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Dexamethasone suppression tests

Author Section Editor Deputy Editor
Andre Lacroix, MD Lynnette K Nieman, MD Kathryn A Martin, MD

Last literature review version 18.2: May 2010 | This topic last updated: October 6, 2008 (More)

INTRODUCTION — Dexamethasone suppression tests are used to assess the status of the hypothalamic-pituitary-adrenal (HPA) axis and
for the differential diagnosis of adrenal hyperfunction. The low-dose dexamethasone suppression tests are used to assess nonsuppressible
cortisol production by adrenal incidentalomas and to differentiate patients with Cushing's syndrome of any cause from patients who do not
have Cushing's syndrome. The high-dose dexamethasone suppression tests help to distinguish patients with Cushing's disease (Cushing's
syndrome caused by pituitary hypersecretion of corticotropin [ACTH]) from most patients with the ectopic ACTH syndrome (Cushing's
syndrome caused by nonpituitary ACTH-secreting tumors).

This topic will review the basic principles of the dexamethasone suppression tests. Additional information on their role in determining the
diagnosis and the cause of subclinical and clinical Cushing's syndrome is discussed separately. (See "The adrenal incidentaloma" and
"Establishing the diagnosis of Cushing's syndrome" and "Establishing the cause of Cushing's syndrome".)

DEXAMETHASONE SUPPRESSION TESTS — The dexamethasone suppression tests assess the pituitary corticotroph cell response to
glucocorticoid negative feedback inhibition of ACTH secretion. Dexamethasone is a potent glucocorticoid, about 30 to 40 times more potent
than cortisol. Thus, the average daily maintenance dosage of dexamethasone for a patient with adrenal insufficiency is 0.5 mg, versus 20 mg
for hydrocortisone.

Dexamethasone and steroid measurements — Measurements of serum, salivary and urinary cortisol by current assays are unaffected by the
presence of dexamethasone. Antibodies used in current cortisol immunoassays are directed toward the D ring of the molecule and react very
poorly with dexamethasone, which has a 16-alpha-methyl modification of the D ring. Structurally-based assays such as mass spectrometry or
high pressure liquid chromatography fully discriminate the two steroids.

Low-dose dexamethasone suppression tests — The binding of dexamethasone to glucocorticoid receptors in corticotroph cells inhibits
pituitary ACTH secretion. Dexamethasone directly inhibits steroidogenesis in rat adrenals [ 1], but in humans, dexamethasone has no
inhibitory effect on steroid production when exogenous ACTH is infused [ 2].

If the HPA axis is normal, any supraphysiologic dose of dexamethasone is sufficient to suppress pituitary ACTH secretion. This should lead
to reductions in cortisol secretion and its concentration in serum, saliva as well as in the 24-hour urine excretion.

Two main protocols are used. No special precautions are required, as side effects are virtually absent, and either test can be conducted on an
outpatient basis by a compliant patient. Obviously, the test cannot be conducted if the patient is receiving exogenous ACTH or other
glucocorticoids.

Overnight screening test — The overnight test is a quick screening test for nonsuppressible cortisol production and subclinical or clinical
Cushing's syndrome [ 3,4]. Dexamethasone (1 mg, ie, two tablets of 0.5 mg) is taken orally between 11 PM and midnight, and a single blood
sample is drawn at 8 AM the next morning for assay of serum cortisol and, if available, serum dexamethasone. A dose of 0.3 mg/m2 surface
area can be used in children [ 5]. The dose does not need to be adjusted in obese adults [ 6].

When initially studied in healthy individuals, the 8 AM normal serum cortisol concentration was less than 5 µg/dL (140 nmol/L), and the
serum dexamethasone concentration 0.08 to 6.5 ng/mL (0.2 to 17 nmol/L) [ 7].

The criterion for interpretation of the test has been revised based on the observation that, using current, more specific immunoassays, most
normal individuals suppress their 8 AM cortisol value of less than 2 µg/dL (55 nmol/L) [ 8-10].

The 2008 Endocrine Society Guidelines suggest a diagnostic cortisol criterion of 1.8 mcg/dl (50 nmol/L), recognizing that this choice will
optimize sensitivity but decrease specificity [ 11].

