Castinetti et al.

Orphanet Journal of Rare Diseases 2012, 7:41

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REVIEW Open Access

Cushing’s disease
Frederic Castinetti*, Isabelle Morange, Bernard Conte-Devolx and Thierry Brue*

Abstract
Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased
morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein
wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict
algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting
microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including
anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks
(metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential
pathophysiological mechanisms, diagnostic approaches, and therapies.

Disease name and synonyms Cushing’s disease is an extremely rare condition in chil-
Cushing’s disease, corticotroph adenoma, pituitary dren, with a peak in adults in the 3rd or 4th decade.
dependent Cushing’s syndrome. Cushing’s disease leads to death if untreated; it is re-
Chronic glucocorticoid excess, or Cushing’s syn- sponsible for increased morbidity and mortality, due to
drome, may be due to ACTH-dependent (80% cases) or cardiovascular complications, infections and psychiatric
–independent (20% cases) causes (Table 1). The latter disturbances [3,4].
are mainly due to benign (60%) or malignant (40%) ad-
renal tumors. ACTH overproduction may be of pituit- Clinical and biological characteristics
ary origin (85% cases) or result from ectopic tumor Clinical characteristics
secretion (15% cases). The term Cushing’s disease is Hypercortisolic state may include several clinical signs [5,6]
specifically applied to ACTH-secreting pituitary tumors.
Cushing’s disease, first described by Harvey Cushing in – Obesity: obesity with centripetal fat deposition (face,
1932, represents the most frequent cause of Cushing’s supraclavicular and dorso-cervical fat pads), facial
syndrome [1]. plethora, rounded face, buffalo-hump
Cushing’s disease is defined by Adrenocorticotropin – Signs of protein wasting: thin skin, abdominal purple
hormone (ACTH) hypersecretion, induced by a cortico- to red and wide cutaneous striae (abdomen, flanks,
troph adenoma, and leading to cortisol hypersecretion breasts, hips, axillae), easy bruising, slow healing,
(associated with androgens hypersecretion). muscle wasting (lower limbs muscle atrophy)
– Bone wasting leading to osteoporosis (possibly
Epidemiology leading to fractures)
The incidence of Cushing’s syndrome is estimated to be – High blood pressure
equal to 1–3 cases per million inhabitants per year, – Impaired immune defense mechanisms with
whereas its prevalence is close to 40 cases per million increased rate of infections
inhabitants. Of note, prevalence of hypercortisolism is – Gonadal dysfunction and hyperandrogenism:
thought to be equal to 2-5% of patients with poorly con- hirsutism (more frequently on the face), menstrual
trolled diabetes and hypertension. Female preponder- irregularity (oligoamenorrhea, amenorrhea)
ance is generally assumed to be close to 3:1 [2]. – Mild to severe psychic disturbances(anxiety,
depression, irritability. . .)
* Correspondence: [email protected]; [email protected]
Department of Endocrinology and Reference Center for Rare Pituitary The most frequent sign is obesity: abnormal fat distri-
Diseases La Timone Hospital, Aix-Marseille University, Marseille, France bution is considered as the most sensitive sign [7].
© 2012 Castinetti et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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Table 1 Classification of most frequent causes of to non-secreting pituitary adenomas: diagnosis is made
Cushing’s syndrome by the pathologist [12]. Finally, rare cases of aggressive
ACTH dependent Cushing’s disease or ACTH secreting pituitary adenomas or carcinomas have been reported
Cushing’s syndrome pituitary adenoma [13]. Whether hyperplasia of corticotroph cells is or not
Ectopic ACTH secretion a required initial step before the genesis of corticotroph
ACTH independent Adrenal adenoma adenoma remains a matter of debate. The origin of the
Cushing’s syndrome disease, primary pituitary condition or secondary to an
Adrenal carcinoma
abnormality in the hypothalamus (chronic stimulation
Bilateral adrenal hyperplasia
by CRH [14]), remains a matter of debate.
Iatrogenic Cushing’s syndrome
(Exogenous glucocorticoid exposure)
Genetic predisposition Cushing’s disease can be part of
Pseudo-Cushing’s Obesity
syndrome Multiple Endocrine Neoplasia Type 1, due to mutations of
Alcoholism
the menin gene. It is a rare syndrome, transmitted in an
Depression autosomal dominant manner, which associates hyperpara-
Modified from Williams Textbook, 12th Edition thyroidism, endocrine tumors, and pituitary adenomas in
20-50% cases. Most of these are somatotroph or lacto-
Evidence of protein wasting (osteoporosis, myopathy) is troph, but corticotroph adenomas have been described in
the most specific sign. Conjunction of both should 5-10% of cases. AIP (Aryl hydrocarbon receptor Interacting
theoretically allow to distinguish between hypercortiso- Protein) mutations have been reported in familial pituitary
lism and simple obesity. However, the severity of hyper- adenomas: secretion profile is usually somatotroph or
cortisolism can be highly variable, which frequently lactotroph, whereas very rare cases of CD have also been
makes the diagnosis difficult. Moreover, hypersecretion reported [15].
profiles can be cyclical, leading to very modest pheno-
typic signs in some patients (subclinical Cushing’s syn- Potentially involved molecular mechanisms Triggering
drome) [8]. In most cases, diagnosis depends on a high signals leading to Cushing’s disease remain unclear. Onco-
index of suspicion, rather than a florid clinical pheno- genes do not appear to be involved, as somatic mutations
type. Of note, none of the signs can allow to differentiate are usually not present in corticotroph adenomas cells.
Cushing’s disease from any other etiology of hypercorti- Recent studies in mice identified a potential role of loss of
solism, except in case of tumor related symptoms such function of Brg1 (brahma-related gene 1) and HDAC2
as headaches or visual field defect (in macroadenomas). (Histone Deacetylase 2) in the pathogenesis of Cushing’s
disease. Both proteins form a complex with the gluco-
Biological characteristics corticoid receptor and the orphan nuclear receptor nu-
Non-specific biological signs may include hypokalemia clear growth factor IB (NGFI-B) to repress POMC
and impaired glucose tolerance or diabetes. Blood count secretion. Interestingly, about 50% of corticotroph aden-
may show increased hemoglobin, increased neutrophils omas do not express these proteins anymore. The loss of
and decreased lymphocytes or eosinophils. Brg1 could lead to overexpression of cyclin E, leading to
increased cell proliferation and sporadic hyperplasia or
Etiopathogenesis tumors. Interestingly, tumors with a loss of nuclear
