Skip to main content

Cushing’s disease


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, corticotroph adenoma, pituitary dependent Cushing’s syndrome.

Chronic glucocorticoid excess, or Cushing’s syndrome, may be due to ACTH-dependent (80% cases) or –independent (20% cases) causes (Table1). The latter are mainly due to benign (60%) or malignant (40%) adrenal tumors. ACTH overproduction may be of pituitary origin (85% cases) or result from ectopic tumor secretion (15% cases). The term Cushing’s disease is specifically applied to ACTH-secreting pituitary tumors. Cushing’s disease, first described by Harvey Cushing in 1932, represents the most frequent cause of Cushing’s syndrome[1].

Table 1 Classification of most frequent causes of Cushing’s syndrome

Cushing’s disease is defined by Adrenocorticotropin hormone (ACTH) hypersecretion, induced by a corticotroph adenoma, and leading to cortisol hypersecretion (associated with androgens hypersecretion).


The incidence of Cushing’s syndrome is estimated to be equal to 1–3 cases per million inhabitants per year, whereas its prevalence is close to 40 cases per million inhabitants. Of note, prevalence of hypercortisolism is thought to be equal to 2-5% of patients with poorly controlled diabetes and hypertension. Female preponderance is generally assumed to be close to 3:1[2]. Cushing’s disease is an extremely rare condition in children, with a peak in adults in the 3rd or 4th decade. Cushing’s disease leads to death if untreated; it is responsible for increased morbidity and mortality, due to cardiovascular complications, infections and psychiatric disturbances[3, 4].

Clinical and biological characteristics

Clinical characteristics

Hypercortisolic state may include several clinical signs[5, 6]

  • Obesity: obesity with centripetal fat deposition (face, supraclavicular and dorso-cervical fat pads), facial plethora, rounded face, buffalo-hump

  • Signs of protein wasting: thin skin, abdominal purple to red and wide cutaneous striae (abdomen, flanks, breasts, hips, axillae), easy bruising, slow healing, muscle wasting (lower limbs muscle atrophy)

  • Bone wasting leading to osteoporosis (possibly leading to fractures)

  • High blood pressure

  • Impaired immune defense mechanisms with increased rate of infections

  • Gonadal dysfunction and hyperandrogenism: hirsutism (more frequently on the face), menstrual irregularity (oligoamenorrhea, amenorrhea)

  • Mild to severe psychic disturbances(anxiety, depression, irritability…)

The most frequent sign is obesity: abnormal fat distribution is considered as the most sensitive sign[7]. Evidence of protein wasting (osteoporosis, myopathy) is the most specific sign. Conjunction of both should theoretically allow to distinguish between hypercortisolism and simple obesity. However, the severity of hypercortisolism can be highly variable, which frequently makes the diagnosis difficult. Moreover, hypersecretion profiles can be cyclical, leading to very modest phenotypic signs in some patients (subclinical Cushing’s syndrome)[8]. In most cases, diagnosis depends on a high index of suspicion, rather than a florid clinical phenotype. Of note, none of the signs can allow to differentiate Cushing’s disease from any other etiology of hypercortisolism, except in case of tumor related symptoms such as headaches or visual field defect (in macroadenomas).

Biological characteristics

Non-specific biological signs may include hypokalemia and impaired glucose tolerance or diabetes. Blood count may show increased hemoglobin, increased neutrophils and decreased lymphocytes or eosinophils.


Characteristics of corticotroph adenomas

Cushing’s disease is frequently due to monoclonal benign and slow growing microadenomas (less than 10 mm)[9, 10]. Plasma ACTH (and cortisol) classically lose their physiologic circadian periodicity. They are partially resistant to physiologic stimuli (i.e., glucocorticoids), and do not respond to the normal feedback negative loop. In contrast, corticotroph adenomas are inappropriately sensitive to CRH and AVP. Altered CRH secretion as well as POMC qualitative changes in gene expression were also reported to be involved in the pathogenesis of Cushing’s disease. Cushing’s disease can be more atypical: secretion profiles are sometimes cyclic, with hypersecretion preceding a long period of normal secretion[8, 11]. Some corticotroph adenomas are called “silent” as they are clinically and biologically comparable to non-secreting pituitary adenomas: diagnosis is made by the pathologist[12]. Finally, rare cases of aggressive pituitary adenomas or carcinomas have been reported[13]. Whether hyperplasia of corticotroph cells is or not a required initial step before the genesis of corticotroph adenoma remains a matter of debate. The origin of the disease, primary pituitary condition or secondary to an abnormality in the hypothalamus (chronic stimulation by CRH[14]), remains a matter of debate.

