Newell Price2006

Seminar
Cushing’s syndrome
John Newell-Price, Xavier Bertagna, Ashley B Grossman, Lynnette K Nieman
Cushing’s syndrome results from lengthy and inappropriate exposure to excessive glucocorticoids. Untreated, it has Lancet 2006; 367: 1605–17
significant morbidity and mortality. The syndrome remains a challenge to diagnose and manage. Here, we review the Division of Clinical Sciences,
current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches. We University of Sheffield,
Northern General Hospital,
provide diagnostic algorithms and recommendations for management.
Sheffield, UK
(J Newell-Price FRCP);
Cushing’s syndrome results from lengthy and inappropriate prove that control of cortisol excess is more beneficial than Department of Endocrinology,
exposure to excessive concentrations of circulating free attention to more specific abnormalities of metabolic and Royal Hallamshire Hospital,
Sheffield, UK (J Newell-Price);
glucocorticoids. When presentation is florid, diagnosis is cardiovascular risk. The presentation and investigation of Département d’Endocrinologie
usually straightforward. However, this diagnosis is adrenal incidentalomas with sub-clinical Cushing’s de l’Institut Cochin-INSERM U-
increasingly being considered when the phenotype is syndrome is beyond the scope of this Seminar. 567, Faculté de Médecine René
subtle, and in common disorders such as type 2 diabetes Descartes, Université Paris 5,
Paris, France
and obesity. Only once the diagnosis of Cushing’s Causes of Cushing’s syndrome (Prof X Bertagna MD);
syndrome is established can the underlying cause be Endogenous Cushing’s syndrome is more common in Department of Endocrinology,
searched for. This investigation is frequently a complex women than men and is divided into corticotropin- William Harvey Research
process needing all the skill of doctors, endocrinologists, dependent and corticotropin-independent causes Institute, Queen Mary School
of Medicine and Dentistry,
chemical pathologists, radiologists, and surgeons.1–3 We (table 1). Overall, corticotropin-dependent causes account London, UK
review advances in the understanding of the biology of for about 80–85% of cases, and of these, 80% are due to (Prof A B Grossman FRCP); and
Cushing’s syndrome and discuss its diagnosis, differential pituitary adenomas (Cushing’s disease), with the Reproductive Endocrinology
diagnosis, and management. We focus on recent remaining 20% or so due to ectopic corticotropin and Medicine Branch, National
Institute of Child Health and
developments and highlight areas of controversy. syndrome.10–12 Ectopic corticotropin secretion most Human Development, National
The most common cause of Cushing’s syndrome is usually takes place with small-cell carcinoma of the Institutes of Health, Bethesda,
use of supraphysiological amounts of exogenous lung and bronchial carcinoid tumours, but might also MD 20891-1109, USA
glucocorticoids, including topical or inhaled corticosteroids arise with almost any endocrine tumour from many (L K Nieman MD)
(iatrogenic Cushing’s syndrome). Thus, adequate different organs (eg, phaeochromocytoma, pancreatic Correspondence to:
Dr John Newell-Price
knowledge of an individual’s medication history is essential neuroendocrine tumours, gut carcinoids). Classically, Division of Clinical Sciences,
for diagnosis. Rarely, patients might present with factitious when due to small-cell carcinoma of the lung, or widely University of Sheffield, Northern
Cushing’s syndrome, with covert use of glucocorticoids, metastatic cancer, ectopic corticotropin syndrome can General Hospital, Sheffield
which can be a substantial diagnostic challenge, especially have a rapid onset with severe features, although in S5 7AU, UK
j.newellprice@sheffield.ac.uk
if hydrocortisone is being taken, since use of this substance some patients a paraneoplastic wasting syndrome can
will cause raised concentrations of circulating cortisol. mask hypercortisolism, and hypokalaemia might be a
Here, we will focus on endogenous Cushing’s syndrome. clue to diagnosis. By contrast, the clinical phenotype
(and some biochemical features) of carcinoid tumours
Epidemiology and prognosis can be indistinguishable from that of Cushing’s
Patients with incompletely controlled Cushing’s syndrome disease.10,11
have a five-fold excess mortality, lending urgency to its Corticotropin-independent Cushing’s syndrome is due
ascertainment,4 although this rate might not necessarily in most instances to a unilateral tumour: adrenal adenoma
apply to patients with the subtle clinical and biochemical in 60% and adrenal carcinoma in 40% of cases. Very rare
phenotype being increasingly diagnosed. Depending on adrenal causes of Cushing’s syndrome are corticotropin-
the population studied, incidence of the disorder ranges independent macronodular adrenal hyperplasia, primary
from 0·7 to 2·4 per million population per year.4–6 New pigmented nodular adrenal disease (either as isolated
data, however, suggest that Cushing’s syndrome is more
common than had previously been thought. In screening Search strategy and selection criteria
studies of obese patients with type 2 diabetes, especially
those with poor blood glucose control and hypertension, We searched MEDLINE from January, 2000, to October, 2005.
the reported prevalence of Cushing’s syndrome is between We used search terms “Cushing’s” OR “Cushing’s” AND
2% and 5%.7–9 In these studies, diagnosis of the disorder “Syndrome”. We selected publications from this 5-year
was not suspected on the basis of clinical features, but period, but our search also included other commonly
patients’ metabolic control improved after intervention for referenced and highly regarded older publications known to
their Cushing’s syndrome. If confirmed in further large- us, and those that we judged appropriate. Several review
scale prospective studies, these data suggest that more articles or book chapters were included because they provided
widespread screening for Cushing’s syndrome in such comprehensive overviews beyond the scope of this Seminar.
patients is warranted, although researchers still need to
www.thelancet.com Vol 367 May 13, 2006 1605

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disease. About 90% of tumours express the corticotropin-

Proportion Female:male
releasing hormone-1 receptor, as evidenced by the release
Corticotropin-dependent
of corticotropin in response to exogenously administered
Cushing’s disease 70% 3·5:1·0
corticotropin-releasing hormone. Tumours also express
Ectopic corticotropin syndrome 10% 1:1
the vasopressin-3 receptor and respond to vasopressin
Unknown source of corticotropin* 5% 5:1
and desmopressin in vitro and in vivo.27,28 In ectopic
Corticotropin-independent
corticotropin syndrome, study of the human DMS-79 cell
Adrenal adenoma 10% 4:1
line—a small-cell lung cancer model—has shown that
Adrenal carcinoma 5% 1:1
POMC is activated by transcription factors distinct from
Macronodular hyperplasia <2% 1:1
those in the pituitary (including E2F factors)29,30 that are
Primary pigmented nodular adrenal
disease <2% 1:1
able to bind the promoter in an unmethylated state.31 By
McCune-Albright syndrome <2% 1:1
contrast, carcinoid tumours, which have a more benign
behaviour, show a molecular phenotype closer to that of
*Patients might ultimately prove to have Cushing’s disease. pituitary corticotrope tumours.32
Table 1: Causes of Cushing’s syndrome By contrast with the above, we know more about rare
causes of adrenal Cushing’s syndrome. Corticotropin-
disease or as part of Carney complex), and McCune- independent macronodular adrenal hyperplasia is
Albright syndrome.1,2,13 characterised in many cases by aberrant expression of
receptors in both adrenal glands that are not normally
Pathogenesis present (ectopic expression) or by amplified expression
Although Cushing’s disease is the most common form of receptors that are usually present (eutopic expression).13
of endogenous Cushing’s syndrome, little is known Cortisol secretion in these patients is mediated by
about the underlying pathogenesis of these pituitary functional membrane receptors for gastric inhibitory
tumours.14 In general, corticotrope tumours show peptide (food-dependent Cushing’s);33–36 vasopressin;37–40
especially low expression of the cyclin-dependent inhibitor catecholamines;41,42 interleukin 1;43 leptin;44 lutenising
p27,15 overexpression of cyclin E,16 and a high Ki67 hormone;45 serotonin, or possibly by other unrecognised
expression indicative of high proliferative activity. ligands.13 In cases in which receptors are coupled to
Preponderance of reproductive-aged women might enhanced cyclic AMP, activation is thought to cause
suggest a role of oestrogen, and there is a male hyperplasia, frequently over many years.33 Furthermore,
predominance in prepubertal Cushing’s disease.17 the in-vitro responses of adrenal tissue obtained at
Corticotrope tumours are usually only a few mm in surgery from these patients parallels the in-vivo response
diameter, on average 6 mm, and are larger than 1 cm to peptides.46 The fact that these receptors might be
(macroadenoma) in only 6% of cases.18 present in bilateral macronodular adrenal hyperplasia
More is known about the synthesis and secretion of associated with subclinical Cushing’s syndrome
corticotropin.19 Corticotrope tumours express the pro- emphasises their potential causative role,47 and further
opiomelanocortin gene (POMC), the peptide product of weight is given to this notion by the finding that
which is subsequently cleaved to corticotropin. By expression of gastric inhibitory peptide is sufficient to
contrast with most microadenomas, such processing is induce adrenocortical growth.48 Thus, such aberrant or
relatively inefficient in corticotrope macroadenomas, excessive receptor expression seems to play an important
which secrete large amounts of unprocessed POMC.18,20,21 pathological part. The causes of abnormal expression of
Some pituitary macroadenomas are silent corticotrope these receptors are not known. Aberrant receptors also
adenomas and can present with tumour mass effects (eg, occur in unilateral adenomas but much less commonly
optic chiasm compression) alone. Patients with an initial than in corticotropin-independent macronodular adrenal
absence of features of Cushing’s syndrome might hyperplasia.49 Adrenal glands from patients with
progress to overt disease. These tumours can be corticotropin-dependent disease also show expression of
diagnosed preoperatively, and followed up postoperatively, gastric inhibitory peptide receptors.50 Activation of the
by measuring the amount of POMC in plasma.22 corticotropin receptor pathway might be associated with
Tumours causing Cushing’s disease are resistant to the aberrant expression of gastric inhibitory peptide receptors
effects of glucocorticoids, but POMC expression and that eventually causes corticotropin-independent disease,
corticotropin secretion are nevertheless partly reduced by and such aberrant expression could be merely an
high doses of dexamethasone in 80% of cases.1,23 Recent epiphenomenon of the hyperplastic drive. Finally, a
data show loss of corticotropin receptor expression on constitutively active mutant corticotropin receptor has
corticotropes, enhanced inactivation of cortisol by 11β- been identified in a patient with corticotropin-
hydroxysteroid dehydrogenase,24,25 and reduced expression independent Cushing’s syndrome.51
of bridging protein, which is associated with Primary pigmented nodular adrenal disease causes
glucocorticoid feedback.26 These data somewhat account small nodules on the adrenal gland that might not be
for the resistance to glucocorticoids apparent in Cushing’s visualised on imaging. Diagnosis can be difficult to make,
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because features might be mild and cyclic in nature. It can Clinical features of Cushing’s syndrome
be sporadic or part of Carney complex (an autosomal Table 2 summarises clinical features of Cushing’s
dominant multiple neoplasia syndrome); most cases syndrome. These are variably present in any given patient
present in late childhood or in young adults.52,53 Of the very and can differ in a cyclic way, causing diagnostic difficulty.
rare forms of familial Cushing’s syndrome, Carney The diagnosis is being increasingly considered in patients
complex is the most frequent and needs lifelong with metabolic syndrome, who might have mild features
surveillance for potentially fatal complications, including of slow onset, and diagnosis can be a substantial
cardiac myxomas. Germline mutations of the regulatory diagnostic challenge. Signs that most reliably distinguish
subunit R1A of protein kinase A (PRKAR1A) are present Cushing’s syndrome from obesity are those of protein
in about 45% of patients with Carney complex54,55 and in wasting—presence of thin skin in the young, easy
sporadic primary pigmented nodular adrenal disease.56 bruising, and proximal weakness. In children, presenting
These patients with Carney complex and sporadic primary features differ, with obesity and decreased linear growth
pigmented nodular adrenal disease show a paradoxical especially evident.66–70 Important data shows the difference
rise in cortisol secretion in response to dexamethasone in presentation between women and men, with purple
associated with heightened expression of the glucocorticoid striae, muscle atrophy, osteoporosis, and kidney stones
receptor.57 more frequent in men.71 Renal stones are present in about
McCune-Albright syndrome is due to a postzygotic 50% of all patients,72 but are usually not apparent clinically.
activating mutation in the GNAS1 gene. The resulting Gonadal dysfunction is common in both sexes. Adverse
tissue mosaicism produces a varied phenotype, and the effects of glucocorticoids on bone metabolism are shown
disease can present in the first few weeks of life. These by decreased bone-mineral density, although the exact
mutations lead to constitutive steroidogenesis in the incidence is not known73 and it tends to return to normal
affected adrenal nodules.58 Mutations of GNAS1 have also over time after effective treatment.74 Bone loss can be
been seen in corticotropin-independent macronodular more severe in primary adrenal Cushing’s syndrome than
adrenal hyperplasia.59 pituitary-dependent Cushing’s syndrome.75,76
With respect to adrenal cortical tumours, new data More than 70% of patients with Cushing’s syndrome
show a high rate of β catenin mutations, particularly in can present with psychiatric symptoms ranging from
adenomas,60 and rarely mutations of PRKAR1A.61 anxiety to frank psychosis; if present, depression is often
Molecular changes that distinguish adrenal cortical agitated in nature. Some degree of psychiatric disturbance
carcinomas from adenomas are being increasingly frequently persists after cure of Cushing’s syndrome.
recognised: in carcinomas, allele loss or loss of imprinting Impairment in short-term memory and cognition is
at the 11p15 locus is common.62 This loss is associated common and can persist for at least a year after
with overexpression of insulin-like growth factor II and treatment.77 These effects are associated with a reduction
reduced expression of p57/KIP2 62,63 an imbalance that in apparent brain volume that slowly reverses after
favours cell growth. A specific germline mutation of correction of hypercortisolaemia.78 Patients continue to
TP53 was associated with a high rate of adrenocortical have impaired quality of life even after resolution of
carcinoma in Brazilian patients.64,65 cortisol excess79–81 and should be counselled about this
impairment.
Proportion Cortisol excess predisposes to hypertension and
Obesity or weight gain 95%* glucose intolerance. Patients with Cushing’s syndrome
Facial plethora 90% are at increased cardiovascular risk, which might not
Rounded face 90% return fully to normal after remission.82–84 Hyper-
Decreased libido 90% homocysteinaemia and reduced serum folate con-
Thin skin 85% centrations present in active disease return to normal
Decrease linear growth in children 70–80% during remission,85 suggesting that ongoing cardio-
Menstrual irregularity 80% vascular risk is not related to these factors. The adverse
Hypertension 75% metabolic profile is also evident from imaging studies
Hirsutism 75% showing hepatic steatosis (20% of patients)86 and
Depression/emotional lability 70% increased visceral fat.87
Easy bruising 65%
Glucose intolerance 60% Biochemical diagnosis of hypercortisolaemia
Weakness 60% Diagnostic assessment is usually prompted by clinical
Osteopenia or fracture 50% suspicion, but in certain groups of patients without
Nephrolithiasis 50% classic clinical features, screening might be warranted,
such as in poorly controlled and hypertensive diabetic
*100% in children. 67
patients and men with unexplained osteoporosis (figure 1).