However, in some patients with Cushing's disease, 8 AM serum cortisol concentration has been reported to suppress to 1.8 µg/dL (50 nmol/L)
after 1 mg overnight dexamethasone [ 9]. It is likely that this phenomenon is not as rare as previously thought:

• A review of a single practitioner's experience in 103 patients with Cushing's syndrome showed that 14 of 80 (18 percent) with Cushing's
disease suppressed to less than 5 µg/dL, and 6 of 80 (8 percent) suppressed to less than 2 µg/dL (55 nmol/L) [ 12].

• In another study of 97 patients with Cushing's syndrome using a slightly higher 1.5 mg dexamethasone dose, four suppressed to between
1.2 and 2.8 µg/dL (34 and 77 nmol/L) [ 13].

Thus, the 1-mg low-dose dexamethasone tests should not be used as the sole criterion for excluding the diagnosis of Cushing's syndrome.

Conversely, the 1-mg low-dose test has a significant false-positive rate when sensitivity is maximized. Using a serum cortisol criterion of less

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Conversely, the 1-mg low-dose test has a significant false-positive rate when sensitivity is maximized. Using a serum cortisol criterion of less
than 3.6 µg/dL, the test has a 12 to 15 percent false positive rate [ 3,4,14]. If, however, the criterion for suppression of serum cortisol is
increased to less than 7.2 µg/dL (200 nmol/L), the false positive rate falls to 7 percent [ 4]. This suggests that the use of multiple criteria may
be useful in interpreting the test [ 13].

• In one study of 97 patients with Cushing's syndrome and 101 in whom the diagnosis was excluded, using a 1.5 mg test dosage, 100 percent
specificity was achieved only at a cut-off threshold of 14.3 µg/dL (395 nmol/L) [ 13].

• If the concentration is between 1.2 and 14.3 µg/dL (34 to 395 nmol/L), the test is equivocal. In the study mentioned above, the test
sensitivity and specificity were 91 percent at a criterion of 6.3 µg/dL (175 nmol/L). The sensitivity increased to 100 percent, but the
specificity decreased to 41 percent, at a criterion of 1.2 µg/dL (33 nmol/L) [ 13]. Patients with equivocal responses may be normal, or they
may have Cushing's syndrome or pseudo-Cushing's syndrome [ 15]. They require additional tests to exclude Cushing's syndrome. (See
"Establishing the diagnosis of Cushing's syndrome", section on 'Pseudo-Cushing's syndrome'.)

• If the morning serum cortisol concentration is greater than 14.3 µg/mL (395 nmol/L), the patient probably has Cushing's syndrome, and
further diagnostic tests must be performed to confirm the diagnosis and determine its etiology.

Salivary cortisol has been used as an endpoint for the test. (See "Measurement of cortisol in serum and saliva".) When measured by a
radiocompetition assay, the salivary cortisol concentration at 8 AM after 1 mg dexamethasone given at midnight was 0.8 ± 0.4 ng/mL (2.1 ±
1.1 nmol/L) (range, 0.6 to 1.1 ng/mL [1.7 to 3 nmol/L]) in 101 normal subjects, which gave a sensitivity and specificity of 100 percent [ 16].
A criterion of less than 1 ng/mL (2.8 nmol/L) also achieved 100 percent diagnostic accuracy for distinguishing between 27 patients with
Cushing's syndrome and 64 normal controls [ 14]. Another study found a 91 percent sensitivity for Cushing's syndrome, but the criterion for
interpretation was a percent of the obese range [ 17].

The available commercial assays for salivary cortisol require spitting into a cup or using a collection device, and use different assay
techniques. Because results may vary among laboratories, it is important to use an assay that has been validated for this purpose and provides
an appropriate criterion for its interpretation [ 18]. (See "Measurement of cortisol in serum and saliva".)

Standard two-day, 2 mg test — The two-day test is used to assess suppressibility in patients with an equivocal overnight test or in patients
who have not had an overnight test. Dexamethasone, 0.5 mg is taken orally every six hours, usually at 8 AM, 2 PM, 8 PM, and 2 AM, for a
total of eight doses. The dose can be modified in children who weigh less than about 45 kg [ 19]. Blood is drawn two or six hours after the
last dose for measurement of cortisol and dexamethasone (and ACTH, if desired). The response also has been evaluated using urine
corticosteroid excretion during a baseline day and the second day of dexamethasone administration, but this is not currently recommended
(see below).

