in combination, and their effect can be monitored by measuring plasma and urinary cortisol (Fig. 5). Mifepristone (also known as RU486), which blocks the peripheral action of cortisol, is useful in theory but difficult to administer in practice,128,129 because there is no measure of effective dosage other than the relief of symptoms, and one can easily induce hypocortisolism. In patients with indolent, nonresectable tumors, bilateral adrenalectomy is a rational treatment for the hypercortisolism. Primary Adrenal Disease

Bilateral total adrenalectomy is required in patients with bilateral micronodular or macronodular adrenal hyperplasia, and unilateral adrenalectomy in those with adrenal adenoma or carcinoma (Fig. 5). Patients with hyperplasia or adenomas are almost always cured, but those with carcinomas almost invariably have recurrences that are not amenable to either irradiation or chemotherapy.133 Adrenal enzyme inhibitors can be given to control hypercortisolism. Mitotane, a specific adrenocorticolytic agent, may offer these patients their one hope of cure.134,135 It is merely palliative in patients with residual or recurrent disease.136 However, when administered in a daily dose of 4 g to patients with no detectable disease after initial surgery, it may prevent recurrence (Fig. 5).135,137-139 Mitotane often causes anorexia, nausea, lassitude, and somnolence, which may be due to adrenal insufficiency or to the drug itself, and it may also cause ataxia and other central nervous system symptoms. Patients taking the drug often need increased doses of glucocorticoid- and mineralocorticoidreplacement therapy.140 Gastrointestinal symptoms can be minimized by increasing the dose gradually, always giving half of it at bedtime. Aggressive surgical resection of recurrent or metastatic disease may prolong life.141 SUMMARY Cushing’s syndrome is usually caused by the secretion of corticotropin or cortisol by a pituitary or adrenal tumor, respectively, or by ectopic secretion of corticotropin. It is possible to determine the specific abnormality in most patients, but it can sometimes be difficult to decide whether the patient has hypercortisolism

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and whether it is primary or due to major depressive disorder or to the stress of other diseases. Determining the cause of the hypercortisolism involves performing multiple tests in a logical sequence; the results should all be consistent with the same diagnosis. Treatment should aim to cure the hypercortisolism and to eliminate any tumor that threatens the patient’s health, while minimizing the chance of an endocrine deficiency or long-term dependence on medications. REFERENCES 1. Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;50: 137-95. 2. Vale W, Rivier C, Brown MR, et al. Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 1983;39:24570. 3. Owens MJ, Nemeroff CB. Physiology and pharmacology of corticotropinreleasing factor. Pharmacol Rev 1991;43:425-73. 4. DeBold CR, Sheldon WR, DeCherney GS, et al. Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin-releasing factor. J Clin Invest 1984;73:533-8. 5. Vale W, Vaughan J, Smith M, Yamamoto G, Rivier J, Rivier C. Effects of synthetic ovine corticotropin-releasing factor, glucocorticoids, catecholamines, neurohypophysial peptides, and other substances on cultured corticotropic cells. Endocrinology 1983;113:1121-31. 6. Jackson RV, DeCherney GS, DeBold CR, et al. Synthetic ovine corticotropin-releasing hormone: simultaneous release of proopiolipomelanocortin peptides in man. J Clin Endocrinol Metab 1984;58:740-3. 7. Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 1984;5:25-44. 8. Eberwine JH, Jonassen JA, Evinger MJ, Roberts JL. Complex transcriptional regulation by glucocorticoids and corticotropin-releasing hormone of proopiomelanocortin gene expression in rat pituitary cultures. DNA 1987; 6:483-92. 9. Keller-Wood ME, Dallman MF. Corticosteroid inhibition of ACTH secretion. Endocr Rev 1984;5:1-24. 10. Calogero AE, Gallucci WT, Gold PW, Chrousos GP. Multiple feedback regulatory loops upon rat hypothalamic corticotropin-releasing hormone secretion: potential clinical implications. J Clin Invest 1988;82:767-74. 11. Herman JP, Schafer MK, Thompson RC, Watson SJ. Rapid regulation of corticotropin-releasing hormone gene transcription in vivo. Mol Endocrinol 1992;6:1061-9. 12. Oldfield EH, Doppman JL, Nieman LK, et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 1991;325:897-905. 13. Findling JW, Kehoe ME, Shaker JL, Raff H. Routine inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin (ACTH)dependent Cushing’s syndrome: early recognition of the occult ectopic ACTH syndrome. J Clin Endocrinol Metab 1991;73:408-13. 14. Trainer PJ, Besser M. Cushing’s syndrome. In: Besser GM, Thorner MO, eds. Clinical endocrinology. 2nd ed. London: Times Mirror International, 1994:8.1-8.10. 15. Magiakou MA, Mastorakos G, Oldfield EH, et al. Cushing’s syndrome in children and adolescents: presentation, diagnosis, and therapy. N Engl J Med 1994;331:629-36. 16. Fahlbusch R, Buchfelder M, Müller OA. Transsphenoidal surgery for Cushing’s disease. J R Soc Med 1986;79:262-9. 17. Mampalam TJ, Tyrrell JB, Wilson CB. Transsphenoidal microsurgery for Cushing disease: a report of 216 cases. Ann Intern Med 1988;109:48793. 18. Kaiser FE, Orth DN, Mukai K, Oppenheimer JH. A pituitary parasellar tumor with extracranial metastases and high, partially suppressible levels of adrenocorticotropin and related peptides. J Clin Endocrinol Metab 1983; 57:649-53. 19. Gabrilove JL, Anderson PJ, Halmi NS. Pituitary pro-opiomelanocortin-cell carcinoma occurring in conjunction with a glioblastoma in a patient with Cushing’s disease and subsequent Nelson’s syndrome. Clin Endocrinol (Oxf) 1986;25:117-26. 20. Nawata H, Higuchi K, Ikuyama S, et al. Corticotropin-releasing hormoneand adrenocorticotropin-producing pituitary carcinoma with metastases to the liver and lung in a patient with Cushing’s disease. J Clin Endocrinol Metab 1990;71:1068-73. 21. Gicquel C, Le Bouc Y, Luton JP, Girard F, Bertagna X. Monoclonality of corticotroph macroadenomas in Cushing’s disease. J Clin Endocrinol Metab 1992;75:472-5.

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Vol. 332

No. 12

MEDICAL PROGRESS

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New England Journal of Medicine

CORRECTION

Cushing’s Syndrome Cushing’s Syndrome . On page 792, in Figure 1, at the bottom of the panel on Cushing’s disease, the thick purple lines (denoting hypersecretion) for cortisol and corticotropin should have been dotted purple lines (denoting suppressed secretion). We regret the error.

N Engl J Med 1995;332:1527-a

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