Table 2: Clinical features of Cushing’s syndrome1,67,71,72 Biochemical confirmation of the hypercortisolaemic state
must be established before any attempt at differential

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Moreover, if there is renal impairment with a glomerular

Clinical suspicion/screening at-risk groups filtration rate of less than 30·0 mL/min, or an incomplete
collection, the urinary free cortisol concentration might be
falsely low.91 Review of the volume amount and correction
•Elevated urinary free cortisol (three 24 h collections) for creatinine concentration might be helpful in assessing
•Serum cortisol >50 nmol/L on dexamethasone-suppression testing
•Plasma midnight cortisol: sleeping >50 nmol/L: awake >207nmol/L whether the collection is complete.
•Elevated late-night salivary cortisol
Low-dose dexamethasone-suppression tests
If needed—on occasion: Two tests are in widespread use: the overnight and the
Dexamethasone-CRH test
Desmopressin test 48-h dexamethasone-suppression tests. In the overnight
test, 1 mg of dexamethasone is given at 2300 h and the
Hypercortisolism/Cushing’s syndrome confirmed concentration of cortisol in serum measured the next day
at 0800–0900 h. In the 48-h test, dexamethasone is given
at the dose of 0·5 mg every 6 h for 2 days at 0900 h,
If doubt remains—repeat and seek further opinion 1500 h, 2100 h, and 0300 h with measurements of cortisol
in serum at 0900 h at the start and end of the test. To
Figure 1: Diagnosis of Cushing’s syndrome exclude Cushing’s syndrome, the concentration of
CRH=corticotropin-releasing hormone. cortisol in serum should be less than 50 nmol/L after
either test.1,91 The 48-h test, although more cumbersome
diagnosis: failure to do so will result in misdiagnosis, than the overnight test, is more specific and with adequate
inappropriate treatment, and poor management. regular instructions can be done by outpatients. In both
Hypercortisolaemia is also seen in some patients with tests, caution needs to be exercised if there is potential
depression, alcoholism, anorexia nervosa, generalised malabsorption of dexamethasone or if patients are on
resistance to glucocorticoids, and late pregnancy. drugs that increase hepatic clearance of dexamethasone,
However, by contrast with true endogenous Cushing’s such as carbamazepine, phenytoin, phenobarbital, or
syndrome, the biochemical findings improves when the rifampicin.92 Patients receiving oestrogen treatment, or
underlying disorder has resolved. Establishing a diagnosis who are pregnant, might have an increase in the amount
of Cushing’s syndrome on the rare occasion that it of cortisol-binding globulin. Since commercial cortisol
presents in pregnancy is a substantial challenge.88,89 assays measure total cortisol, this could give a false-
No sole test is perfect; every one has different positive result on dexamethasone-suppression testing.
sensitivities and specificities and several are usually Oral oestrogens need to be stopped for a period of
needed. Investigation should be done when there is no 4–6 weeks so that cortisol-binding globulin can return to
acute concurrent illness (eg, infection or heart failure) basal values. Furthermore, the cortisol assay should be
because these can cause false-positive results. Three known to be accurate at these low levels.
main tests in use for diagnosis of Cushing’s syndnrome Some 3–8% of patients with Cushing’s disease retain
are: 24-h urinary free cortisol, low-dose dexamethasone- sensitivity to dexamethasone and show suppression of
suppression test, and assessment of midnight plasma serum cortisol to less than 50 nmol/L on either test.93,94
cortisol or late-night salivary cortisol. Additionally, a false-positive rate of up to 30% has been
reported in other admitted patients and healthy
Urinary free cortisol individuals.95 Thus, if clinical suspicion remains high,
Measurement of urinary cortisol is a direct assessment of repeated tests and other investigations are indicated.
circulating free (biologically active) cortisol. Excess
circulating cortisol saturates the binding proteins and is Midnight plasma cortisol or late-night salivary cortisol
excreted in urine as free cortisol, accounting for its Normal circadian rhythm of cortisol secretion is lost in
usefulness as a marker of hypercortisolaemia.23 Values patients with Cushing’s syndrome. A single sleeping
four-fold greater than the upper limit of normal are rare midnight plasma cortisol concentration of less than
except in Cushing’s syndrome.90 A single measurement 50 nmol/L effectively excludes Cushing’s syndrome at
has low sensitivity for patients with intermittent the time of the test and this might be especially helpful in
hypercortisolaemia.1,91 Low specificity is a common patients in whom there has been incomplete suppression
drawback, since in antibody-based assays the on dexamethasone testing. Concentrations of more than
concentrations of urinary free cortisol overlap those seen 50 nmol/L are noted in individuals with Cushing’s
in patients with other causes of hypercortisolaemia.1,91 syndrome, even those who suppress serum cortisol on
Use of high-performance liquid chromatography and low-dose dexamethasone testing,96 but this cutoff lacks
tandem mass spectrometry might improve diagnostic specificity because patients with acute illness also have
accuracy, although substances such as digoxin and values above this concentration. An awake midnight
carbamazepine can produce peaks in the high-performance concentration of cortisol in plasma of more than
liquid chromatography assay that give falsely high values.91 207 nmol/L differentiates between Cushing’s syndrome

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and other causes of hypercortisolaemia but can miss

mild disease diagnosis in about 7% of cases.97–99 Cushing's syndrome
Late-night salivary cortisol