The normal response to the two-day test consists of the following:

• Urinary cortisol excretion should fall to less than 10 mcg (27 nmol) per 24 hours on the second day of dexamethasone administration.

• Serum cortisol concentration is less than 5 mcg/dL (140 nmol/L), a plasma ACTH concentration is less than 5 pg/mL (1.1 pmol/L), and a
serum dexamethasone concentration is between 2.0 and 6.5 ng/mL (5 to 17 nmol/L) [ 7].

• When using more specific assays to measure serum cortisol, the criteria for suppression are lower. In one retrospective study of 245
patients with ACTH-dependent Cushing's, evaluation of serum cortisol concentrations at 24 and 48 hours during the two-day low-dose
dexamethasone suppression test correctly identified 98 percent of patients (a serum cortisol concentration <1.8 mcg/dL (50 nmol/L) at either
time was considered to be indicative of complete suppression) [ 20]. (See "Measurement of cortisol in serum and saliva".)

• Smaller prospective studies examining patients suspected of having Cushing's syndrome reported 90 to 100 percent sensitivity and 97 to
100 percent specificity using a serum cortisol concentration of 1.4 or 2.2 mcg/dL (38 or 60 nmol/L) as the exclusion criterion [ 21-23]. Thus,
use of the 2 mg, two-day test has greater specificity at high sensitivity than the 1 mg overnight test. As a result, this is the better screening
test, with the caveat that it requires more patient effort than the 1-mg test to achieve excellent diagnostic results.

• Urinary 17-OHCS excretion should fall to 2.5 mg (6.9 µmol) or less per 24 hours, irrespective of creatinine excretion (ie, lean body
weight). Urinary 17-OHCS are now rarely utilized.

• Urinary corticosteroid endpoints provide less sensitivity and specificity; serum cortisol endpoints should be used instead. In one study of 39
patients with Cushing's syndrome and 19 with pseudo-Cushing's syndrome, using the criterion of suppressing 17-OHCS excretion to less than
4 mg/d (11 µmol/d) gave a sensitivity and specificity of 69 and 74 percent, respectively. Using urinary cortisol suppression to less than 3.6
µg/d (100 nmol/d) gave a sensitivity and specificity of 56 and 100 percent, respectively [ 21]. In another study, 9 of 54 patients with Cushing's
syndrome suppressed urinary cortisol excretion to less than 10 µg/d (27 nmol/d), while 5 of 30 suppressed 17-OHCS excretion to less than 3
mg/d (8 µmol/d) [ 9]. In a retrospective study, 7 percent of patients with Cushing's syndrome suppressed urinary cortisol to less than 20 µg/d
(55 nmol/d) or 17-OHCS to less than 3.5 mg/d (7 µmol/d) [ 10].

Measuring plasma ACTH, if either of the tests is positive, gives an indication of the etiology of the hypercortisolism: it will usually be high
normal or high in patients with the ectopic ACTH syndrome, within the normal range in those with Cushing's disease, and undetectable in
those with an adrenal tumor.

Diagnostic accuracy of low-dose dexamethasone tests — In a recent meta-analysis, the 1 mg dexamethasone test and the two-day 2 mg test
were both accurate diagnostic tests, but the 2 mg test had slightly less diagnostic accuracy [ 24]:

• For the 1 mg test, 14 studies including 249 patients with Cushing's syndrome out of 5305 undergoing testing (using various diagnostic
criteria), there was a likelihood ratio of 16.4 (CI 9.3-28.8) for an abnormal result and 0.06 (0.03-0.14) for a normal result.

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• For the 1 mg test, 14 studies including 249 patients with Cushing's syndrome out of 5305 undergoing testing (using various diagnostic
criteria), there was a likelihood ratio of 16.4 (CI 9.3-28.8) for an abnormal result and 0.06 (0.03-0.14) for a normal result.

• For the two-day 2 mg test, 8 studies were identified, including 136 patients with Cushing's syndrome out of 323 who were tested. It found a
likelihood ratio of 7.3 (CI 3.6-15.2) for an abnormal result and 0.18 (CI 0.06-0.52) for a normal result.