Characteristics of corticotroph adenomas Cushing’s localization of Brg1 seem to be more responsive to
disease is frequently due to monoclonal benign and slow anticortisolic drugs in vitro compared to the ones with a
growing microadenomas (less than 10 mm) [9,10]. complete loss of Brg1 oncogene [16,17].
Plasma ACTH (and cortisol) classically lose their physio- Transcription factors involved in progenitors prolifera-
logic circadian periodicity. They are partially resistant to tion and differentiation during pituitary embryogenesis
physiologic stimuli (i.e., glucocorticoids), and do not could also be involved in pituitary tumorigenesis. TPIT
respond to the normal feedback negative loop. In deficiency is known to result in congenital isolated corti-
contrast, corticotroph adenomas are inappropriately cotroph deficiency. Patients with other pituitary tran-
sensitive to CRH and AVP. Altered CRH secretion as scription factors mutations (PROP1, LHX3, LHX4,
well as POMC qualitative changes in gene expression HESX1) usually present combined pituitary hormone de-
were also reported to be involved in the pathogenesis of ficiencies including inconstant corticotroph deficiency.
Cushing’s disease. Cushing’s disease can be more As some of these factors are still expressed at adult age,
atypical: secretion profiles are sometimes cyclic, with and their role is not precisely known, it could be tempt-
hypersecretion preceding a long period of normal secre- ing to speculate on potential roles of an overexpression
tion [8,11]. Some corticotroph adenomas are called of these proteins in pituitary adenomas ontogenesis.
“silent” as they are clinically and biologically comparable However, to our knowledge, no mutation of any
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transcription factor has ever been identified in patients pseudo Cushing’s syndrome might be difficult despite
presenting with corticotroph adenomas [18,19]. the use of previously described screening methods [6].
CRH injection coupled with dexamethasone suppression
Diagnosis test, is in favor of Cushing’s syndrome with 90% sensitiv-
Diagnosis of Cushing’s disease is difficult [20]. Clinical ity and 84% specificity in the presence of peak
signs and symptoms are often non-specific; no single cortisol > 580 nmol/l and ACTH > 50 pg/ml [31].
biological test combines optimal sensitivity and specifi- Steps for positive diagnosis of Cushing’s syndrome are
city for the diagnosis of hypercortisolism and for the de- summarized in Figure 1.
termination of its etiology [21]. Moreover, pituitary and When the presence of CS is confirmed, diagnosis ap-
adrenal imaging can sometimes be confusing. proach will determine if the secretion is ACTH-dependent
Several steps are needed to first confirm the diagnosis or not. Early morning undetectable ACTH levels (< 10 pg/
of hypercortisolism and then determine its origin: the ml) will lead to a diagnosis of ACTH independent hyper-
first will be to confirm the lack of exposure to exogen- cortisolism (autonomous adrenal hypersecretion), whereas
ous glucocorticoids that induces the same clinical char- inappropriately normal or increased levels (> 10 pg/ml)
acteristics as Cushing’s syndrome and makes will be in favor of an ACTH-dependent hypercortisolism.
hypercortisolism screening unavailable [22]. In normal ACTH dependent CS includes Cushing’s disease (CD)
subjects, cortisol levels reach a peak at early morning and, more rarely, ectopic ACTH secretion (EAS) [32].
and a nadir < 50 nmol/l around midnight. Patients with Distinction between both is difficult, and frequently
Cushing’s syndrome lose this circadian rhythm. As a requires the use of several diagnostic methods [33]:
consequence, early morning ACTH and cortisol values
are of poor diagnostic value in the screening methods of – high dose dexamethasone suppression test (8 mg/day
hypercortisolism. In contrast a midnight cortisol during 2 days): a decrease of more than 50% urinary
value > 200 nmol/l is strongly suggestive of Cushing’s cortisol level is observed in 90% of patients with CD,
syndrome [23]. Evaluation of the circardian rhythm of compared with less than 50% of those with EAS. Of
cortisol is however not recommended as a first line note, more than 90% suppression of urinary cortisol
screening method for hypercortisolism. has 100% specificity in the diagnosis of Cushing’s
We will not detail precisely all methods and tests pro- disease [2].
posed to confirm a diagnosis of hypercortisolism (or – CRH test (100 μg intra-venously): more than 50%
Cushing’s syndrome, CS): these criteria have been widely ACTH and 20% cortisol increase is in favor of
described in recent consensus conferences[6,24]. First Cushing’s disease. Sensitivity and specificity are close
line screening methods should include either to 90% [34].
– Desmopressin test (10 μg intravenously), ACTH and
– 24-hour urinary free cortisol, repeated at least twice; cortisol increases similar to those observed with the
values should be above 220–330 nmol/24 h CRH test are in favor of CD with 70% sensitivity and
depending on the assays, in Cushing’s syndrome, 85% specificity [20,35]
keeping in mind that normal values can be seen in
8-15% of patients with Cushing’s syndrome [25] Concordant responses to at least 2/3 of these tests
– cortisol response to 1 mg-overnight dexamethasone should lead to the diagnosis of Cushing’s disease, and
suppression test: cortisol value < 50 nmol/l (< 2 μg/dl) pituitary MRI. However, the sensitivity of MRI in CD is
excludes Cushing’s syndrome with high sensitivity hardly greater than 60-70% and specificity close to 85%,
(95%) but low specificity [26]. as most corticotroph adenomas are microadenomas. In
– cortisol response to low dose dexamethasone one study, 10% of the general population presented MRI pi-
suppression test (0.5 mg dexamethasone every 6 tuitary images of less than 5 mm that might be considered
hours during 48 hours): cortisol value < 50 nmol/l as adenomas [36]. Cushing’s disease diagnosis is thus con-
(< 2 μg/dl) excludes Cushing’s syndrome with a firmed in the presence of an adenoma > 6 mm and con-
sensitivity and specificity close to 100% [27]. cordant responses to tests.
– or late night salivary cortisol [25,28,29] : a cortisol In the lack of an image suggesting a pituitary adenoma
value > 2 ng/ml (5.5 nmol/l) has a 100% sensitivity on MRI despite dynamic tests in favor of CD, or in case
and 96% specificity for Cushing’s syndrome [30]. of discordant tests, bilateral intra-petrosal sinus sam-
pling (stimulated by CRH or desmopressin) should be
Pseudo Cushing’s syndrome is defined by the presence performed: it will give a definite answer to confirm the
of partial clinical signs of hypercortisolism. It can be etiology of ACTH dependent CS. The principle is to
induced by chronic alcohol consumption, depression measure a ratio defined by central ACTH/peripheral
and obesity. Diagnosis between Cushing’s syndrome and ACTH. A central to peripheral plasma ACTH ratio
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CUSHING’S SYNDROME ?