Reports have renewed interest in measurement of Measure plasma corticotropin
salivary cortisol concentrations for diagnosis of Cushing’s
On occasion, CRH test
syndrome. Salivary cortisol indicates the amount of free
circulating cortisol, and its ease of collection and stability
<1·1 pmol/L on two 3·3 pmol/L
at room temperature make it a highly suitable screening or more occasions
procedure for outpatient assessment.98,100–109 Diagnostic
ranges vary between reports because of the different
assays and the comparison groups used to set cutoff Corticotropin-independent Corticotropin-dependent*
points. The test has a sensitivity and specificity of between Cushing's syndrome Cushing's syndrome
95% and 98%. Since salivary cortisol concentrations are

an order of magnitude lower than those of serum cortisol,
Adrenal imaging with CT Pituitary MRI and
the performance of the local assay must be known and CRH test+/–HDDST:
the appropriate cutoff point used. The test is of particular Adenoma >6 mm
Small or no
and
use in the assessment of cyclic Cushing’s syndrome108 Response to CRH test
adenoma
and in children.102,103 Adrenal No adrenal
and
lesion lesion
Suppression on
dexamethasone test Inconclusive BIPSS
Other tests
When doubt remains about diagnosis the dexamethasone- Adenoma
suppressed corticotropin-releasing hormone test110,111 and Carcinoma
the desmopressin test112,113 are promising diagnostic AIMAH Positive No
procedures. However, their diagnostic accuracy needs corticotropin corticotropin
? PPNAD gradient gradient
further validation. ? Exogenous
glucocorticoid
Establishing the cause of Cushing’s syndrome CT/MRI—thorax/abdomen
Once a diagnosis of Cushing’s syndrome is established, Somatostatin scintigraphy
the next step is to establish cause, which is best done in
major referral centres (figure 2). Investigation will vary
depending on availability of biochemical tests and Cushing's disease Ectopic corticotropin
imaging methods. The first step is to measure or ?ectopic corticotropin
concentrations of corticotropin in plasma. Concentrations
consistently lower than 1·1 pmol/L (5 pg/mL) indicate Figure 2: Diagnosis of cause of Cushing’s syndrome
corticotropin-independent Cushing’s syndrome and CRH=corticotropin-releasing hormone. AIMAH=corticotropin-independent macronodular hyperplasia.
PPNAD=primary pigmented nodular adrenal disease. BIPSS=bilateral inferior petrosal sinus sampling. SCLC=small-
attention can be turned to imaging the adrenal gland
cell lung cancer. HDDST=high-dose dexamethasone-suppression test. *If clear evidence of overt ectopic
with CT. Concentrations of corticotropin persistently corticotropin (eg, SCLC) BIPSS might not be needed.
greater than 3·3 pmol/L (15 pg/mL) almost always result
from corticotropin-dependent pathologies and need diagnosis of corticotropin-independent Cushing’s
investigation. Values between these two limits need syndrome with normal appearances of the adrenal glands
cautious interpretation because patients with Cushing’s on imaging, genetic testing for mutations of PRKAR1A or
disease and adrenal pathologies might have intermediate assessment of other features of Carney’s complex
values.1,91,114 Plasma should be separated rapidly and stored (lentigines, myxoma) can be of benefit as a diagnostic
at –40°C to avoid degradation and a falsely low result. A procedure. Exogenous glucocorticoid ingestion should be
positive corticotrophin-releasing hormone test shows an reconsidered also in this setting.
corticotropin-dependent hypercortisolism in a few
patients with Cushing’s disease with low baseline Corticotropin-dependent Cushing’s syndrome
corticotropin plasma concentrations. Overview
Differentiating between pituitary and non-pituitary sites of
Corticotropin-independent Cushing’s syndrome excess corticotropin secretion can be a considerable
In corticotropin-independent Cushing’s syndrome caused challenge in clinical endocrinology. Carcinoid tumours can
by an adrenal adenoma, carcinoma, or corticotropin- be clinically indistinguishable from Cushing’s disease and
independent macronodular adrenal hyperplasia, the are frequently difficult to identify with imaging, especially
anatomical cause is invariably visible on imaging with if radiological (pituitary, thoracic, pancreatic) so-called
CT.115 In primary pigmented nodular adrenal disease, the incidentalomas complicate interpretation. As a result,
adrenal glands can appear normal. Thus, in an established biochemical assessment rather than imaging is used to

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differentiate between pituitary and non-pituitary causes.10,11 test is of restricted usefulness in the differential diagnosis
In women with corticotropin-dependent Cushing’s of corticotropin-dependent Cushing’s syndrome.123,124
syndrome, nine out of ten cases will be due to Cushing’s Similarly, a combined test with corticotropin-releasing
disease. It is against this pretest likelihood that the hormone and desmopressin has been used,125 but larger
performance of any test needs to be judged. The results of series have suggested that overlap remains between
corticotropin-releasing hormone and dexamethasone tests responses in patients with Cushing’s disease and ectopic
and pituitary MRI should be judged together, and bilateral corticotropin syndrome.126 Responses to both corticotropin-
inferior petrosal sinus sampling is recommended unless releasing hormone testing and the high-dose
there is a clear diagnosis (figure 2). dexamethasone suppression test are also more frequently
High concentrations of cortisol can either saturate the discordant in patients with Cushing’s disease secondary to
11β-hydroxysteroid dehydrogenase type II enzyme in the a pituitary macroadenoma.18
kidney or decrease expression of this enzyme, allowing
cortisol to act even more as a mineralocorticoid.116 The Invasive testing
most common cause of hypokalaemia is the ectopic If a patient has corticotropin-dependent Cushing’s
corticotropin syndrome, but it is also present in patients syndrome, with responses on both dexamethasone
with Cushing’s disease who have very high cortisol suppression and corticotropin-releasing hormone testing
production.1 suggesting pituitary disease, and their pituitary MRI scan
shows an isolated lesion of 6 mm or more, most clinicians
Dynamic non-invasive tests will diagnose Cushing’s disease. A major drawback is that
The high-dose dexamethasone suppression tests (2 mg up to 40% of patients with proven Cushing’s disease have
given every 6 h for 48 h, or a single 8 mg dose) have been normal pituitary MRI scans.114 In these patients, sampling
in widespread use for many years. The tests are based on of the gradient of corticotropin from the pituitary gland to
the relative sensitivity of pituitary corticotrope adenomas the periphery is the most reliable means of discriminating
to the effects of glucocorticoids, compared with the between pituitary and non-pituitary sources of
resistance shown by non-pituitary tumours. About 80% of corticotropin. Since the pituitary effluent drains via the
patients with Cushing’s disease will show suppression of cavernous sinuses to the petrosal sinuses and then jugular
amount of cortisol in serum to a value of less than 50% of bulb, there is a gradient of the value of plasma corticotropin
the basal level.1 The performance of the test is, therefore, compared with the simultaneous peripheral sample when
less than the pretest likelihood of Cushing’s disease and, there is a central source of corticotropin. Bilateral inferior
thus, by itself the high-dose dexamethasone-suppression petrosal sinus sampling is a highly skilled and invasive
test has little diagnostic usefulness.117 Moreover, if the 48-h technique, requiring placement of catheters in both
low-dose dexamethasone-suppression test is used and if inferior petrosal sinuses. Catheter position and venous
suppression of serum cortisol by more than 30% has anatomy are confirmed by venography, because non-
already been shown, there is no further advantage of using uniform drainage is not uncommon. Diagnostic accuracy
the high-dose dexamethasone suppression test.93 We of the test needs corticotropin-releasing hormone to be
would not recommend continued routine use of the high- given. A basal central:peripheral ratio of more than 2:1 or
dose dexamethasone-suppression test, except when a ratio after stimulation with corticotropin-releasing
bilateral inferior petrosal sinus sampling is not available. hormone of more than 3:1 is consistent with Cushing’s
In the corticotropin-releasing hormone test recombinant disease.127 The combined data for many series suggest a
human or ovine-sequence corticotropin-releasing hormone sensitivity and specificity of 94%.128 When corticotropin-
is given as an intravenous bolus dose of either 1 µg/kg or, releasing hormone is unobtainable or too costly,
more usually, 100 µg. This dose stimulates corticotrope desmopressin offers a reasonable alternative, keeping in
tumour cells in the pituitary gland to release corticotropin mind that few patients with ectopic corticotropin secretion
and hence raise cortisol concentrations in serum, although have been studied in this way.
responses are uncommon in ectopic corticotropin Although bilateral inferior petrosal sinus sampling
syndrome. The ovine-sequence corticotropin-releasing remains the gold standard for differentiating between
hormone test has a sensitivity of 93% for Cushing’s disease pituitary and non-pituitary sources of corticotropin, data
based on corticotropin responses at 15 and 30 min.118 Using have highlighted some of the potential pitfalls. In a series
more detailed sampling (up to 90 min) and a stringent of 179 patients, two were noted to have responses
cutoff point of 50% increment in plasma corticotropin, consistent with Cushing’s disease but ultimately turned
ovine-sequence corticotropin-releasing hormone had a out to have the ectopic corticotropin syndrome, while
sensitivity of 86% for Cushing’s disease.119 This sensitivity nine patients had a false-negative response, turning out
also falls below the pretest likelihood, at least in women. to have Cushing’s disease.129 Small-series data have
An almost identical sensitivity is found for human suggested that these false-negative responses can be
sequence peptide sampling at the same timepoints.120 Since identified by simultaneous sampling of prolactin to
the V3 receptor is expressed in pituitary and many ectopic correct values in corticotropin.130,131 It is possible that
tumours secreting corticotropin,14,27,121,122 the desmopressin falsely positive results might be caused by inadequate

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suppression of the normal corticotropes; the duration useful for follow-up,142 because it has a low false-positive
and amount of hypercortisolism should be assessed rate.143 PET with 18-fluorodeoxyglucose is of little benefit
before the test. because these tumours are usually of low metabolic
In adults, bilateral inferior petrosal sinus sampling is activity.144 Although use of 11C-5-hydroxytryptophan has
only 70% accurate for lateralisation of the source of been proposed as an universal imaging technique for
corticotropin within the pituitary gland,1,91 but in children neuroendocrine tumours, few patients have been
it can have greater accuracy for this purpose than MRI.132 studied145 and further experience is needed to establish its
Sampling from the cavernous sinuses directly does not usefulness. Despite detailed investigation, the cause of
improve accuracy.133 corticotropin production might remain occult in 5–15%
Sampling from the internal jugular vein has been of patients, and these patients need continued follow-up,
proposed as a simplified procedure compared with this rate decreasing with time.10,11
bilateral inferior petrosal sinus sampling. Direct
comparison in the same patients has shown internal Management
jugular vein sampling to be inferior to bilateral inferior Medical therapies to lower cortisol
petrosal sinus sampling.134 This test can, however, have Metyrapone, ketoconazole, and mitotane can all be used to
usefulness in centres with limited sampling experience, lower cortisol by directly inhibiting synthesis and secretion
where bilateral inferior petrosal sinus sampling should be in the adrenal gland.2,19 Metyrapone and ketoconazole are
reserved for instances when the results are negative.135 enzyme inhibitors and have rapid onset of action, but
frequently control of hypercortisolism is lost with
Imaging corticotropin oversecretion in Cushing’s disease (known as
CT gives the best resolution of adrenal anatomy. In escape). These drugs are not usually effective as the sole
corticotropin-dependent Cushing’s syndrome, nodules long-term treatment of the disorder, and are used mainly
can arise, and adrenal hyperplasia is not always either in preparation for surgery or as adjunctive treatment
symmetrical, causing diagnostic confusion with a after surgery, pituitary radiotherapy, or both procedures.2
unilateral primary adrenal cause if the biochemistry is Mitotane acts as an adrenolytic drug with delayed onset but
not strictly assessed. In 30% of patients with Cushing’s longlasting action, but there is no escape occurrence.
disease, the adrenal glands appear normal, whereas in Medical treatment can also be used in patients who are
ectopic corticotropin the adrenal glands are virtually unwilling or unfit to undergo surgery. These drugs have
always homogeneously enlarged.136 gastrointestinal side-effects, and with ketoconazole,
Up to 40% of corticotrope adenomas causing Cushing’s hepatocellular dysfunction is frequently noted and rare
disease in adults are not visible on MRI scanning.114 Those cases of hepatic failure described.146 Treatment can be used
that are visible usually do not enhance with gadolinium long term for patients with ectopic corticotropin secretion,
on T1-weighted imaging. Use of dynamic MRI with but some centres opt for adrenalectomy in that setting.10,147
administration of intravenous contrast media and rapid For acute control of severe hypercortisolaemia when the
sequence acquisition does not improve the overall oral route is not available, the short-acting anaesthetic agent
diagnostic rate. However, spoiled gradient sequences etomidate can be very useful,148,149 including in children.150 In
might have high sensitivity in adults137 and children.138 patients with corticotropin-independent macronodular
There is also a 10% rate of pituitary incidentalomas in the adrenal hyperplasia, cortisol secretion can be controlled by
normal population,139 emphasising the need for careful blocking the aberrantly expressed receptor—eg, propranolol
biochemical discrimination of pituitary from non-pituitary use with aberrant β adrenergic receptor expression—or
sources of corticotropin. In the absence of a pituitary suppressing the ligand of the illegitimate receptor by giving
macroadenoma, an abnormal MRI scan is not conclusive somatostatin analogues in gastric inhibitory peptide-
evidence in favour of Cushing’s disease. responsive corticotropin-independent macronodular
Axial imaging with thin-cut multislice CT of the thorax adrenal hyperplasia or leuprolide in luteinising hormone-
and abdomen, MRI of the thorax, or both procedures, dependent Cushing’s syndrome.13,41,45,151
has the highest detection rate for ectopic corticotropin
syndrome.10–12 Most patients harbour small neuro- New therapies to reduce corticotropin
endocrine tumours, which can express somatostatin There has been renewed interest in use of agents that
receptors and might be disclosed on somatostatin- might directly inhibit the secretion of corticotropin by
receptor scintigraphy. However, although standard corticotrope tumours. The peroxisome proliferator
somatostatin scintigraphy can confirm functionality for a activated receptor γ agonist rosiglitazone reduced
lesion seen on axial imaging, it has only rarely been corticotropin and cortisol concentrations and prevented
shown to disclose truly occult tumours that are not visible tumour growth in an animal model of Cushing’s disease.152
on CT.1,10–12,140,141 Using higher than standard doses of Although human pituitary corticotrope tumours express
radionucleotide might, in some cases, disclose lesions peroxisome proliferator activated receptor γ,153 studies in
that were otherwise negative on imaging. In patients patients with Cushing’s disease have, unfortunately, been
with recurrent disease, somatostatin scintigraphy can be almost uniformly disappointing. Rosiglitazone achieved