Serum dexamethasone — Measuring serum dexamethasone is recommended for all dexamethasone suppression tests. It provides verification
that the drug was taken and indicates whether the serum concentration is within the limits expected in an individual who metabolizes the
drug normally. Nomograms are available that relate serum dexamethasone concentrations to serum cortisol concentrations in normal subjects
and in patients with Cushing's disease [ 7,25]. Commercial laboratories often provide a range of expected values for a specific dose and
interval until the blood draw. Finding an abnormally high or low serum dexamethasone concentration allows one to interpret the cause of an
unusual serum or urinary cortisol response and to repeat the test, if necessary, with the same or another dexamethasone dosage.

High-dose dexamethasone suppression tests — The basis for the high-dose suppression tests is the fact that ACTH secretion in Cushing's
disease is only relatively resistant to glucocorticoid negative feedback inhibition and will not suppress normally with either the overnight 1
mg or the two-day low-dose test [ 26,27]. By increasing the dose of dexamethasone four- to eightfold (ie, 12 to 16 times the usual daily
maintenance dosage), ACTH secretion can be suppressed in most patients with Cushing's disease. In contrast, most nonpituitary malignant
tumors that produce ACTH ectopically (such as oat-cell lung carcinomas) are not responsive to glucocorticoid negative feedback; adrenal
tumors that cause Cushing's syndrome are not dependent on ACTH secretion. In both of these disorders, pituitary ACTH secretion is already
suppressed. As a result, dexamethasone cannot suppress ACTH secretion further and has no effect on cortisol secretion at any dosage.
However, this test need not be performed for primary adrenal disease, the diagnosis of which should have been established by the
combination of simultaneous high serum cortisol and low plasma ACTH concentrations (versus the normal or high plasma ACTH
concentrations with a pituitary or ectopic ACTH-secreting tumor).

Several high dose dexamethasone suppression tests are in use:

Overnight 8 mg test — Dexamethasone (8 mg) is taken orally between 11 PM and midnight, and a single blood sample is drawn at 8 AM the
next day for measurement of serum cortisol and, if one wishes, plasma ACTH and serum dexamethasone. With this protocol, the 8 AM
serum cortisol concentration is less than 5 µg/dL (140 nmol/L) in most patients with Cushing's disease (ie, a pituitary tumor), and is usually
undetectable in normals.

An alternative test strategy involves calculation of the suppression of morning serum cortisol concentration on the day before and after
dexamethasone administration, and considering a 50 (or 69) percent or more suppression to indicate Cushing's disease [ 28]. This approach
yielded a 77 to 92 percent sensitivity and 57 to 100 percent specificity in studies that used various time points for blood collection and
included up to seven patients with ectopic ACTH secretion [ 28-30].

Standard two-day, 8 mg test — The patient collects at least one baseline 24-hour urine specimen, usually beginning at 8 AM. After the
baseline collection is completed, the patient begins taking 2 mg of dexamethasone orally every six hours for a total of eight doses, usually at
8 AM, 2 PM, 8 PM, and 2 AM, and the urine collections are continued. In practice, this test is often performed immediately after completing
the low-dose dexamethasone suppression test (if the test is positive) and no intervening baseline urine collection is obtained. The urine
collections are assayed for urinary free cortisol, and creatinine. In addition, a blood specimen can be collected six hours after the last dose of
dexamethasone for measurement of cortisol, dexamethasone, and ACTH.

This protocol leads to the following values in normal subjects:

• Urinary free cortisol excretion is less than 5 µg (14 nmol) per 24 hours.

• Serum cortisol and plasma ACTH concentrations are low and usually undetectable.

• Serum dexamethasone concentrations range from about 8 to 20 ng/mL (20 to 51 nmol/L) [ 7].

Most patients with Cushing's disease demonstrate a significant (ie, greater than day-to-day baseline variation) reduction in urinary cortisol
excretion [ 26]. About 70 percent suppress urinary cortisol excretion by more than 90 percent [ 30]. As in the low-dose tests, serum cortisol
concentrations respond similarly and reinforce the urinary steroid results. Plasma ACTH concentrations are also significantly suppressed in
patients with Cushing's disease, and serum dexamethasone concentrations provide information about compliance and steroid metabolism.

The vast majority of patients with the ectopic ACTH syndrome from malignant tumors fail to suppress with high-dose dexamethasone. The
study mentioned above reported that two or three of six patients with ectopic ACTH secretion and 86 percent of patients with Cushing's
disease showed suppression of urinary and/or serum cortisol [ 10].