Exogenous glucocorticoid
Perform first test
exposure ?

24 hour UFC (at least twice) or Overnight 1mg DST or Late

night salivary cortisol or 48 hour 2mg DST

Normal Abnormal

Perform a Second test (among the

UNLIKELY four previous ones)

Normal Abnormal

UNLIKELY CUSHING’S SYNDROME

Figure 1 Steps necessary to confirm the diagnosis of Cushing’s syndrome.

exceeding 2 (or 3 after stimulation by CRH) is in favor Differential diagnosis

of Cushing’s disease[37-40] .In case of ACTH dependent
hypercortisolism, if the initial etiologic workup is not in – Chronic exogenous administration of
favor of a pituitary origin, complementary morphologic glucocorticoids
investigation including tomodensitometric whole body – Pseudo-Cushing states as described previously
examination should be performed. Some teams prefer to – ACTH dependent Cushing’s syndrome: Ectopic
perform systematically a thoraco–abdomino-pelvic scan ACTH secretion (see above)
in each patient with ACTH dependent Cushing’s syn- – ACTH independent Cushing’s syndrome will be
drome, whatever the status of tests and MRI. The limit ruled out by inappropriately normal or increased
of this approach is identical to the one reported with pi- ACTH levels.
tuitary MRI, as some patients might have bronchial inci- – Functional hypercortisolism during pregnancy
dentalomas not responsible for ectopic ACTH secretion,
and leading to a misdiagnosis [33]. Steps necessary for Clinical management
the etiological diagnosis of ACTH dependent Cusging’s Transsphenoidal surgery is the first line treatment of
syndrome are summarized in Figure 2. Cushing’s disease[41,42]. It allows remission in 60-90%

And clinical/biological parameters

ACTH > 10 pg/ml in favor of Cushing’s syndrome (as
described in Figure 1)