Seminar
only short-term control of cortisol, with later escape.154,155 Cushing’s syndrome. Unfortunately, this goal often is
Similarly, the PPAR γ agonist pioglitazone (at licensed precluded by metastatic or occult disease, which is then
doses) did not affect corticotropin concentrations.156 treated medically or by adrenalectomy.10,11
Rosiglitazone at 1·5 times licensed dose did not decrease
the high amounts of corticotropin caused by corticotrope Adrenal surgery
tumour progression after bilateral adrenalectomy (Nelson’s Laparoscopic surgery is now the treatment of choice for
syndrome).157 Although these data are disappointing, it unilateral adrenal adenomas.182–190 Prognosis after removal
might be that higher doses or more potent agonists are of an adenoma is good, although, by contrast, the outlook
needed, but at present the use of PPAR γ ligands cannot be is almost uniformly poor in patients with adrenocortical
recommended. Corticotrope tumours may also express the carcinomas. These latter tumours frequently present
dopamine 2 receptor, and short-term administration of with metastases and are characterised by a dismal 5-year
cabergoline at a dose of 1–3 mg per week can reduce survival. They are not usually radiosensitive or
hypercortisolism in up to 40% of cases,158 but larger studies chemosensitive and the most important predictor of
are needed. A newer somatostatin analogue, SOM-230, outcome in this disease is the ability to do a complete
reduces corticotropin secretion in cell-culture models and resection.191
in culture of human corticotrope tumour cells.159 The In any cause of corticotropin-dependent Cushing’s
results of first trials in human beings are awaited: syndrome, total bilateral adrenalectomy induces a rapid
preliminary results look encouraging.160 In ectopic resolution of the clinical features. After surgery, patients
corticotropin syndrome, occasionally the somatostatin need lifelong treatment with glucocorticoids and
analogues octreotide and lanreotide directly inhibit mineralocorticoids. With low morbidity associated with
corticotropin secretion,140,141 or their combined use with laparoscopic adrenal surgery, this approach is being
high-dose cabergoline might be of benefit.161 Finally, considered more frequently, and possibly even as main
preliminary data in an animal model suggest that retinoic treatment in some individuals with Cushing’s disease,
acid might cause direct inhibition of corticotropin secretion especially when disease is severe or because of patient
from corticotrope tumours.162 preference. A major concern after bilateral adrenalectomy
in patients with Cushing’s disease is the development of
Surgery Nelson’s syndrome—a locally aggressive pituitary tumour
Tumour-specific surgery that secretes high concentrations of corticotropin,
Several series, including many within the past 5 years, resulting in pigmentation. Whether the tumour
have shown the results and long-term follow-up of trans- progression is a result of the lack of cortisol feedback
sphenoidal surgery for Cushing’s disease.18,163–179 Trans- after adrenalectomy, or whether the progression results
sphenoidal surgery offers the potential for a selective from corticotrope tumours that were programmed to
microadenectomy of the causative corticotrope adenoma behave in an aggressive manner from the beginning, is
leaving the remaining pituitary function intact. Taking all controversial.192 The tumour itself might be treated with
published series together, the quoted initial remission rate further surgery or radiotherapy.193 Some clinicians
is between 60% and 80% (<15% for macroadenomas18) but advocate pituitary radiotherapy at the time of
with a relapse rate of up to 20% when followed up for adrenalectomy to reduce the risk of this syndrome,194 but
many years. It is probable that these variations result from others have not confirmed this finding.192
varying surgical skill and from controversy about the
characterisation of remission or continuing disease in the Pituitary radiotherapy
postoperative period. If there is clear persistent disease Persisting hypercortisolaemia after trans-sphenoidal
postoperatively, immediate reoperation might be of surgery can be treated with pituitary radiotherapy.
benefit.180,181 Patients who are hypocortisolaemic in the Conventional fractionated radiotherapy is a very effective
immediate postoperative period need glucocorticoid means of treatment but is associated with long-term
treatment until the hypothalamo-pituitary-adrenal axis hypopituitarism,195 and can be very delayed in
recovers full activity usually 6–18 months after surgery. effectiveness, although it tends to be more rapidly
On long-term follow-up (10 years), however, the overall curative in children.196 Use of stereotactic radiosurgery
remission rate is about 60%, whereas on careful endocrine has also been reported.197,198 Despite enthusiasm for the
testing in some series, there can be deficiencies of other gamma knife, a relapse rate of up to 20% after treatment
pituitary hormones in up to 50% of cases.172 Although has been shown,199 which does not compare favourably
long-term remission is most probable when postoperative with conventional radiotherapy. It might, however, be
concentration of cortisol in serum is low (<50 nmol/L), more rapidly effective.
there is no threshold value that fully excludes possible
recurrence. These data emphasise the ongoing need for Conclusions
alternative therapies directed against the pituitary gland. Diagnosis and management of Cushing’s syndrome
Resection of the tumour producing corticotropin remains a considerable challenge. Our understanding of
ectopically is optimum treatment for this cause of the pathogenesis has advanced, but mainly with respect to