Genetic predisposition

Cushing’s disease can be part of Multiple Endocrine Neoplasia Type 1, due to mutations of the menin gene. It is a rare syndrome, transmitted in an autosomal dominant manner, which associates hyperparathyroidism, endocrine tumors, and pituitary adenomas in 20-50% cases. Most of these are somatotroph or lactotroph, but corticotroph adenomas have been described in 5-10% of cases. AIP (Aryl hydrocarbon receptor Interacting Protein) mutations have been reported in familial pituitary adenomas: secretion profile is usually somatotroph or lactotroph, whereas very rare cases of CD have also been reported[15].

Potentially involved molecular mechanisms

Triggering signals leading to Cushing’s disease remain unclear. Oncogenes do not appear to be involved, as somatic mutations are usually not present in corticotroph adenomas cells. Recent studies in mice identified a potential role of loss of function of Brg1 (brahma-related gene 1) and HDAC2 (Histone Deacetylase 2) in the pathogenesis of Cushing’s disease. Both proteins form a complex with the glucocorticoid receptor and the orphan nuclear receptor nuclear growth factor IB (NGFI-B) to repress POMC secretion. Interestingly, about 50% of corticotroph adenomas do not express these proteins anymore. The loss of Brg1 could lead to overexpression of cyclin E, leading to increased cell proliferation and sporadic hyperplasia or tumors. Interestingly, tumors with a loss of nuclear localization of Brg1 seem to be more responsive to anticortisolic drugs in vitro compared to the ones with a complete loss of Brg1 oncogene[16, 17].

Transcription factors involved in progenitors proliferation and differentiation during pituitary embryogenesis could also be involved in pituitary tumorigenesis. TPIT deficiency is known to result in congenital isolated corticotroph deficiency. Patients with other pituitary transcription factors mutations (PROP1 LHX3 LHX4 HESX1) usually present combined pituitary hormone deficiencies including inconstant corticotroph deficiency. As some of these factors are still expressed at adult age, and their role is not precisely known, it could be tempting to speculate on potential roles of an overexpression of these proteins in pituitary adenomas ontogenesis. However, to our knowledge, no mutation of any transcription factor has ever been identified in patients presenting with corticotroph adenomas[18, 19].


Diagnosis of Cushing’s disease is difficult[20]. Clinical signs and symptoms are often non-specific; no single biological test combines optimal sensitivity and specificity for the diagnosis of hypercortisolism and for the determination of its etiology[21]. Moreover, pituitary and adrenal imaging can sometimes be confusing.

Several steps are needed to first confirm the diagnosis of hypercortisolism and then determine its origin: the first will be to confirm the lack of exposure to exogenous glucocorticoids that induces the same clinical characteristics as Cushing’s syndrome and makes hypercortisolism screening unavailable[22]. In normal subjects, cortisol levels reach a peak at early morning and a nadir < 50 nmol/l around midnight. Patients with Cushing’s syndrome lose this circadian rhythm. As a consequence, early morning ACTH and cortisol values are of poor diagnostic value in the screening methods of hypercortisolism. In contrast a midnight cortisol value > 200 nmol/l is strongly suggestive of Cushing’s syndrome[23]. Evaluation of the circardian rhythm of cortisol is however not recommended as a first line screening method for hypercortisolism.

We will not detail precisely all methods and tests proposed to confirm a diagnosis of hypercortisolism (or Cushing’s syndrome, CS): these criteria have been widely described in recent consensus conferences[6, 24]. First line screening methods should include either

  • 24-hour urinary free cortisol, repeated at least 24-hour urinary free cortisol, repeated at least twice; values should be above 220–330?nmol/24?h depending on the assays, in Cushing’s syndrome, keeping in mind that normal values can be seen in 8-15% of patients with Cushing’s syndrome[25]

  • cortisol response to 1?mg-overnight dexamethasone suppression test: cortisol value?<?50?nmol/l (< 2?µg/dl) excludes Cushing’s syndrome with high sensitivity (95%) but low specificity[26].