ACTH DEPENDENT CUSHING’S SYNDROME

High dose DST and/or CRH test

Pituitary MRI
and/or Desmopressin test

Adenoma > 6 Adenoma < 6

Discordant Concordant
mm mm

Surgery BIPSS Surgery

Negative Positive

Ectopic ACTH secretion CUSHING’S DISEASE CONFIRMED

Figure 2 Steps necessary for the etiological diagnosis of ACTH-dependent Cushing’s syndrome.
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of microadenomas, and 50-70% of macroadenomas, drawback of these drugs is that they are only suspen-
depending on local invasion and the experience of the sive, i.e. hypercortisolism may be controlled but still
neurosurgeon[43-45]. Remission should be defined by uncured, requiring a long-term period of treatment.
normal ACTH and cortisol circadian rhythms, and There are 4 main indications of medical treatment: in
suppressed cortisol value after overnight/low dose dexa- case of contra-indication or refusal of surgery, in the
methasone suppression test. lack of adenoma image on pituitary MRI, waiting for
The appropriateness of surgery in the lack of visua- radiation techniques to be effective, as a multimodality
lized pituitary adenoma remains a matter of debate [46]. approach in the rare cases of pituitary carcinomas.
When extensive samplings and dynamic tests confirm
that hypercortisolism is due to Cushing’s disease, and pi- Steroidogenesis inhibitors
tuitary MRI seems normal, literature data report a range
of surgical efficacy varying from less than 50 to 70% of  Op’DDD (mitotane, LysodrenW) is derived from
remission, often associated with induced hypopituitarism insecticide dichloro-diphenyl- dichloroethane
and/or diabetes insipidus. The risk of late recurrence (DDD). Op’DDD inhibits side chain cleavage of
after presumably curative surgery is estimated to be cholesterol and also other cytochrome P450
close to 25% [47]. Several criteria have been reported as enzymes (11-alpha and 18-hydroxylase) and non-
predictive factors for long-term remission: low immedi- P450 enzyme (3 beta-hydroxysteroiddeshydrogenase).
ate post-surgical early morning cortisol/ACTH levels, In Cushing’s disease, it is used as an inhibitor of
cortisol suppression after 1 mg overnight dexametha- cortisol secretion.Op’DDD is usually effective in more
sone suppression test, lack of cortisol/ACTH response than 50% cases, and frequently induces adrenal
to desmopressin or coupled dexamethasone desmopres- atrophy; however, gastro-intestinal tolerance is usually
sin test [48-51]. However, it is still difficult to predict bad, and there is a 4-week delay to obtain maximal
which patients are at greater risk of recurrence, as some efficacy due to its accumulation in adipose tissue.
patients uncured immediately after surgery, might how- There is a narrow difference between efficacy and
ever present delayed remission [52]. As a consequence, toxicity levels. Main side effects are digestive (nausea,
and due to the high risk of recurrence, it seems difficult vomiting, diarrhea), neurologic (sleepiness, asthenia)
to talk about “cure” in patients with surgically treated and metabolic (hypercholesterolemia). Mitotane
Cushing’s disease; the term “remission” seems more ap- modifies metabolic clearance of steroids with
propriate. In other words, even long-term remission consequent gynecomastia in men and alteration of
after surgery should lead to at least a prolonged clinical contraceptive effects of pills [56,57]. Pregnancy is
close follow-up. forbidden during mitotane therapy and for two years
In case of immediate surgical failure or late recur- after drug withdrawal due to teratogenic effects
rence, several therapeutic modalities are available: sec- [41,58,59].
ond pituitary surgery, medical treatments, radiation  Ketoconazole is an antifungal agent with
techniques, or bilateral adrenalectomy[53]. Only some steroidogenesis inhibitor effects linked to inhibition
of these treatments (surgery, and radiation techniques of cytochrome P450 enzymes. It was reported to
after à prolonged period) can lead to long-term normalize cortisol levels in Cushing’s disease in
remission. about 50% of cases. Side effects include rare severe
liver injury (1/15000 cases), and gastro-intestinal
Second surgery intolerance [60].
Several teams reported the benefits of a second surgical  Metyrapone (MétopironeW) is a pyridine derivative
procedure, either in the first days following initial that blocks cortisol synthesis by mainly inhibition of
surgery, or later. A recent study reported a possibility of 11 beta hydroxylase. Metyrapone is rapidly effective
delayed remission after initial surgery in about 5% of in about 50% of hypercortisolic states: it usually
cases. This should be in favor of a delayed rather than induced low blood potassium levels, and
an immediate approach. Efficacy is usually observed in hyperandrogenism [61].
50-70% of cases, frequently associated with an increased  Etomidate (HypnomidateW) is an intravenous
risk of hypopituitarism, diabetes insipidus, and cerebro- anaesthetic agent. It inhibits cortisol synthesis by
spinal fluid leak [54,55]. inhibiting CYP11B1 with 11-beta hydroxylase
activity, and cytochrome P450scc at high
Medical treatments concentrations. Etomidate is a very potent
Medical treatments aim at decreasing synthesis and anticortisolic drug, limited by the fact that it can
secretion of cortisol, blocking glucocorticoid recep- only be used intravenously: it should thus be
tors, or inhibiting ACTH secretion. The main reserved for severe hypercortisolic states [62].
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Glucocorticoid receptor antagonist hypersecretion by antisecretory therapy for a short