Seminar
the very rare causes of Cushing’s syndrome, although the 17 Storr HL, Isidori AM, Monson JP, Besser GM, Grossman AB,
underlying pathogenesis of the most common cause— Savage MO. Prepubertal Cushing’s disease is more common in
males, but there is no increase in severity at diagnosis.
Cushing’s disease—remains to be elucidated. Cushing’s J Clin Endocrinol Metab 2004; 89: 3818–20.
syndrome can be present in up to 2% of patients with 18 Woo YS, Isidori AM, Wat WZ, et al. Clinical and biochemical
poorly controlled type 2 diabetes, and has great implications characteristics of adrenocorticotropin-secreting macroadenomas.
J Clin Endocrinol Metab 2005; 90: 4963–69.
for screening of this at-risk population. Measurement of 19 Bertagna X R-DM, Giulhaume B, Girard F, Luton JP. Cushing’s
cortisol in saliva has emerged as a promising screening disease. Malden: Blackwell, 2002.
tool, and might be especially suited for this purpose. In 20 Gibson S, Ray DW, Crosby SR, et al. Impaired processing of
proopiomelanocortin in corticotroph macroadenomas.
view of the complexity of diagnosis, differential diagnosis, J Clin Endocrinol Metab 1996; 81: 497–502.
and further management, patients presenting with 21 Ray DW, Gibson S, Crosby SR, Davies D, Davis JR, White A.
Cushing’s syndrome warrant referral to major centres. The Elevated levels of adrenocorticotropin (ACTH) precursors in
outcome of treatment for the most common cause of post-adrenalectomy Cushing’s disease and their regulation by
glucocorticoids. J Clin Endocrinol Metab 1995; 80: 2430–36.
Cushing’s syndrome—Cushing’s disease—remains 22 Raffin-Sanson ML, de Keyzer Y, Bertagna X. Proopiomelanocortin, a
disappointing, and further developments are needed in polypeptide precursor with multiple functions: from physiology to
this area. pathological conditions. Eur J Endocrinol 2003; 149: 79–90.
23 Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic
Conflict of interest statement tests. Ann Intern Med 1990; 112: 434–44.
We declare that we have no conflict of interest. 24 Korbonits M, Bujalska I, Shimojo M, et al. Expression of 11 beta-
Acknowledgments hydroxysteroid dehydrogenase isoenzymes in the human pituitary:
induction of the type 2 enzyme in corticotropinomas and other
We thank Sarah Adnett for her expert assistance in preparing the
pituitary tumors. J Clin Endocrinol Metab 2001; 86: 2728–33.
manuscript. This research was supported in part by the National
25 Morris DG, Kola B, Borboli N, et al. Identification of
Institute of Child Health and Human Development, NIH (LKN salary).
adrenocorticotropin receptor messenger ribonucleic acid in the
References human pituitary and its loss of expression in pituitary adenomas.
1 Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis J Clin Endocrinol Metab 2003; 88: 6080–87.
and differential diagnosis of Cushing’s syndrome and pseudo- 26 Bilodeau SSV-K, Figarella-Branger D, Brue T, Drouin J. [OR32-2]
Cushing’s states. Endocr Rev 1998; 19: 647–72. Molecular mechanism of glucocorticoid resistance in Cushings
2 Nieman LK. Cushing’s syndrome. Philadephia: WB Saunders, 2001. disease. Endocrine Society’s 87th Annual Meeting 2005, San Diego,
3 Bertagna X, Raux-Demay M-C, Guilhaume B, Girard F, Luton J-P. CA, June 4–7, 2005. http://www.endo-society.org) (accessed October,
Cushing’s disease. Malden: Blackwell, 2002. 2005).
4 Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late 27 Dahia PL, Ahmed-Shuaib A, Jacobs RA, et al. Vasopressin receptor
prognosis of Cushing’s syndrome: a population-based study. expression and mutation analysis in corticotropin-secreting tumors.
J Clin Endocrinol Metab 2001; 86: 117–23. J Clin Endocrinol Metab 1996; 81: 1768–71.
5 Etxabe J, Vazquez JA. Morbidity and mortality in Cushing’s disease: 28 de Keyzer Y, Lenne F, Auzan C, et al. The pituitary V3 vasopressin
an epidemiological approach. Clin Endocrinol (Oxf) 1994; 40: 479–84. receptor and the corticotroph phenotype in ectopic ACTH
6 Ambrosi B, Bochicchio D, Ferrario R, Colombo P, Faglia G. syndrome. J Clin Invest 1996; 97: 1311–18.
Screening tests for Cushing’s syndrome. Clin Endocrinol (Oxf) 29 Picon A, Leblond-Francillard M, Raffin-Sanson ML, Lenne F,
1990; 33: 809–11. Bertagna X, de Keyzer Y. Functional analysis of the human pro-
7 Catargi B, Rigalleau V, Poussin A, et al. Occult Cushing’s syndrome opiomelanocortin promoter in the small cell lung carcinoma cell
in type-2 diabetes. J Clin Endocrinol Metab 2003; 88: 5808–13. line DMS-79. J Mol Endocrinol 1995; 15: 187–94.
8 Contreras LN, Cardoso E, Lozano MP, Pozzo J, Pagano P, 30 Picon A, Bertagna X, de Keyzer Y. Analysis of the human
Claus-Hermbeg H. Detection of preclinical Cushing’s syndrome in proopiomelanocortin gene promoter in a small cell lung carcinoma
overweight type 2 diabetic patients. Medicina (B Aires) 2000; 60: cell line reveals an unusual role for E2F transcription factors.
326–30. Oncogene 1999; 18: 2627–33.
9 Leibowitz G, Tsur A, Chayen SD, et al. Pre-clinical Cushing’s 31 Newell-Price J, King P, Clark AJ. The CpG island promoter of the
syndrome: an unexpected frequent cause of poor glycaemic control human proopiomelanocortin gene is methylated in nonexpressing
in obese diabetic patients. Clin Endocrinol (Oxf) 1996; 44: 717–22. normal tissue and tumors and represses expression. Mol Endocrinol
2001; 15: 338–48.
10 Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK.
Cushing’s syndrome due to ectopic corticotropin secretion: twenty 32 Pascual-Le Tallec L, Dulmet E, Bertagna X, de Keyzer Y. Identification
years’ experience at the National Institutes of Health. of genes associated with the corticotroph phenotype in bronchial
J Clin Endocrinol Metab 2005; 90: 4955–62. carcinoid tumors. J Clin Endocrinol Metab 2002; 87: 5015–22.
11 Isidori AM, Kaltsas GA, Pozza C, et al. The ectopic 33 Chabre O, Liakos P, Vivier J, et al. Cushing’s syndrome due to a
adrenocorticotrophin syndrome: clinical features, diagnosis, gastric inhibitory polypeptide-dependent adrenal adenoma: insights
management and long-term follow-up. J Clin Endocrinol Metab into hormonal control of adrenocortical tumorigenesis.
2006; 91: 371–77. J Clin Endocrinol Metab 1998; 83: 3134–43.
12 Wajchenberg BL, Mendonca BB, Liberman B, et al. Ectopic 34 Lacroix A, Bolte E, Tremblay J, et al. Gastric inhibitory polypeptide-
adrenocorticotropic hormone syndrome. Endocr Rev 1994; 15: dependent cortisol hypersecretion—a new cause of Cushing’s
752–87. syndrome. N Engl J Med 1992; 327: 974–80.
13 Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal 35 Lebrethon MC, Avallet O, Reznik Y, et al. Food-dependent Cushing’s
hormone receptors in adrenal Cushing’s syndrome. Endocr Rev syndrome: characterization and functional role of gastric inhibitory
2001; 22: 75–110. polypeptide receptor in the adrenals of three patients.
14 Dahia PL, Grossman AB. The molecular pathogenesis of
corticotroph tumors. Endocr Rev 1999; 20: 136–55. 36 N’Diaye N, Tremblay J, Hamet P, De Herder WW, Lacroix A.
Adrenocortical overexpression of gastric inhibitory polypeptide
15 Lidhar K, Korbonits M, Jordan S, et al. Low expression of the cell receptor underlies food-dependent Cushing’s syndrome.
cycle inhibitor p27Kip1 in normal corticotroph cells, corticotroph J Clin Endocrinol Metab 1998; 83: 2781–85.
tumors, and malignant pituitary tumors. J Clin Endocrinol Metab
1999; 84: 3823–30. 37 Horiba N, Suda T, Aiba M, et al. Lysine vasopressin stimulation of
cortisol secretion in patients with adrenocorticotropin-independent
16 Jordan S, Lidhar K, Korbonits M, Lowe DG, Grossman AB. Cyclin D macronodular adrenal hyperplasia. J Clin Endocrinol Metab 1995; 80:
and cyclin E expression in normal and adenomatous pituitary. 2336–41.
Eur J Endocrinol 2000; 143: R1–6.

Seminar
38 Arnaldi G, Gasc JM, de Keyzer Y, et al. Variable expression of the 57 Bourdeau I, Lacroix A, Schurch W, Caron P, Antakly T,
V1 vasopressin receptor modulates the phenotypic response of Stratakis CA. Primary pigmented nodular adrenocortical disease:
steroid-secreting adrenocortical tumors. J Clin Endocrinol Metab paradoxical responses of cortisol secretion to dexamethasone occur
1998; 83: 2029–35. in vitro and are associated with increased expression of the
39 Perraudin V, Delarue C, De Keyzer Y, et al. Vasopressin-responsive glucocorticoid receptor. J Clin Endocrinol Metab 2003; 88: 3931–37.
adrenocortical tumor in a mild Cushing’s syndrome: in vivo and in 58 Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E,
vitro studies. J Clin Endocrinol Metab 1995; 80: 2661–67. Spiegel AM. Activating mutations of the stimulatory G protein in
40 Lacroix A, Tremblay J, Touyz RM, et al. Abnormal adrenal and the McCune-Albright syndrome. N Engl J Med 1991; 325: 1688–95.
vascular responses to vasopressin mediated by a V1-vasopressin 59 Fragoso MC, Domenice S, Latronico AC, et al. Cushing’s syndrome
receptor in a patient with adrenocorticotropin-independent secondary to adrenocorticotropin-independent macronodular
macronodular adrenal hyperplasia, Cushing’s syndrome, and adrenocortical hyperplasia due to activating mutations of GNAS1
orthostatic hypotension. J Clin Endocrinol Metab 1997; 82: 2414–22. gene. J Clin Endocrinol Metab 2003; 88: 2147–51.
41 Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P. 60 Tissier F, Cavard C, Groussin L, et al. Mutations of beta-catenin in
Propranolol therapy for ectopic beta-adrenergic receptors in adrenal adrenocortical tumors: activation of the Wnt signaling pathway is a
Cushing’s syndrome. N Engl J Med 1997; 337: 1429–34. frequent event in both benign and malignant adrenocortical
42 Mircescu H, Jilwan J, N’Diaye N, et al. Are ectopic or abnormal tumors. Cancer Res 2005; 65: 7622–27.
membrane hormone receptors frequently present in adrenal 61 Bertherat J, Groussin L, Sandrini F, et al. Molecular and functional
Cushing’s syndrome? J Clin Endocrinol Metab 2000; 85: 3531–36. analysis of PRKAR1A and its locus (17q22-24) in sporadic
43 Willenberg HS, Stratakis CA, Marx C, Ehrhart-Bornstein M, adrenocortical tumors: 17q losses, somatic mutations, and protein
Chrousos GP, Bornstein SR. Aberrant interleukin-1 receptors in a kinase A expression and activity. Cancer Res 2003; 63: 5308–19.
cortisol-secreting adrenal adenoma causing Cushing’s syndrome. 62 Gicquel C, Bertagna X, Gaston V, et al. Molecular markers and long-
N Engl J Med 1998; 339: 27–31. term recurrences in a large cohort of patients with sporadic
44 Pralong FP, Gomez F, Guillou L, Mosimann F, Franscella S, adrenocortical tumors. Cancer Res 2001; 61: 6762–67.
Gaillard RC. Food-dependent Cushing’s syndrome: possible 63 Giordano TJ, Thomas DG, Kuick R, et al. Distinct transcriptional
involvement of leptin in cortisol hypersecretion. profiles of adrenocortical tumors uncovered by DNA microarray
J Clin Endocrinol Metab 1999; 84: 3817–22. analysis. Am J Pathol 2003; 162: 521–31.
45 Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in 64 Latronico AC, Pinto EM, Domenice S, et al. An inherited mutation
luteinizing hormone—dependent Cushing’s syndrome. outside the highly conserved DNA-binding domain of the p53
N Engl J Med 1999; 341: 1577–81. tumor suppressor protein in children and adults with sporadic
46 Bertherat J, Contesse V, Louiset E, et al. In vivo and in vitro adrenocortical tumors. J Clin Endocrinol Metab 2001; 86: 4970–73.
screening for illegitimate receptors in adrenocorticotropin- 65 Ribeiro RC, Sandrini F, Figueiredo B, et al. An inherited p53
independent macronodular adrenal hyperplasia causing Cushing’s mutation that contributes in a tissue-specific manner to pediatric
syndrome: identification of two cases of gonadotropin/gastric adrenal cortical carcinoma. Proc Natl Acad Sci USA 2001; 98:
inhibitory polypeptide-dependent hypercortisolism. 9330–35.
J Clin Endocrinol Metab 2005; 90: 1302–10. 66 Davies JH, Storr HL, Davies K, et al. Final adult height and body
47 Bourdeau I, D’Amour P, Hamet P, Boutin JM, Lacroix A. Aberrant mass index after cure of paediatric Cushing’s disease.
membrane hormone receptors in incidentally discovered bilateral Clin Endocrinol (Oxf) 2005; 62: 466–72.
macronodular adrenal hyperplasia with subclinical Cushing’s 67 Savage MO, Lienhardt A, Lebrethon MC, et al. Cushing’s disease in
syndrome. J Clin Endocrinol Metab 2001; 86: 5534–40. childhood: presentation, investigation, treatment and long-term
48 Mazzuco TL, Chabre O, Sturm N, Feige JJ, Thomas M. Ectopic outcome. Horm Res 2001; 55 (suppl 1): 24–30.
expression of the gastric inhibitory polypeptide receptor gene is a 68 Savage MO, Lebrethon MC, Blair JC, et al. Growth abnormalities
sufficient genetic event to induce benign adrenocortical tumor in a associated with adrenal disorders and their management. Horm Res
xenotransplantation model. Endocrinology 2006; 147: 782–90. 2001; 56 (suppl 1): 19–23.
49 Groussin L, Perlemoine K, Contesse V, et al. The ectopic expression 69 Magiakou MA, Mastorakos G, Oldfield EH, et al. Cushing’s
of the gastric inhibitory polypeptide receptor is frequent in syndrome in children and adolescents. Presentation, diagnosis, and
adrenocorticotropin-independent bilateral macronodular adrenal therapy. N Engl J Med 1994; 331: 629–36.
hyperplasia, but rare in unilateral tumors. J Clin Endocrinol Metab 70 Weber A, Trainer PJ, Grossman AB, et al. Investigation, management
2002; 87: 1980–85. and therapeutic outcome in 12 cases of childhood and adolescent
50 Swords FM, Aylwin S, Perry L, et al. The aberrant expression of the Cushing’s syndrome. Clin Endocrinol (Oxf) 1995; 43: 19–28.
gastric inhibitory polypeptide (GIP) receptor in adrenal hyperplasia: 71 Pecori Giraldi F, Moro M, Cavagnini F. Gender-related differences
does chronic adrenocorticotropin exposure stimulate up-regulation in the presentation and course of Cushing’s disease.
of GIP receptors in Cushing’s disease? J Clin Endocrinol Metab J Clin Endocrinol Metab 2003; 88: 1554–58.
2005; 90: 3009–16.
72 Faggiano A, Pivonello R, Melis D, et al. Nephrolithiasis in Cushing’s
51 Swords FM, Baig A, Malchoff DM, et al. Impaired desensitization of disease: prevalence, etiopathogenesis, and modification after
a mutant adrenocorticotropin receptor associated with apparent disease cure. J Clin Endocrinol Metab 2003; 88: 2076–80.
constitutive activity. Mol Endocrinol 2002; 16: 2746–53.
73 Di Somma C, Pivonello R, Loche S, et al. Severe impairment of
52 Storr HL, Mitchell H, Swords FM, et al. Clinical features, diagnosis, bone mass and turnover in Cushing’s disease: comparison between
treatment and molecular studies in paediatric Cushing’s syndrome childhood-onset and adulthood-onset disease. Clin Endocrinol (Oxf)
due to primary nodular adrenocortical hyperplasia. 2002; 56: 153–58.
Clin Endocrinol (Oxf) 2004; 61: 553–59.
74 Scommegna S, Greening JP, Storr HL, et al. Bone mineral density
53 Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular at diagnosis and following successful treatment of pediatric
features of the Carney complex: diagnostic criteria and Cushing’s disease. J Endocrinol Invest 2005; 28: 231–35.
recommendations for patient evaluation. J Clin Endocrinol Metab
75 Minetto M, Reimondo G, Osella G, Ventura M, Angeli A, Terzolo M.
2001; 86: 4041–46.
Bone loss is more severe in primary adrenal than in pituitary-
54 Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene dependent Cushing’s syndrome. Osteoporos Int 2004; 15: 855–61.
encoding the protein kinase A type I-alpha regulatory subunit in
76 Ohmori N, Nomura K, Ohmori K, Kato Y, Itoh T, Takano K.
patients with the Carney complex. Nat Genet 2000; 26: 89–92.
Osteoporosis is more prevalent in adrenal than in pituitary
55 Casey M, Vaughan CJ, He J, et al. Mutations in the protein kinase A Cushing’s syndrome. Endocr J 2003; 50: 1–7.
R1alpha regulatory subunit cause familial cardiac myxomas and
77 Forget H, Lacroix A, Cohen H. Persistent cognitive impairment
Carney complex. J Clin Invest 2000; 106: R31–38.
following surgical treatment of Cushing’s syndrome.
56 Groussin L, Jullian E, Perlemoine K, et al. Mutations of the Psychoneuroendocrinology 2002; 27: 367–83.
PRKAR1A gene in Cushing’s syndrome due to sporadic primary
78 Bourdeau I, Bard C, Noel B, et al. Loss of brain volume in
pigmented nodular adrenocortical disease. J Clin Endocrinol Metab
endogenous Cushing’s syndrome and its reversibility after correction
2002; 87: 4324–29.
of hypercortisolism. J Clin Endocrinol Metab 2002; 87: 1949–54.