  • cortisol response to low dose dexamethasone suppression test (0.5?mg dexamethasone every 6 hours during 48 hours): cortisol value?<?50?nmol/l (< 2?µg/dl) excludes Cushing’s syndrome with a sensitivity and specificity close to 100%[27].

  • or late night salivary cortisol[25, 28, 29] : a cortisol value?>?2?ng/ml (5.5?nmol/l) has a 100% sensitivity and 96% specificity for Cushing’s syndrome[30].

Pseudo Cushing’s syndrome is defined by the presence of partial clinical signs of hypercortisolism. It can be induced by chronic alcohol consumption, depression and obesity. Diagnosis between Cushing’s syndrome and pseudo Cushing’s syndrome might be difficult despite the use of previously described screening methods[6]. CRH injection coupled with dexamethasone suppression test, is in favor of Cushing’s syndrome with 90% sensitivity and 84% specificity in the presence of peak cortisol > 580 nmol/l and ACTH > 50 pg/ml[31].

Steps for positive diagnosis of Cushing’s syndrome are summarized in Figure1.

Figure 1
figure 1

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

When the presence of CS is confirmed, diagnosis approach will determine if the secretion is ACTH-dependent or not. Early morning undetectable ACTH levels (< 10 pg/ml) will lead to a diagnosis of ACTH independent hypercortisolism (autonomous adrenal hypersecretion), whereas inappropriately normal or increased levels (> 10 pg/ml) will be in favor of an ACTH-dependent hypercortisolism.

ACTH dependent CS includes Cushing’s disease (CD) and, more rarely, ectopic ACTH secretion (EAS)[32]. Distinction between both is difficult, and frequently requires the use of several diagnostic methods[33]:

  • high dose dexamethasone suppression test (8 mg/day during 2 days): a decrease of more than 50% urinary cortisol level is observed in 90% of patients with CD, compared with less than 50% of those with EAS. Of note, more than 90% suppression of urinary cortisol has 100% specificity in the diagnosis of Cushing’s disease [2].

  • CRH test (100 μg intra-venously): more than 50% ACTH and 20% cortisol increase is in favor of Cushing’s disease. Sensitivity and specificity are close to 90% [34].

  • Desmopressin test (10 μg intravenously), ACTH and cortisol increases similar to those observed with the CRH test are in favor of CD with 70% sensitivity and 85% specificity [20, 35]

Concordant responses to at least 2/3 of these tests should lead to the diagnosis of Cushing’s disease, and pituitary MRI. However, the sensitivity of MRI in CD is hardly greater than 60-70% and specificity close to 85%, as most corticotroph adenomas are microadenomas. In one study, 10% of the general population presented MRI pituitary images of less than 5 mm that might be considered as adenomas[36]. Cushing’s disease diagnosis is thus confirmed in the presence of an adenoma > 6 mm and concordant responses to tests.

In the lack of an image suggesting a pituitary adenoma on MRI despite dynamic tests in favor of CD, or in case of discordant tests, bilateral intra-petrosal sinus sampling (stimulated by CRH or desmopressin) should be performed: it will give a definite answer to confirm the etiology of ACTH dependent CS. The principle is to measure a ratio defined by central ACTH/peripheral ACTH. A central to peripheral plasma ACTH ratio exceeding 2 (or 3 after stimulation by CRH) is in favor of Cushing’s disease[3740] .In case of ACTH dependent hypercortisolism, if the initial etiologic workup is not in favor of a pituitary origin, complementary morphologic investigation including tomodensitometric whole body examination should be performed. Some teams prefer to perform systematically a thoraco–abdomino-pelvic scan in each patient with ACTH dependent Cushing’s syndrome, whatever the status of tests and MRI. The limit of this approach is identical to the one reported with pituitary MRI, as some patients might have bronchial incidentalomas not responsible for ectopic ACTH secretion, and leading to a misdiagnosis[33]. Steps necessary for the etiological diagnosis of ACTH dependent Cusging’s syndrome are summarized in Figure2.

Figure 2
figure 2

Steps necessary for the etiological diagnosis of ACTH-dependent Cushing’s syndrome.

Differential diagnosis

  • Chronic exogenous administration of glucocorticoids

  • Pseudo-Cushing states as described previously

  • ACTH dependent Cushing’s syndrome: Ectopic ACTH secretion (see above)

  • ACTH independent Cushing’s syndrome will be ruled out by inappropriately normal or increased ACTH levels.