Mifepristone is currently the only available glucocorticoid period of time before bilateral adrenalectomy, but this
receptor antagonist. Only rare cases have been reported to specific point has never been really evaluated. The
date. The drug seems to be highly effective in controlling major and expected side effect of bilateral adrenalect-
clinical signs of hypercortisolism. However, due to its omy is adrenal insufficiency. Another possible adverse
mode of action, there is a high risk of hypokalemia, and effects is Nelson’s syndrome, which is a pituitary tumor
there is no biological means to monitor the patient. Treat- progression observed after adrenalectomy [73].
ment dose adjustment is thus only based on subjective
signs [63]. Temozolomide
In rare cases, CD can be induced by aggressive pituitary
ACTH-lowering agents tumors, and still more rarely by pituitary carcinomas.
Cabergoline is a dopamine agonist well known for its Due to frequent recurrences, they usually require repeat
anti-secretory and anti-tumoral efficacy in prolactinomas. surgery, and aggressive treatments. The rarity of cases
Corticotroph adenomas can express dopamine receptors. makes it difficult to define a consensual therapeutic
Recent studies reported that about 25% of patients treated approach. Recent studies pointed out the benefits of
by high doses of carbergoline for CD could be controlled temozolomide, but prospective long-term studies will be
as well [64-66]. A strict echocardiographic follow-up is necessary to ascertain this point [74-76].
required, due to a dose-dependent risk of valvulopathy.
Pasireotide is a somatostatin agonist with a particular Prognosis
binding affinity for somatostatin receptor (sstr) isoforms The risks of chronic hypercortisolic state include excess
1, 2, 3 and 5. This specific affinity for sstr5 could be of morbidity and mortality due to increased cardio-vascular
major interest in CD. Clinical trials are ongoing to deter- risk factors (hypertension, dyslipidemia, diabetes melli-
mine efficiency of this drug. Preliminary results suggest tus, metabolic syndrome) leading to heart defect. More-
that pasireotide is able to decrease cortisol levels in the over, hypercortisolism is responsible for coagulopathy
majority of patients, but only few reach normalized [77] and atherosclerosis [78], which also increase the risk
values. There is a risk of induction or worsening of to develop cardiovascular diseases. Recent data suggest
hyperglycemia in 1/3 cases [67-69]. that part of these defects due to hypercortisolism might
remain after remission [78] even if the mortality rate
Radiation techniques would go back to normal [79]. Frequency of infectious
Radiation techniques have been widely used as a treat- diseases is also increased, as well as delayed healing.
ment of Cushing’s disease. Different techniques are avail- Hypercortisolism can induce severe osteoporosis in
able, mainly based on fractionated radiotherapy or about 30% cases, and osteopenia in half of them. Also,
stereotactic radiosurgery. Radiotherapy induces remis- acute cortisol excess can induce severe hypokalemia, as
sion in the majority of cases, but also panhypopituitar- well as elevated blood pressure levels, and sometimes
ism in more than 80% of patients [70]. Due to the slow psychiatric signs [26,80]. Finally, more than half of
decrease of ACTH levels, delay to remission can vary patients with CS can present with psychiatric signs, from
from 2–3 to 10 years, depending on initial hormone mild to severe depression, and cognitive dysfunction
levels. Stereotactic radiosurgery is delivered in a single [81].
session. It is theoretically a more precise technique, lead-
ing to a lower risk of hypopituitarism. However, the rate Future prospects
of remission is lower, reported in only 50% of cases. Future research should focus on
Radiosurgery should thus be reserved for small and low
secreting lesions [71]. For both techniques, medical 1. The pathophysiological mechanisms leading to
treatments need to be given between the procedure and corticotroph adenomas. Only rare data are available
maximal efficacy, i.e. for 2–5 years, to control cortisol on the early events leading to pituitary adenomas in
hypersecretion waiting for normalization. general, and corticotroph adenomas in particular.
2. The way to improve sensitivity/specificity of
Bilateral adrenalectomy diagnostic methods for subclinical Cushing’s
It can be used either in case of failure of pituitary sur- syndrome. Some patients are diagnosed with
gery, or when hypercortisolism is severe, requiring a Cushing’s syndrome several years after a prolonged
rapidly active treatment. Bilateral adrenalectomy treatment for hypertension, osteoporosis. . .
resolves cortisol hypersecretion in the vast majority of 3. The way to diagnose earlier patients with a high risk
cases, with a low risk of perioperative complications of post-surgical recurrence. About 20% of patients
[72]. One might consider trying to decrease the level of with what is supposedly the best predictive factor of
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remission (low cortisol levels immediately after in GR trans-repression of the pituitary POMC gene and misexpression in
surgery) still present long term recurrence of their Cushing disease. Genes Dev 2006, 20:2871–2886.
17. Drouin J, Bilodeau S, Vallette S: Of old and new diseases: genetics of pituitary
disease. ACTH excess (Cushing) and deficiency. Clin Genet 2007, 72:175–182.
4. The development of safe and effective medical 18. Davis SW, Castinetti F, Carvalho LR, Ellsworth BS, Potok MA, Lyons RH,
treatments. Currently available drugs are either Brinkmeier ML, Raetzman LT, Carninci P, Mortensen AH, et al: Molecular
mechanisms of pituitary organogenesis: In search of novel regulatory
poorly effective and/or have bad tolerance. genes. Mol Cell Endocrinol 2010, 323(1):4–19.
19. Kelberman D, Rizzoti K, Lovell-Badge R, Robinson IC, Dattani MT: Genetic
Abbreviations regulation of pituitary gland development in human and mouse. Endocr
CS: Cushing’s syndrome; CD: Cushing’s disease; EAS: Ectopic ACTH Secretion. Rev 2009, 30:790–829.
20. Nieman LK: Difficulty in the diagnosis of Cushing disease. Nat Clin Pract
Competing interests Endocrinol Metab 2006, 2:53–57. quiz following 57.
The authors declare that they have no competing interest. 21. Tabarin A, Perez P: Pros and cons of screening for occult Cushing
syndrome. Nat Rev Endocrinol 2011, 7(8):445–455.
Acknowledgements 22. Hopkins RL, Leinung MC: Exogenous Cushing's syndrome and