An effectiveness analysis of 73 patients with ACTH-dependent Cushing's syndrome examined the results from the overnight or two-day 8
mg test and found 81 percent sensitivity and 67 percent specificity for differentiating Cushing's disease from ectopic ACTH secretion [ 31].
In this study, the diagnostic groups showed complete overlap in responses, with suppression ranging from 0 to 99 percent, suggesting that this
test cannot be used alone for the differential diagnosis of ACTH-dependent Cushing's syndrome.

Perhaps as many as one-half of patients with ACTH-secreting pulmonary carcinoid tumors and occasionally other tumors, such as thymic
carcinoid tumors, hepatomas, and pheochromocytomas, respond with decreased tumor secretion of ACTH and reduced urinary steroid
excretion [ 32-34]. While pulmonary carcinoid tumors represent only about 5 to 40 percent of patients with ectopic ACTH secretion in
various series [ 35], they represent a difficult diagnostic problem because they are often occult and may mimic the clinical features of
Cushing's disease without the short course, severe hypercortisolism and hypokalemia considered more typical of ectopic ACTH secretion
from malignant tumors such as oat-cell lung carcinomas. (See "Bronchial carcinoid tumors".)

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Cushing's disease without the short course, severe hypercortisolism and hypokalemia considered more typical of ectopic ACTH secretion
from malignant tumors such as oat-cell lung carcinomas. (See "Bronchial carcinoid tumors".)

One report suggested a mechanism by which dexamethasone suppression might occur in these patients [ 34]. Six of eight ACTH-producing
bronchial carcinoids expressed both proopiomelanocortin (POMC) and the vasopressin V3 receptor on the cell surface, a phenotype similar
to pituitary corticotrophs [ 27]. in contrast, POMC and V3 receptor expression were much lower in dexamethasone nonresponsive
noncarcinoid ACTH-producing tumors.

It is prudent to perform at least one test in addition to the dexamethasone suppression test, even in patients who meet current criteria for
suppression, as the specificity of this test is less than 100 percent [ 31]. (See "Establishing the diagnosis of Cushing's syndrome".)

Intravenous dexamethasone suppression tests — Several versions of an intravenous test have been utilized and serve both in the initial and
differential diagnosis of Cushing's syndrome within one day, while avoiding the potential difficulties of drug compliance and absorption with
oral dexamethasone. Dexamethasone is infused at 1 mg/hour IV for four [ 36], five [ 37], or seven [ 38] hours, or at 5 mcg/kg/hour for five
hours [ 39]. Plasma cortisol is suppressed to levels < 1.4 to 3.0 mcg/dL (<38 to 83 nmol/L) in the evening and the following morning in
normal or obese individuals and is above these levels at 9:00 AM in patients with CS, with a sensitivity and specificity of 100 and 90 percent,
respectively [ 38]. Differentiation between Cushing's disease and ectopic ACTH or ACTH-independent Cushing's syndrome can be made on
the basis of a 50 percent decrease in plasma cortisol that occurs following dexamethasone infusion in patients with Cushing's disease.
However, similar to the oral high-dose dexamethasone suppression test, specificity is incomplete, as some patients with Cushing's disease fail
to suppress cortisol in response to dexamethasone and some benign ectopic ACTH cases do suppress cortisol in response to dexamethasone
Less than 5 percent of patients with Cushing's disease fail to suppress cortisol with oral or IV high doses of dexamethasone (usually patients
with large corticotroph tumors), whereas doses >16 mg/day may cause suppression in such patients [ 26]. Although all the dexamethasone
suppression tests are useful, none of them correctly categorizes every patient with ACTH-dependent Cushing's syndrome.

SOURCES OF ERROR — There are several common sources of error in the dexamethasone suppression tests:

• Improper urine collection — This problem can be detected by measurement of creatinine excretion. The creatinine value provides reliable
information about the reproducibility of a series of urine collections and some information about the completeness of an isolated collection.
In adults under the age of 50 years, daily creatinine excretion should be 20 to 25 mg/kg (177 to 221 µmol/kg) lean body weight in men and 15
to 20 mg/kg (133 to 177 µmol/kg) lean body weight in women. From the ages of 50 to 90 years, there is a progressive 50 percent decline in
creatinine excretion (to about 10 mg/kg in men), due primarily to a fall in muscle mass. (See "Calculation of the creatinine clearance" and
"Patient information: Collection of a 24-hour urine specimen".) The use of serum rather than urinary endpoints obviates this source of error.