  • Functional hypercortisolism during pregnancy

Clinical management

Transsphenoidal surgery is the first line treatment of Cushing’s disease[41, 42]. It allows remission in 60-90% of microadenomas, and 50-70% of macroadenomas, depending on local invasion and the experience of the neurosurgeon[4345]. Remission should be defined by normal ACTH and cortisol circadian rhythms, and suppressed cortisol value after overnight/low dose dexamethasone suppression test.

The appropriateness of surgery in the lack of visualized pituitary adenoma remains a matter of debate[46]. When extensive samplings and dynamic tests confirm that hypercortisolism is due to Cushing’s disease, and pituitary MRI seems normal, literature data report a range of surgical efficacy varying from less than 50 to 70% of remission, often associated with induced hypopituitarism and/or diabetes insipidus. The risk of late recurrence after presumably curative surgery is estimated to be close to 25%[47]. Several criteria have been reported as predictive factors for long-term remission: low immediate post-surgical early morning cortisol/ACTH levels, cortisol suppression after 1 mg overnight dexamethasone suppression test, lack of cortisol/ACTH response to desmopressin or coupled dexamethasone desmopressin test[4851]. However, it is still difficult to predict which patients are at greater risk of recurrence, as some patients uncured immediately after surgery, might however present delayed remission[52]. As a consequence, and due to the high risk of recurrence, it seems difficult to talk about “cure” in patients with surgically treated Cushing’s disease; the term “remission” seems more appropriate. In other words, even long-term remission after surgery should lead to at least a prolonged clinical close follow-up.

In case of immediate surgical failure or late recurrence, several therapeutic modalities are available: second pituitary surgery, medical treatments, radiation techniques, or bilateral adrenalectomy[53]. Only some of these treatments (surgery, and radiation techniques after à prolonged period) can lead to long-term remission.

Second surgery

Several teams reported the benefits of a second surgical procedure, either in the first days following initial surgery, or later. A recent study reported a possibility of delayed remission after initial surgery in about 5% of cases. This should be in favor of a delayed rather than an immediate approach. Efficacy is usually observed in 50-70% of cases, frequently associated with an increased risk of hypopituitarism, diabetes insipidus, and cerebrospinal fluid leak[54, 55].

Medical treatments

Medical treatments aim at decreasing synthesis and secretion of cortisol, blocking glucocorticoid receptors, or inhibiting ACTH secretion. The main drawback of these drugs is that they are only suspensive, i.e. hypercortisolism may be controlled but still uncured, requiring a long-term period of treatment. There are 4 main indications of medical treatment: in case of contra-indication or refusal of surgery, in the lack of adenoma image on pituitary MRI, waiting for radiation techniques to be effective, as a multimodality approach in the rare cases of pituitary carcinomas.

Steroidogenesis inhibitors

  • Op’DDD (mitotane, Lysodren®) is derived from insecticide dichloro-diphenyl- dichloroethane (DDD). Op’DDD inhibits side chain cleavage of cholesterol and also other cytochrome P450 enzymes (11-alpha and 18-hydroxylase) and non-P450 enzyme (3 beta-hydroxysteroiddeshydrogenase). In Cushing’s disease, it is used as an inhibitor of cortisol secretion.Op’DDD is usually effective in more than 50% cases, and frequently induces adrenal atrophy; however, gastro-intestinal tolerance is usually bad, and there is a 4-week delay to obtain maximal efficacy due to its accumulation in adipose tissue. There is a narrow difference between efficacy and toxicity levels. Main side effects are digestive (nausea, vomiting, diarrhea), neurologic (sleepiness, asthenia) and metabolic (hypercholesterolemia). Mitotane modifies metabolic clearance of steroids with consequent gynecomastia in men and alteration of contraceptive effects of pills[56, 57]. Pregnancy is forbidden during mitotane therapy and for two years after drug withdrawal due to teratogenic effects[41, 58, 59].

  • Ketoconazole is an antifungal agent with steroidogenesis inhibitor effects linked to inhibition of cytochrome P450 enzymes. It was reported to normalize cortisol levels in Cushing’s disease in about 50% of cases. Side effects include rare severe liver injury (1/15000 cases), and gastro-intestinal intolerance[60].

  • Metyrapone (Métopirone®) is a pyridine derivative that blocks cortisol synthesis by mainly inhibition of 11 beta hydroxylase. Metyrapone is rapidly effective in about 50% of hypercortisolic states: it usually induced low blood potassium levels, and hyperandrogenism[61].