The authors would like to thank the Head of the Department of glucocorticoid withdrawal. Endocrinol Metab Clin North Am 2005,
Neurosurgery (Pr Dufour), La Timone Hospital, Marseille, France. 34:371–384. ix.
23. Newell-Price J, Trainer P, Perry L, Wass J, Grossman A, Besser M: A single
Authors’ contributions sleeping midnight cortisol has 100 % sensitivity for the diagnosis of
The authors contributed equally to this review. They read and approved the Cushing's syndrome. Clin Endocrinol (Oxf ) 1995, 43:545–550.
final version of the manuscript. 24. Guignat L, Bertherat J: The diagnosis of Cushing's syndrome: an
Endocrine Society Clinical Practice Guideline: commentary from a
Received: 13 May 2011 Accepted: 18 June 2012 European perspective. Eur J Endocrinol 2010, 163:9–13.
Published: 18 June 2012 25. Findling JW, Raff H: Screening and diagnosis of Cushing's syndrome.
Endocrinol Metab Clin North Am 2005, 34:385–402. ix-x.
References 26. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP,
1. Bertagna X, Guignat L, Groussin L, Bertherat J: Cushing's disease. Best Pract Fava GA, Findling JW, Gaillard RC, Grossman AB, et al: Diagnosis and
Res Clin Endocrinol Metab 2009, 23:607–623. complications of Cushing's syndrome: a consensus statement. J Clin
2. Melmed S, Polonsky K, Reed Larsen P, Kronenberg H: William's Textbook of Endocrinol Metab 2003, 88:5593–5602.
Endocrinology. 12th edition. Philadelphia: Elsevier/Saunders; 2011. 27. Newell-Price J, Trainer P, Besser M, Grossman A: The diagnosis and
3. Steffensen C, Bak AM, Rubeck KZ, Jorgensen JO: Epidemiology of Cushing's differential diagnosis of Cushing's syndrome and pseudo-Cushing's
syndrome. Neuroendocrinology 2010, 92(Suppl 1):1–5. states. Endocr Rev 1998, 19:647–672.
4. Jeffcoate WJ, Silverstone JT, Edwards CR, Besser GM: Psychiatric 28. Carroll T, Raff H, Findling JW: Late-night salivary cortisol for the diagnosis
manifestations of Cushing's syndrome: response to lowering of plasma of Cushing syndrome: a meta-analysis. Endocr Pract 2009, 15:335–342.
cortisol. Q J Med 1979, 48:465–472. 29. Nunes ML, Vattaut S, Corcuff JB, Rault A, Loiseau H, Gatta B, Valli N,
5. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing's syndrome. Letenneur L, Tabarin A: Late-night salivary cortisol for diagnosis of overt
Lancet 2006, 367:1605–1617. and subclinical Cushing's syndrome in hospitalized and ambulatory
6. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, patients. J Clin Endocrinol Metab 2009, 94:456–462.
Montori VM: The diagnosis of Cushing's syndrome: an Endocrine Society 30. Yaneva M, Mosnier-Pudar H, Dugue MA, Grabar S, Fulla Y, Bertagna X:
Clinical Practice Guideline. J Clin Endocrinol Metab 2008, 93:1526–1540. Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome
7. Ross EJ, Linch DC: Cushing's syndrome–killing disease: discriminatory value of various causes. J Clin Endocrinol Metab 2004, 89:3345–3351.
of signs and symptoms aiding early diagnosis. Lancet 1982, 2:646–649. 31. Tirabassi G, Papa R, Faloia E, Boscaro M, Arnaldi G: Corticotrophin-releasing
8. Alexandraki KI, Kaltsas GA, Isidori AM, Akker SA, Drake WM, Chew SL, hormone and desmopressin tests in the differential diagnosis between
Monson JP, Besser GM, Grossman AB: The prevalence and characteristic Cushing's disease and pseudo-Cushing state: a comparative study. Clin
features of cyclicity and variability in Cushing's disease. Eur J Endocrinol Endocrinol (Oxf ) 2011, 75:666–672.
2009, 160:1011–1018. 32. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK: Cushing's
9. Gicquel C, Le Bouc Y, Luton JP, Girard F, Bertagna X: Monoclonality of syndrome due to ectopic corticotropin secretion: twenty years'
corticotroph macroadenomas in Cushing's disease. J Clin Endocrinol experience at the National Institutes of Health. J Clin Endocrinol Metab
Metab 1992, 75:472–475. 2005, 90:4955–4962.
10. Woo YS, Isidori AM, Wat WZ, Kaltsas GA, Afshar F, Sabin I, Jenkins PJ, 33. Boscaro M, Arnaldi G: Approach to the patient with possible Cushing's
Monson JP, Besser GM, Grossman AB: Clinical and biochemical syndrome. J Clin Endocrinol Metab 2009, 94:3121–3131.
characteristics of adrenocorticotropin-secreting macroadenomas. J Clin 34. Chrousos GP, Schulte HM, Oldfield EH, Gold PW, Cutler GB Jr, Loriaux DL:
Endocrinol Metab 2005, 90:4963–4969. The corticotropin-releasing factor stimulation test. An aid in the
11. Brew Atkinson A, Mullan KR: What is the best approach to suspected evaluation of patients with Cushing's syndrome. N Engl J Med 1984,
cyclical Cushing syndrome? Strategies for managing Cushing's 310:622–626.
Syndrome with variable laboratory data. Clin Endocrinol (Oxf ) 2011, Still 35. Tsagarakis S, Tsigos C, Vasiliou V, Tsiotra P, Kaskarelis J, Sotiropoulou C,
epub ahead of print 2011 Feb 26. Raptis SA, Thalassinos N: The desmopressin and combined CRH-
12. Raverot G, Wierinckx A, Jouanneau E, Auger C, Borson-Chazot F, Lachuer J, desmopressin tests in the differential diagnosis of ACTH-dependent
Pugeat M, Trouillas J: Clinical, hormonal and molecular characterization of Cushing's syndrome: constraints imposed by the expression of V2
pituitary ACTH adenomas without (silent corticotroph adenomas) and vasopressin receptors in tumors with ectopic ACTH secretion. J Clin
with Cushing's disease. Eur J Endocrinol 2010, 163:35–43. Endocrinol Metab 2002, 87:1646–1653.
13. Holthouse DJ, Robbins PD, Kahler R, Knuckey N, Pullan P: Corticotroph 36. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH: Pituitary
pituitary carcinoma: case report and literature review. Endocr Pathol 2001, magnetic resonance imaging in normal human volunteers: occult
12:329–341. adenomas in the general population. Ann Intern Med 1994, 120:817–820.
14. Biller BM: Pathogenesis of pituitary Cushing's syndrome. Pituitary versus 37. Batista D, Gennari M, Riar J, Chang R, Keil MF, Oldfield EH, Stratakis CA: An
hypothalamic. Endocrinol Metab Clin North Am 1994, 23:547–554. assessment of petrosal sinus sampling for localization of pituitary
15. Yaneva M, Vandeva S, Zacharieva S, Daly AF, Beckers A: Genetics of microadenomas in children with Cushing disease. J Clin Endocrinol Metab
Cushing's syndrome. Neuroendocrinology 2010, 92(Suppl 1):6–10. 2006, 91:221–224.
16. Bilodeau S, Vallette-Kasic S, Gauthier Y, Figarella-Branger D, Brue T, Berthelet 38. Castinetti F, Morange I, Dufour H, Jaquet P, Conte-Devolx B, Girard N, Brue
F, Lacroix A, Batista D, Stratakis C, Hanson J, et al: Role of Brg1 and HDAC2 T: Desmopressin test during petrosal sinus sampling: a valuable tool to
Castinetti et al. Orphanet Journal of Rare Diseases 2012, 7:41 Page 8 of 9
http://www.ojrd.com/content/7/1/41