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79 Lindsay JR, Nansel T, Baid S, Gumowski J, Nieman LK. Long-term 101 Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening
impaired quality of life in Cushing’s syndrome despite initial test for Cushing’s syndrome. J Clin Endocrinol Metab 1998; 83:
improvement after surgical remission. J Clin Endocrinol Metab 2006; 2681–86.
91: 447–53. 102 Castro M, Elias PC, Quidute AR, Halah FP, Moreira AC. Out-patient
80 Heald AH, Ghosh S, Bray S, et al. Long-term negative impact on screening for Cushing’s syndrome: the sensitivity of the combination
quality of life in patients with successfully treated Cushing’s of circadian rhythm and overnight dexamethasone suppression
disease. Clin Endocrinol (Oxf) 2004; 61: 458–65. salivary cortisol tests. J Clin Endocrinol Metab 1999; 84: 878–82.
81 van Aken MO, Pereira AM, Biermasz NR, et al. Quality of life in 103 Gafni RI, Papanicolaou DA, Nieman LK. Nighttime salivary cortisol
patients after long-term biochemical cure of Cushing’s disease. measurement as a simple, noninvasive, outpatient screening test for
J Clin Endocrinol Metab 2005; 90: 3279–86. Cushing’s syndrome in children and adolescents. J Pediatr 2000; 137:
82 Faggiano A, Pivonello R, Spiezia S, et al. Cardiovascular risk factors 30–35.
and common carotid artery caliber and stiffness in patients with 104 Martinelli CE Jr, Sader SL, Oliveira EB, Daneluzzi JC, Moreira AC.
Cushing’s disease during active disease and 1 year after disease Salivary cortisol for screening of Cushing’s syndrome in children.
remission. J Clin Endocrinol Metab 2003; 88: 2527–33. Clin Endocrinol (Oxf) 1999; 51: 67–71.
83 Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G. High 105 Papanicolaou DA, Mullen N, Kyrou I, Nieman LK. Nighttime salivary
cardiovascular risk in patients with Cushing’s syndrome according to cortisol: a useful test for the diagnosis of Cushing’s syndrome.
1999 WHO/ISH guidelines. Clin Endocrinol (Oxf) 2004; 61: 768–77. J Clin Endocrinol Metab 2002; 87: 4515–21.
84 Zacharieva S, Atanassova I, Nachev E, et al. Markers of vascular 106 Castro M, Elias LL, Elias PC, Moreira AC. A dose-response study of
function in hypertension due to Cushing’s syndrome. salivary cortisol after dexamethasone suppression test in Cushing’s
Horm Metab Res 2005; 37: 36–39. disease and its potential use in the differential diagnosis of Cushing’s
85 Terzolo M, Allasino B, Bosio S, et al. Hyperhomocysteinemia in syndrome. Clin Endocrinol (Oxf) 2003; 59: 800–05.
patients with Cushing’s syndrome. J Clin Endocrinol Metab 2004; 89: 107 Trilck M, Flitsch J, Ludecke DK, Jung R, Petersenn S. Salivary cortisol
3745–51. measurement—a reliable method for the diagnosis of Cushing’s
86 Rockall AG, Sohaib SA, Evans D, et al. Hepatic steatosis in syndrome. Exp Clin Endocrinol Diabetes 2005; 113: 225–30.
Cushing’s syndrome: a radiological assessment using computed 108 Yaneva M, Mosnier-Pudar H, Dugue MA, Grabar S, Fulla Y,
tomography. Eur J Endocrinol 2003; 149: 543–48. Bertagna X. Midnight salivary cortisol for the initial diagnosis of
87 Rockall AG, Sohaib SA, Evans D, et al. Computed tomography Cushing’s syndrome of various causes. J Clin Endocrinol Metab 2004;
assessment of fat distribution in male and female patients with 89: 3345–51.
Cushing’s syndrome. Eur J Endocrinol 2003; 149: 561–67. 109 Viardot A, Huber P, Puder J, Zulewski H, Keller U, Muller B.
88 Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s Reproducibility of nighttime salivary cortisol and its use in the
syndrome during pregnancy: personal experience and review of the diagnosis of hypercortisolism as compared to urinary free cortisol and
literature. J Clin Endocrinol Metab 2005; 90: 3077–83. overnight dexamethasone suppression test. J Clin Endocrinol Metab
89 Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in 2005; 90: 5730–36.
pregnancy: challenges in disease detection and treatment. 110 Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. The
Endocr Rev 2005; 26: 775–99. dexamethasone-suppressed corticotropin-releasing hormone
90 Yanovski JA, Cutler GB Jr. Glucocorticoid action and the clinical stimulation test differentiates mild Cushing’s disease from normal
features of Cushing’s syndrome. Endocrinol Metab Clin North Am physiology. J Clin Endocrinol Metab 1998; 83: 348–52.
1994; 23: 487–509. 111 Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. Corticotropin-
91 Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and releasing hormone stimulation following low-dose dexamethasone
complications of Cushing’s syndrome: a consensus statement. administration: a new test to distinguish Cushing’s syndrome from
J Clin Endocrinol Metab 2003; 88: 5593–602. pseudo-Cushing’s states. JAMA 1993; 269: 2232–38.
92 Putignano P, Kaltsas GA, Satta MA, Grossman AB. The effects of 112 Coiro V, Volpi R, Capretti L, Caffarri G, Chiodera P. Desmopressin
anti-convulsant drugs on adrenal function. Horm Metab Res 1998; and hexarelin tests in alcohol-induced pseudo-Cushing’s syndrome.
30: 389–97. J Intern Med 2000; 247: 667–73.
93 Isidori AM, Kaltsas GA, Mohammed S, et al. Discriminatory value 113 Moro M, Putignano P, Losa M, Invitti C, Maraschini C, Cavagnini F.
of the low-dose dexamethasone suppression test in establishing the The desmopressin test in the differential diagnosis between
diagnosis and differential diagnosis of Cushing’s syndrome. Cushing’s disease and pseudo-Cushing states. J Clin Endocrinol Metab
J Clin Endocrinol Metab 2003; 88: 5299–306. 2000; 85: 3569–74.
94 Findling JW, Raff H, Aron DC. The low-dose dexamethasone 114 Invitti C, Pecori Giraldi F, de Martin M, Cavagnini F. Diagnosis and
suppression test: a reevaluation in patients with Cushing’s management of Cushing’s syndrome: results of an Italian multicentre
syndrome. J Clin Endocrinol Metab 2004; 89: 1222–26. study. Study Group of the Italian Society of Endocrinology on the
Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis.
95 Crapo L. Cushing’s syndrome: a review of diagnostic tests.
Metabolism 1979; 28: 955–77.
115 Rockall AG, Babar SA, Sohaib SA, et al. CT and MR imaging of the
96 Newell-Price J, Trainer P, Perry L, Wass J, Grossman A, Besser M.
adrenal glands in ACTH-independent cushing syndrome.
A single sleeping midnight cortisol has 100% sensitivity for the
Radiographics 2004; 24: 435–52.
diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 1995; 43:
545–50. 116 Stewart PM, Walker BR, Holder G, O’Halloran D, Shackleton CH. 11
beta-hydroxysteroid dehydrogenase activity in Cushing’s syndrome:
97 Papanicolaou DA, Yanovski JA, Cutler GB Jr, Chrousos GP,
explaining the mineralocorticoid excess state of the ectopic
Nieman LK. A single midnight serum cortisol measurement
adrenocorticotropin syndrome. J Clin Endocrinol Metab 1995; 80:
distinguishes Cushing’s syndrome from pseudo-Cushing states.
3617–20.
117 Aron DC, Raff H, Findling JW. Effectiveness versus efficacy: the
98 Putignano P, Toja P, Dubini A, Pecori Giraldi F, Corsello SM,
limited value in clinical practice of high dose dexamethasone
Cavagnini F. Midnight salivary cortisol versus urinary free and
suppression testing in the differential diagnosis of
midnight serum cortisol as screening tests for Cushing’s syndrome.
adrenocorticotropin-dependent Cushing’s syndrome.
99 Reimondo G, Allasino B, Bovio S, Paccotti P, Angeli A, Terzolo M.
118 Nieman LK, Oldfield EH, Wesley R, Chrousos GP, Loriaux DL,
Evaluation of the effectiveness of midnight serum cortisol in the
Cutler GB Jr. A simplified morning ovine corticotropin-releasing
diagnostic procedures for Cushing’s syndrome. Eur J Endocrinol
hormone stimulation test for the differential diagnosis of
2005; 153: 803–09.
adrenocorticotropin-dependent Cushing’s syndrome.
100 Viardot A, Huber P, Puder JJ, Zulewski H, Keller U, Muller B. J Clin Endocrinol Metab 1993; 77: 1308–12.
Reproducibility of nighttime salivary cortisol and its use in the
119 Reimondo G, Paccotti P, Minetto M, et al. The corticotrophin-
diagnosis of hypercortisolism compared with urinary free cortisol
releasing hormone test is the most reliable noninvasive method to
and overnight dexamethasone suppression test.
differentiate pituitary from ectopic ACTH secretion in Cushing’s
syndrome. Clin Endocrinol (Oxf) 2003; 58: 718–24.