  • Etomidate (Hypnomidate®) is an intravenous anaesthetic agent. It inhibits cortisol synthesis by inhibiting CYP11B1 with 11-beta hydroxylase activity, and cytochrome P450scc at high concentrations. Etomidate is a very potent anticortisolic drug, limited by the fact that it can only be used intravenously: it should thus be reserved for severe hypercortisolic states[62].

Glucocorticoid receptor antagonist

Mifepristone is currently the only available glucocorticoid receptor antagonist. Only rare cases have been reported to date. The drug seems to be highly effective in controlling clinical signs of hypercortisolism. However, due to its mode of action, there is a high risk of hypokalemia, and there is no biological means to monitor the patient. Treatment dose adjustment is thus only based on subjective signs[63].

ACTH-lowering agents

Cabergoline is a dopamine agonist well known for its anti-secretory and anti-tumoral efficacy in prolactinomas. Corticotroph adenomas can express dopamine receptors. Recent studies reported that about 25% of patients treated by high doses of carbergoline for CD could be controlled as well[6466]. A strict echocardiographic follow-up is required, due to a dose-dependent risk of valvulopathy.

Pasireotide is a somatostatin agonist with a particular binding affinity for somatostatin receptor (sstr) isoforms 1, 2, 3 and 5. This specific affinity for sstr5 could be of major interest in CD. Clinical trials are ongoing to determine efficiency of this drug. Preliminary results suggest that pasireotide is able to decrease cortisol levels in the majority of patients, but only few reach normalized values. There is a risk of induction or worsening of hyperglycemia in 1/3 cases[6769].

Radiation techniques

Radiation techniques have been widely used as a treatment of Cushing’s disease. Different techniques are available, mainly based on fractionated radiotherapy or stereotactic radiosurgery. Radiotherapy induces remission in the majority of cases, but also panhypopituitarism in more than 80% of patients[70]. Due to the slow decrease of ACTH levels, delay to remission can vary from 2–3 to 10 years, depending on initial hormone levels. Stereotactic radiosurgery is delivered in a single session. It is theoretically a more precise technique, leading to a lower risk of hypopituitarism. However, the rate of remission is lower, reported in only 50% of cases. Radiosurgery should thus be reserved for small and low secreting lesions[71]. For both techniques, medical treatments need to be given between the procedure and maximal efficacy, i.e. for 2–5 years, to control cortisol hypersecretion waiting for normalization.

Bilateral adrenalectomy

It can be used either in case of failure of pituitary surgery, or when hypercortisolism is severe, requiring a rapidly active treatment. Bilateral adrenalectomy resolves cortisol hypersecretion in the vast majority of cases, with a low risk of perioperative complications[72]. One might consider trying to decrease the level of hypersecretion by antisecretory therapy for a short period of time before bilateral adrenalectomy, but this specific point has never been really evaluated. The major and expected side effect of bilateral adrenalectomy is adrenal insufficiency. Another possible adverse effects is Nelson’s syndrome, which is a pituitary tumor progression observed after adrenalectomy[73].


In rare cases, CD can be induced by aggressive pituitary tumors, and still more rarely by pituitary carcinomas. Due to frequent recurrences, they usually require repeat surgery, and aggressive treatments. The rarity of cases makes it difficult to define a consensual therapeutic approach. Recent studies pointed out the benefits of temozolomide, but prospective long-term studies will be necessary to ascertain this point[7476].


The risks of chronic hypercortisolic state include excess morbidity and mortality due to increased cardio-vascular risk factors (hypertension, dyslipidemia, diabetes mellitus, metabolic syndrome) leading to heart defect. Moreover, hypercortisolism is responsible for coagulopathy[77] and atherosclerosis[78], which also increase the risk to develop cardiovascular diseases. Recent data suggest that part of these defects due to hypercortisolism might remain after remission[78] even if the mortality rate would go back to normal[79]. Frequency of infectious diseases is also increased, as well as delayed healing. Hypercortisolism can induce severe osteoporosis in about 30% cases, and osteopenia in half of them. Also, acute cortisol excess can induce severe hypokalemia, as well as elevated blood pressure levels, and sometimes psychiatric signs[26, 80]. Finally, more than half of patients with CS can present with psychiatric signs, from mild to severe depression, and cognitive dysfunction[81].