discriminate pituitary or ectopic ACTH-dependent Cushing's syndrome. 60. Castinetti F, Morange I, Jaquet P, Conte-Devolx B, Brue T: Ketoconazole
Eur J Endocrinol 2007, 157:271–277. revisited: a preoperative or postoperative treatment in Cushing's
39. Kaskarelis IS, Tsatalou EG, Benakis SV, Malagari K, Komninos I, Vassiliadi D, disease. Eur J Endocrinol 2008, 158:91–99.
Tsagarakis S, Thalassinos N: Bilateral inferior petrosal sinuses sampling in 61. Obinata D, Yamaguchi K, Hirano D, Yoshida T, Soma M, Takahashi S:
the routine investigation of Cushing's syndrome: a comparison with MRI. Preoperative management of Cushing's syndrome with metyrapone for
AJR Am J Roentgenol 2006, 187:562–570. severe psychiatric disturbances. Int J Urol 2008, 15:361–362.
40. Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, 62. Mettauer N, Brierley J: A novel use of etomidate for intentional adrenal
Cutler GB Jr, Loriaux DL: Petrosal sinus sampling with and without suppression to control severe hypercortisolemia in childhood. Pediatr Crit
corticotropin-releasing hormone for the differential diagnosis of Care Med 2009, 10:e37–40.
Cushing's syndrome. N Engl J Med 1991, 325:897–905. 63. Castinetti F, Fassnacht M, Johanssen S, Terzolo M, Bouchard P, Chanson P,
41. Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Do Cao C, Morange I, Pico A, Ouzounian S, et al: Merits and pitfalls of
Buchfelder M, Colao A, Hermus AR, Hofland LJ, et al: Treatment of mifepristone in Cushing's syndrome. Eur J Endocrinol 2009, 160:1003–1010.
adrenocorticotropin-dependent Cushing's syndrome: a consensus 64. Vilar L, Naves LA, Azevedo MF, Arruda MJ, Arahata CM, Moura ESL, Agra R,
statement. J Clin Endocrinol Metab 2008, 93:2454–2462. Pontes L, Montenegro L, Albuquerque JL, Canadas V: Effectiveness of
42. Tritos NA, Biller BM, Swearingen B, Medscape: Management of Cushing cabergoline in monotherapy and combined with ketoconazole in the
disease. Nat Rev Endocrinol 2011, 7:279–289. management of Cushing's disease. Pituitary 2010, 13:123–129.
43. Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Muller OA, Fahlbusch R: 65. Petrossians P, Thonnard AS, Beckers A: Medical treatment in Cushing's
Long-term results after microsurgery for Cushing disease: experience syndrome: dopamine agonists and cabergoline. Neuroendocrinology 2010,
with 426 primary operations over 35 years. J Neurosurg 2008, 108:9–18. 92(Suppl 1):116–119.
44. Hoybye C, Grenback E, Thoren M, Hulting AL, Lundblad L, von Holst H, 66. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A,
Anggard A: Transsphenoidal surgery in Cushing disease: 10 years of Lombardi G, Hofland LJ, Lamberts SW, Colao A: The medical treatment of
experience in 34 consecutive cases. J Neurosurg 2004, 100:634–638. Cushing's disease: effectiveness of chronic treatment with the dopamine
45. Shimon I, Ram Z, Cohen ZR, Hadani M: Transsphenoidal surgery for agonist cabergoline in patients unsuccessfully treated by surgery. J Clin
Cushing's disease: endocrinological follow-up monitoring of 82 patients. Endocrinol Metab 2009, 94:223–230.
Neurosurgery 2002, 51:57–61. discussion 61–52. 67. Arnaldi G, Boscaro M: Pasireotide for the treatment of Cushing's disease.
46. Jagannathan J, Sheehan JP, Jane JA Jr: Evaluation and management of Expert Opin Investig Drugs 2010, 19:889–898.
Cushing syndrome in cases of negative sellar magnetic resonance 68. Feelders RA, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR,
imaging. Neurosurg Focus 2007, 23:E3. Zelissen PM, van Heerebeek R, de Jong FH, van der Lely AJ, et al:
47. Atkinson AB, Kennedy A, Wiggam MI, McCance DR, Sheridan B: Long-term Pasireotide alone or with cabergoline and ketoconazole in Cushing's
remission rates after pituitary surgery for Cushing's disease: the need for disease. N Engl J Med 2010, 362:1846–1848.
long-term surveillance. Clin Endocrinol (Oxf ) 2005, 63:549–559. 69. Boscaro M, Ludlam WH, Atkinson B, Glusman JE, Petersenn S, Reincke M,
48. Esposito F, Dusick JR, Cohan P, Moftakhar P, McArthur D, Wang C, Swerdloff Snyder P, Tabarin A, Biller BM, Findling J, et al: Treatment of pituitary-
RS, Kelly DF: Clinical review: Early morning cortisol levels as a predictor of dependent Cushing's disease with the multireceptor ligand somatostatin
remission after transsphenoidal surgery for Cushing's disease. J Clin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin
Endocrinol Metab 2006, 91:7–13. Endocrinol Metab 2009, 94:115–122.
49. Valero R, Vallette-Kasic S, Conte-Devolx B, Jaquet P, Brue T: The 70. Estrada J, Boronat M, Mielgo M, Magallon R, Millan I, Diez S, Lucas T, Barcelo
desmopressin test as a predictive factor of outcome after pituitary B: The long-term outcome of pituitary irradiation after unsuccessful
surgery for Cushing's disease. Eur J Endocrinol 2004, 151:727–733. transsphenoidal surgery in Cushing's disease. N Engl J Med 1997,