Seminar
120 Newell-Price J, Morris DG, Drake WM, et al. Optimal response 139 Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH.
criteria for the human CRH test in the differential diagnosis of Pituitary magnetic resonance imaging in normal human volunteers:
ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab occult adenomas in the general population. Ann Intern Med 1994; 120:
2002; 87: 1640–45. 817–20.
121 Arlt W, Dahia PL, Callies F, et al. Ectopic ACTH production by a 140 Lamberts SW, de Herder WW, Krenning EP, Reubi JC. A role of
bronchial carcinoid tumour responsive to desmopressin in vivo and (labeled) somatostatin analogs in the differential diagnosis and
in vitro. Clin Endocrinol (Oxf) 1997; 47: 623–27. treatment of Cushing’s syndrome. J Clin Endocrinol Metab 1994; 78:
122 de Keyzer Y, Rene P, Lenne F, Auzan C, Clauser E, Bertagna X. V3 17–19.
vasopressin receptor and corticotropic phenotype in pituitary and 141 Phlipponneau M, Nocaudie M, Epelbaum J, et al. Somatostatin
nonpituitary tumors. Horm Res 1997; 47: 259–62. analogs for the localization and preoperative treatment of an
123 Newell-Price J. The desmopressin test and Cushing’s syndrome: adrenocorticotropin-secreting bronchial carcinoid tumor.
current state of play. Clin Endocrinol (Oxf) 1997; 47: 173–74. J Clin Endocrinol Metab 1994; 78: 20–24.
124 Tsagarakis S, Tsigos C, Vasiliou V, et al. The desmopressin and 142 Granberg D, Sundin A, Janson ET, Oberg K, Skogseid B, Westlin JE.
combined CRH-desmopressin tests in the differential diagnosis Octreoscan in patients with bronchial carcinoid tumours.
of ACTH-dependent Cushing’s syndrome: constraints imposed Clin Endocrinol (Oxf) 2003; 59: 793–99.
by the expression of V2 vasopressin receptors in tumors with 143 Tsagarakis S, Christoforaki M, Giannopoulou H, et al. A reappraisal
ectopic ACTH secretion. J Clin Endocrinol Metab 2002; 87: 1646–53. of the utility of somatostatin receptor scintigraphy in patients with
125 Newell-Price J, Perry L, Medbak S, et al. A combined test using ectopic adrenocorticotropin Cushing’s syndrome.
desmopressin and corticotropin-releasing hormone in the differential J Clin Endocrinol Metab 2003; 88: 4754–58.
diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 1997; 82: 144 Pacak K, Ilias I, Chen CC, Carrasquillo JA, Whatley M, Nieman LK.
176–81. The role of [(18)F]fluorodeoxyglucose positron emission
126 Tsagarakis S, Kaskarelis IS, Kokkoris P, Malagari C, Thalassinos N. tomography and [(111)In]-diethylenetriaminepentaacetate-D-Phe-
The application of a combined stimulation with CRH and pentetreotide scintigraphy in the localization of ectopic
desmopressin during bilateral inferior petrosal sinus sampling in adrenocorticotropin-secreting tumors causing Cushing’s syndrome.
patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 2000; 52: J Clin Endocrinol Metab 2004; 89: 2214–21.
355–61. 145 Orlefors H, Sundin A, Garske U, et al. Whole-body (11)C-5-
127 Oldfield EH, Doppman JL, Nieman LK, et al. Petrosal sinus hydroxytryptophan positron emission tomography as a universal
sampling with and without corticotropin-releasing hormone for the imaging technique for neuroendocrine tumors: comparison with
differential diagnosis of Cushing’s syndrome. N Engl J Med 1991; somatostatin receptor scintigraphy and computed tomography.
325: 897–905. J Clin Endocrinol Metab 2005; 90: 3392–400.
128 Lindsay JR, Nieman LK. Differential diagnosis and imaging in 146 Nieman LK. Medical therapy of Cushing’s disease. Pituitary 2002; 5:
Cushing’s syndrome. Endocrinol Metab Clin North Am 2005; 34: 77–82.
403–21. 147 Aniszewski JP, Young WF Jr, Thompson GB, Grant CS,
129 Swearingen B, Katznelson L, Miller K, et al. Diagnostic errors after van Heerden JA. Cushing syndrome due to ectopic
inferior petrosal sinus sampling. J Clin Endocrinol Metab 2004; 89: adrenocorticotropic hormone secretion. World J Surg 2001; 25:
3752–63. 934–40.
130 McNally PG, Bolia A, Absalom SR, Falconer-Smith J, Howlett TA. 148 Krakoff J, Koch CA, Calis KA, Alexander RH, Nieman LK. Use of a
Preliminary observations using endocrine markers of pituitary parenteral propylene glycol-containing etomidate preparation for
venous dilution during bilateral simultaneous inferior petrosal the long-term management of ectopic Cushing’s syndrome.
sinus catheterization in Cushing’s syndrome: is combined CRF J Clin Endocrinol Metab 2001; 86: 4104–08.
and TRH stimulation of value? Clin Endocrinol (Oxf) 1993; 39: 149 Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM.
681–86. Emergency and prolonged use of intravenous etomidate to control
131 Findling JW, Kehoe ME, Raff H. Identification of patients with hypercortisolemia in a patient with Cushing’s syndrome and
Cushing’s disease with negative pituitary adrenocorticotropin peritonitis. J Clin Endocrinol Metab 1998; 83: 3542–44.
gradients during inferior petrosal sinus sampling: prolactin as an 150 Greening JE, Brain CE, Perry LA, et al. Efficient short-term control
index of pituitary venous effluent. J Clin Endocrinol Metab 2004; 89: of hypercortisolaemia by low-dose etomidate in severe paediatric
6005–09. Cushing’s disease. Horm Res 2005; 64: 140–43.
132 Lienhardt A, Grossman AB, Dacie JE, et al. Relative contributions of 151 Reznik Y, Allali-Zerah V, Chayvialle JA, et al. Food-dependent
inferior petrosal sinus sampling and pituitary imaging in the Cushing’s syndrome mediated by aberrant adrenal sensitivity to
investigation of children and adolescents with ACTH-dependent gastric inhibitory polypeptide. N Engl J Med 1992; 327: 981–86.
Cushing’s syndrome. J Clin Endocrinol Metab 2001; 86: 5711–14. 152 Heaney AP, Fernando M, Yong WH, Melmed S. Functional PPAR-
133 Liu C, Lo JC, Dowd CF, et al. Cavernous and inferior petrosal sinus gamma receptor is a novel therapeutic target for ACTH-secreting
sampling in the evaluation of ACTH-dependent Cushing’s pituitary adenomas. Nat Med 2002; 8: 1281–87.
syndrome. Clin Endocrinol (Oxf) 2004; 61: 478–86. 153 Heaney AP, Fernando M, Melmed S. PPAR-gamma receptor
134 Erickson D, Huston J 3rd, Young WF Jr, et al. Internal jugular vein ligands: novel therapy for pituitary adenomas. J Clin Invest 2003;
sampling in adrenocorticotropic hormone-dependent Cushing’s 111: 1381–88.
syndrome: a comparison with inferior petrosal sinus sampling. 154 Cannavo S, Arosio M, Almoto B, Dall’Asta C, Ambrosi B.
Clin Endocrinol (Oxf) 2004; 60: 413–19. Effectiveness of long-term rosiglitazone administration in
135 Ilias I, Chang R, Pacak K, et al. Jugular venous sampling: an patients with Cushing’s disease. Clin Endocrinol (Oxf) 2005; 63:
alternative to petrosal sinus sampling for the diagnostic evaluation 118–19.
of adrenocorticotropic hormone-dependent Cushing’s syndrome. 155 Ambrosi B, Dall’Asta C, Cannavo S, et al. Effects of chronic
J Clin Endocrinol Metab 2004; 89: 3795–800. administration of PPAR-gamma ligand rosiglitazone in Cushing’s
136 Sohaib SA, Hanson JA, Newell-Price JD, et al. CT appearance of the disease. Eur J Endocrinol 2004; 151: 173–78.
adrenal glands in adrenocorticotrophic hormone-dependent 156 Suri D, Weiss RE. Effect of pioglitazone on adrenocorticotropic
Cushing’s syndrome. Am J Roentgenol 1999; 172: 997–1002. hormone and cortisol secretion in Cushing’s disease.
137 Patronas N, Bulakbasi N, Stratakis CA, et al. Spoiled gradient J Clin Endocrinol Metab 2005; 90: 1340–46.
recalled acquisition in the steady state technique is superior to 157 Munir A, Song F, Ince P, Ross R, Newell-Price J. A pilot study of
conventional postcontrast spin echo technique for magnetic prolonged high dose rosiglitazone therapy (12mg/day) in Nelson’s
resonance imaging detection of adrenocorticotropin-secreting syndrome. Society for Endocrinology 194rd Annual Meeting 2004,
pituitary tumors. J Clin Endocrinol Metab 2003; 88: 1565–69. London, UK. http://www.endocrine-abstracts.org (accessed October,
138 Batista D, Courkoutsakis NA, Oldfield EH, et al. Detection of 2005).
adrenocorticotropin-secreting pituitary adenomas by magnetic 158 Pivonello R, Ferone D, de Herder WW, et al. Dopamine receptor
resonance imaging in children and adolescents with cushing expression and function in corticotroph pituitary tumors.
disease. J Clin Endocrinol Metab 2005; 90: 5134–40. J Clin Endocrinol Metab 2004; 89: 2452–62.