• Elevated corticosteroid-binding globulin — Women taking exogenous estrogens may have elevated corticosteroid-binding globulin (CBG)
levels with concomitantly increased serum cortisol values. This may result in an apparent lack of suppression. Theoretically, in this setting,
salivary cortisol values would show normal suppression. It may be prudent to measure CBG in women taking estrogens, and to repeat the test
after their discontinuation in patients who have a high CBG value and do not suppress cortisol normally.

• Variation in hormone secretion — Day-to-day variation can occur in hormone secretion by tumors, particularly by malignant pituitary and
nonpituitary ACTH-secreting and cortisol-secreting adrenocortical tumors. This problem can only be detected by serial baseline 24-hour
urine steroid [ 40-42], or salivary cortisol [ 43] determinations. (See "Measurement of cortisol in serum and saliva".)

• Variation in dexamethasone intake or metabolism — Failure of the patient to take the dexamethasone or abnormal metabolism of the
dexamethasone can interfere with interpretation of the test. Drugs that induce hepatic CYP3A4 enzymes, such as barbiturates, phenytoin,
rifampin, troglitazone, carbamazepine, and aminoglutethimide, increase the metabolism of dexamethasone and other steroids [ 44,45]. These
errors can be detected by measuring serum dexamethasone at the appropriate interval after the last dose.

Unusual responses — Urinary steroid excretion of most patients with Cushing's disease is suppressed by high-dose dexamethasone.
Resistance to suppression is more common in patients with higher baseline ACTH and cortisol secretion. In less than five percent of patients
with Cushing's disease, for example, higher doses of dexamethasone (16 to 100 mg/day) are required to produce significant suppression.
These patients tend to have large tumors. [ 46-48].

Higher dexamethasone doses should be considered in patients with a pituitary macroadenoma and ACTH-dependent Cushing's syndrome
whose response to standard high-dose dexamethasone suppression is substantial, but equivocal. Further suppression at higher doses of
dexamethasone is convincing evidence of a pituitary ACTH source, in which case petrosal sinus sampling would not be indicated. In one
study, only three of nineteen patients with Cushing's disease failed to suppress serum cortisol after both 8 and 32 mg dexamethasone [ 49].

Paradoxical responses to dexamethasone in primary pigmented nodular adrenocortical disease — A paradoxical increase in urinary free
cortisol during the sequential low-dose (2 mg) and high-dose (8 mg) six-day dexamethasone suppression testing (the Liddle test) was found in
nine of 13 patients with PPNAD [ 50]. In this study, no paradoxical increase in cortisol was seen in nine patients with macronodular adrenal
disease, but it was observed in 3 of 15 patients with a unilateral adenoma. This delayed "paradoxical" response can be useful diagnostically
to identify otherwise asymptomatic carriers in familial forms of PPNAD or Carney complex or to distinguish PPNAD from other
adrenocortical tumors. (See "Cushing's syndrome due to primary pigmented nodular adrenocortical disease".)

There are also rare reports of "paradoxical" responses to dexamethasone in which cortisol secretion increased, rather than decreased [ 51].
However, most of these reports are poorly documented in terms of reproducibility of the response. In only one well-documented case was the
cause (spontaneous variation in tumor ACTH secretion) defined [ 41].

SUMMARY — Dexamethasone suppression tests are used to assess the status of hypothalamic-pituitary-adrenal (HPA) axis and for the
differential diagnosis of adrenal hyperfunction. The low-dose dexamethasone suppression tests are used to assess non-suppressible cortisol
production by adrenal incidentalomas and to differentiate patients with Cushing's syndrome of any cause from patients who do not have

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production by adrenal incidentalomas and to differentiate patients with Cushing's syndrome of any cause from patients who do not have
Cushing's syndrome. The high-dose dexamethasone suppression tests help to distinguish patients with Cushing's disease (Cushing's syndrome
caused by pituitary hypersecretion of corticotropin [ACTH]) from most patients with the ectopic ACTH syndrome originating from
malignant tumors, but from a smaller proportion of those secondary to benign carcinoid tumors.

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