50. Pereira AM, van Aken MO, van Dulken H, Schutte PJ, Biermasz NR, Smit JW, 336:172–177.
Roelfsema F, Romijn JA: Long-term predictive value of postsurgical 71. Castinetti F, Regis J, Dufour H, Brue T: Role of stereotactic radiosurgery in
cortisol concentrations for cure and risk of recurrence in Cushing's the management of pituitary adenomas. Nat Rev Endocrinol 2010, 6:214–
disease. J Clin Endocrinol Metab 2003, 88:5858–5864. 223.
51. Chen JC, Amar AP, Choi S, Singer P, Couldwell WT, Weiss MH: Transsphenoidal 72. Smith PW, Turza KC, Carter CO, Vance ML, Laws ER, Hanks JB: Bilateral
microsurgical treatment of Cushing disease: postoperative assessment of adrenalectomy for refractory Cushing disease: a safe and definitive
surgical efficacy by application of an overnight low-dose dexamethasone therapy. J Am Coll Surg 2009, 208:1059–1064.
suppression test. J Neurosurg 2003, 98:967–973. 73. Assie G, Bahurel H, Coste J, Silvera S, Kujas M, Dugue MA, Karray F, Dousset
52. Valassi E, Biller BM, Swearingen B, Pecori Giraldi F, Losa M, Mortini P, Hayden B, Bertherat J, Legmann P, Bertagna X: Corticotroph tumor progression
D, Cavagnini F, Klibanski A: Delayed remission after transsphenoidal after adrenalectomy in Cushing's Disease: A reappraisal of Nelson's
surgery in patients with Cushing's disease. J Clin Endocrinol Metab 2010, Syndrome. J Clin Endocrinol Metab 2007, 92:172–179.
95:601–610. 74. Bush ZM, Longtine JA, Cunningham T, Schiff D, Jane JA Jr, Vance ML,
53. Aghi MK: Management of recurrent and refractory Cushing disease. Nat Thorner MO, Laws ER Jr, Lopes MB: Temozolomide treatment for
Clin Pract Endocrinol Metab 2008, 4:560–568. aggressive pituitary tumors: correlation of clinical outcome with O(6)-
54. Wagenmakers MA, Netea-Maier RT, van Lindert EJ, Timmers HJ, Grotenhuis methylguanine methyltransferase (MGMT) promoter methylation and
JA, Hermus AR: Repeated transsphenoidal pituitary surgery (TS) via the expression. J Clin Endocrinol Metab 2010, 95:E280–290.
endoscopic technique: a good therapeutic option for recurrent or 75. Raverot G, Sturm N, de Fraipont F, Muller M, Salenave S, Caron P, Chabre O,
persistent Cushing's disease (CD). Clin Endocrinol (Oxf ) 2009, 70:274–280. Chanson P, Cortet-Rudelli C, Assaker R, et al: Temozolomide treatment in
55. Locatelli M, Vance ML, Laws ER: Clinical review: the strategy of immediate aggressive pituitary tumors and pituitary carcinomas: a French
reoperation for transsphenoidal surgery for Cushing's disease. J Clin multicenter experience. J Clin Endocrinol Metab 2010, 95:4592–4599.
Endocrinol Metab 2005, 90:5478–5482. 76. Bode H, Seiz M, Lammert A, Brockmann MA, Back W, Hammes HP,
56. Nader N, Raverot G, Emptoz-Bonneton A, Dechaud H, Bonnay M, Baudin E, Thome C: SOM230 (pasireotide) and temozolomide achieve sustained
Pugeat M: Mitotane has an estrogenic effect on sex hormone-binding control of tumour progression and ACTH secretion in pituitary
globulin and corticosteroid-binding globulin in humans. J Clin Endocrinol carcinoma with widespread metastases. Exp Clin Endocrinol Diabetes
Metab 2006, 91:2165–2170. 2010, 118:760–763.
57. Robinson BG, Hales IB, Henniker AJ, Ho K, Luttrell BM, Smee IR, Stiel JN: The 77. Trementino L, Arnaldi G, Appolloni G, Daidone V, Scaroni C, Casonato A,
effect of o, p'-DDD on adrenal steroid replacement therapy Boscaro M: Coagulopathy in Cushing's syndrome. Neuroendocrinology
requirements. Clin Endocrinol (Oxf ) 1987, 27:437–444. 2010, 92(Suppl 1):55–59.
58. Cooper PR, Shucart WA: Treatment of Cushing's disease with o, p'-DDD. N 78. Giordano R, Picu A, Marinazzo E, D'Angelo V, Berardelli R, Karamouzis I,
Engl J Med 1979, 301:48–49. Forno D, Zinna D, Maccario M, Ghigo E, Arvat E: Metabolic and
59. Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Hautecouverture M, Cardiovascular Outcomes in Patients with Cushing's Syndrome of
Simon D, Laudat MH, Touitou Y, Bricaire H: Treatment of Cushing's disease Different Aetiologies during Active Disease and 1 Year after Remission.
by O,p'DDD. Survey of 62 cases. N Engl J Med 1979, 300:459–464. Clin Endocrinol (Oxf ) 2011, 75(3):354–360.
Castinetti et al. Orphanet Journal of Rare Diseases 2012, 7:41 Page 9 of 9
http://www.ojrd.com/content/7/1/41

79. Clayton RN, Raskauskiene D, Reulen RC, Jones PW: Mortality and morbidity
in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and
meta-analysis of literature. J Clin Endocrinol Metab 2011, 96:632–642.
80. Cavagnini F, Pecori GF: Epidemiology and follow-up of Cushing's disease.
Ann Endocrinol (Paris) 2001, 62:168–172.
81. Sonino N, Fallo F, Fava GA: Psychosomatic aspects of Cushing's syndrome.
Rev Endocr Metab Disord 2010, 11:95–104.

doi:10.1186/1750-1172-7-41
Cite this article as: Castinetti et al.: Cushing’s disease. Orphanet Journal of
Rare Diseases 2012 7:41.

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