Seminar
159 Hofland LJ, van der Hoek J, Feelders R, et al. The multi-ligand 179 Atkinson AB, Kennedy A, Wiggamvan MI, McCance DR,
somatostatin analogue SOM230 inhibits ACTH secretion by Sheridan B. Long-term remission rates after pituitary surgery for
cultured human corticotroph adenomas via somatostatin receptor Cushing’s disease: the need for long-term surveillance.
type 5. Eur J Endocrinol 2005; 152: 645–54. Clinical Endocrinol (Oxf) 2005; 63: 549–59.
160 Boscaro M, Atkinson A, Bertherat J, Petersenn S, Glusman JE, 180 Trainer PJ, Lawrie HS, Verhelst J, et al. Transsphenoidal
Tran LL. SOM230 Cushing’s disease study group. [p2-531] Early data resection in Cushing’s disease: undetectable serum cortisol as
on the efficacy and safety of the novel multi-ligand somatostatin the definition of successful treatment. Clin Endocrinol (Oxf) 1993;
analog, SOM230, in patients with Cushing’s disease. Endocrine 38: 73–78.
Society, 87th Annual Meeting June 4–7, 2005, San Diego, CA. 181 Locatelli M, Vance ML, Laws ER. Clinical review: the strategy of
http://www.endo-society.org (accessed October, 2005). immediate reoperation for transsphenoidal surgery for Cushing’s
161 Pivonello R, Ferone D, Lamberts SW, Colao A. Cabergoline plus disease. J Clin Endocrinol Metab 2005; 90: 5478–82.
lanreotide for ectopic Cushing’s syndrome. N Engl J Med 2005; 352: 182 Brunt LM, Moley JF, Doherty GM, Lairmore TC, DeBenedetti MK,
2457–58. Quasebarth MA. Outcomes analysis in patients undergoing
162 Paez-Pereda M, Kovalovsky D, Hopfner U, et al. Retinoic acid laparoscopic adrenalectomy for hormonally active adrenal tumors.
prevents experimental Cushing syndrome. J Clin Invest 2001; 108: Surgery 2001; 130: 629–35.
1123–31. 183 Chavez-Rodriguez J, Pasieka JL. Adrenal lesions assessed in the era
163 Benbassat CA, Tsvetov G, Shefet D, Weinstein R, Rappaport ZH. of laparoscopic adrenalectomy: a modern day series. Am J Surg
[Cushing disease: long-term follow-up after transsphenoidal 2005; 189: 581–86.
surgery]. Harefuah 2004; 143: 636–95. 184 Iacobone M, Mantero F, Basso SM, Lumachi F, Favia G. Results and
164 Chee GH, Mathias DB, James RA, Kendall-Taylor P. Transsphenoidal long-term follow-up after unilateral adrenalectomy for ACTH-
pituitary surgery in Cushing’s disease: can we predict outcome? independent hypercortisolism in a series of fifty patients.
Clin Endocrinol (Oxf) 2001; 54: 617–26. J Endocrinol Invest 2005; 28: 327–32.
165 Colombo P, Dall’Asta C, Barbetta L, et al. Usefulness of the 185 Meyer A, Behrend M. Cushing’s syndrome: adrenalectomy and
desmopressin test in the postoperative evaluation of patients with long-term results. Dig Surg 2004; 21: 363–70.
Cushing’s disease. Eur J Endocrinol 2000; 143: 227–34. 186 O’Boyle CJ, Kapadia CR, Sedman PC, Brough WA, Royston CM.
166 Dall’Asta C, Barbetta L, Bonavina L, Beck-Peccoz P, Ambrosi B. Laparoscopic transperitoneal adrenalectomy. Surg Endosc 2003; 17:
Recurrence of Cushing’s disease preceded by the reappearance of 1905–09.
ACTH and cortisol responses to desmopressin test. Pituitary 187 Porpiglia F, Fiori C, Bovio S, et al. Bilateral adrenalectomy for
2005; published online April 28. DOI: 10.1007/s11102-005-0008-9. Cushing’s syndrome: a comparison between laparoscopy and open
167 Estrada J, Garcia-Uria J, Lamas C, et al. The complete normalization surgery. J Endocrinol Invest 2004; 27: 654–58.
of the adrenocortical function as the criterion of cure after 188 Poulose BK, Holzman MD, Lao OB, Grogan EL, Goldstein RE.
transsphenoidal surgery for Cushing’s disease. Laparoscopic adrenalectomy: 100 resections with clinical long-term
J Clin Endocrinol Metab 2001; 86: 5695–99. follow-up. Surg Endosc 2005; 19: 379–85.
168 Hague K, Post KD, Morgello S. Absence of peritumoral Crooke’s 189 Vella A, Thompson GB, Grant CS, van Heerden JA, Farley DR,
change is associated with recurrence in surgically treated Cushing’s Young WF Jr. Laparoscopic adrenalectomy for adrenocorticotropin-
disease. Surg Neurol 2000; 53: 77–81. dependent Cushing’s syndrome. J Clin Endocrinol Metab 2001; 86:
169 Hammer GD, Tyrrell JB, Lamborn KR, et al. Transsphenoidal 1596–99.
microsurgery for Cushing’s disease: initial outcome and long-term 190 Zeh HJ 3rd, Udelsman R. One hundred laparoscopic
results. J Clin Endocrinol Metab 2004; 89: 6348–57. adrenalectomies: a single surgeon’s experience. Ann Surg Oncol
170 Pereira AM, van Aken MO, van Dulken H, et al. Long-term 2003; 10: 1012–17.
predictive value of postsurgical cortisol concentrations for cure and 191 Dackiw AP, Lee JE, Gagel RF, Evans DB. Adrenal cortical
risk of recurrence in Cushing’s disease. J Clin Endocrinol Metab carcinoma. World J Surg 2001; 25: 914–26.
2003; 88: 5858–64. 192 Assie G, Bahurel H, Bertherat J, Kujas M, Legmann P,
171 Pimentel-Filho FR, Silva ME, Nogueira KC, Berger K, Cukiert A, Bertagna X. The Nelson’s syndrome revisited. Pituitary 2004; 7:
Liberman B. Pituitary-adrenal dynamics after ACTH-secreting 209–15.
pituitary tumor resection in patients receiving no steroids post- 193 Kelly PA, Samandouras G, Grossman AB, Afshar F, Besser GM,
operatively. J Endocrinol Invest 2005; 28: 502–08. Jenkins PJ. Neurosurgical treatment of Nelson’s syndrome.
172 Rees DA, Hanna FW, Davies JS, Mills RG, Vafidis J, Scanlon MF. J Clin Endocrinol Metab 2002; 87: 5465–69.
Long-term follow-up results of transsphenoidal surgery for 194 Jenkins PJ, Trainer PJ, Plowman PN, et al. The long-term outcome
Cushing’s disease in a single centre using strict criteria for after adrenalectomy and prophylactic pituitary radiotherapy in
remission. Clin Endocrinol (Oxf) 2002; 56: 541–51. adrenocorticotropin-dependent Cushing’s syndrome.
173 Rollin GA, Ferreira NP, Junges M, Gross JL, Czepielewski MA. J Clin Endocrinol Metab 1995; 80: 165–71.
Dynamics of serum cortisol levels after transsphenoidal surgery in 195 Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of
a cohort of patients with Cushing’s disease. J Clin Endocrinol Metab pituitary irradiation after unsuccessful transsphenoidal surgery in
2004; 89: 1131–39. Cushing’s disease. N Engl J Med 1997; 336: 172–77.
174 Salenave S, Gatta B, Pecheur S, et al. Pituitary magnetic resonance 196 Storr HL, Plowman PN, Carroll PV, et al. Clinical and endocrine
imaging findings do not influence surgical outcome in responses to pituitary radiotherapy in pediatric Cushing’s disease:
adrenocorticotropin-secreting microadenomas. an effective second-line treatment. J Clin Endocrinol Metab 2003; 88:
J Clin Endocrinol Metab 2004; 89: 3371–76. 34–37.
175 Sheehan JM, Lopes MB, Sheehan JP, Ellegala D, Webb KM, 197 Devin JK, Allen GS, Cmelak AJ, Duggan DM, Blevins LS. The
Laws ER Jr. Results of transsphenoidal surgery for Cushing’s efficacy of linear accelerator radiosurgery in the management of
disease in patients with no histologically confirmed tumor. patients with Cushing’s disease. Stereotact Funct Neurosurg 2004; 82:
Neurosurgery 2000; 47: 33–39. 254–62.
176 Shimon I, Ram Z, Cohen ZR, Hadani M. Transsphenoidal surgery 198 Sheehan JM, Vance ML, Sheehan JP, Ellegala DB, Laws ER Jr.
for Cushing’s disease: endocrinological follow-up monitoring of Radiosurgery for Cushing’s disease after failed transsphenoidal
82 patients. Neurosurgery 2002; 51: 57–62. surgery. J Neurosurg 2000; 93: 738–42.
177 Valero R, Vallette-Kasic S, Conte-Devolx B, Jaquet P, Brue T. The 199 Vance ML, Chernavvsky DR, Steiner L, Laws ER. Relapse of
desmopressin test as a predictive factor of outcome after pituitary Cushings disease after successful gamma knife treatment,
surgery for Cushing’s disease. Eur J Endocrinol 2004; 151: 727–33. 0R9-4. Endocrine Society, 87th Annual Meeting June 4–7, 2005,
178 Yap LB, Turner HE, Adams CB, Wass JA. Undetectable postoperative San Diego, CA. http://www.endo-society.org (accessed October,
cortisol does not always predict long-term remission in Cushing’s 2005).
disease: a single centre audit. Clin Endocrinol (Oxf) 2002; 56: 25–31.

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Seminar

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disease. About 90% of tumours express the corticotropin-

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patients and men with unexplained osteoporosis (ﬁgure 1).

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Moreover, if there is renal impairment with a glomerular

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and other causes of hypercortisolaemia but can miss

Late-night salivary cortisol

95% and 98%. Since salivary cortisol concentrations are

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