Future prospects

Future research should focus on

  1. 1.

    The pathophysiological mechanisms leading to corticotroph adenomas. Only rare data are available on the early events leading to pituitary adenomas in general, and corticotroph adenomas in particular.

  2. 2.

    The way to improve sensitivity/specificity of diagnostic methods for subclinical Cushing’s syndrome. Some patients are diagnosed with Cushing’s syndrome several years after a prolonged treatment for hypertension, osteoporosis…

  3. 3.

    The way to diagnose earlier patients with a high risk of post-surgical recurrence. About 20% of patients with what is supposedly the best predictive factor of remission (low cortisol levels immediately after surgery) still present long term recurrence of their disease.

  4. 4.

    The development of safe and effective medical treatments. Currently available drugs are either poorly effective and/or have bad tolerance.



Cushing’s syndrome


Cushing’s disease


Ectopic ACTH Secretion.


  1. Bertagna X, Guignat L, Groussin L, Bertherat J: Cushing's disease. Best Pract Res Clin Endocrinol Metab. 2009, 23: 607-623.

    Article  CAS  PubMed  Google Scholar 

  2. Melmed S, Polonsky K, Reed Larsen P, Kronenberg H: William's Textbook of Endocrinology 12th edition. Philadelphia: Elsevier/Saunders; 2011.

    Google Scholar 

  3. Steffensen C, Bak AM, Rubeck KZ, Jorgensen JO: Epidemiology of Cushing's syndrome. Neuroendocrinology. 2010, 92 (Suppl 1): 1-5.

    Article  CAS  PubMed  Google Scholar 

  4. Jeffcoate WJ, Silverstone JT, Edwards CR, Besser GM: Psychiatric manifestations of Cushing's syndrome: response to lowering of plasma cortisol. Q J Med. 1979, 48: 465-472.

    CAS  PubMed  Google Scholar 

  5. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing's syndrome. Lancet. 2006, 367: 1605-1617.

    Article  CAS  PubMed  Google Scholar 

  6. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93: 1526-1540.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Ross EJ, Linch DC: Cushing's syndrome–killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet. 1982, 2: 646-649.

    Article  CAS  PubMed  Google Scholar 

  8. Alexandraki KI, Kaltsas GA, Isidori AM, Akker SA, Drake WM, Chew SL, Monson JP, Besser GM, Grossman AB: The prevalence and characteristic features of cyclicity and variability in Cushing's disease. Eur J Endocrinol. 2009, 160: 1011-1018.

    Article  CAS  PubMed  Google Scholar 

  9. Gicquel C, Le Bouc Y, Luton JP, Girard F, Bertagna X: Monoclonality of corticotroph macroadenomas in Cushing's disease. J Clin Endocrinol Metab. 1992, 75: 472-475.

    CAS  PubMed  Google Scholar 

  10. Woo YS, Isidori AM, Wat WZ, Kaltsas GA, Afshar F, Sabin I, Jenkins PJ, Monson JP, Besser GM, Grossman AB: Clinical and biochemical characteristics of adrenocorticotropin-secreting macroadenomas. J Clin Endocrinol Metab. 2005, 90: 4963-4969.

    Article  CAS  PubMed  Google Scholar 

  11. Brew Atkinson A, Mullan KR: What is the best approach to suspected cyclical Cushing syndrome? Strategies for managing Cushing's Syndrome with variable laboratory data. Clin Endocrinol (Oxf). 2011, Still epub ahead of print 2011 Feb 26

    Google Scholar 

  12. Raverot G, Wierinckx A, Jouanneau E, Auger C, Borson-Chazot F, Lachuer J, Pugeat M, Trouillas J: Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing's disease. Eur J Endocrinol. 2010, 163: 35-43.

    Article  CAS  PubMed  Google Scholar 

  13. Holthouse DJ, Robbins PD, Kahler R, Knuckey N, Pullan P: Corticotroph pituitary carcinoma: case report and literature review. Endocr Pathol. 2001, 12: 329-341.

    Article  CAS  PubMed  Google Scholar 

  14. Biller BM: Pathogenesis of pituitary Cushing's syndrome. Pituitary versus hypothalamic. Endocrinol Metab Clin North Am. 1994, 23: 547-554.

    CAS  PubMed  Google Scholar 

  15. Yaneva M, Vandeva S, Zacharieva S, Daly AF, Beckers A: Genetics of Cushing's syndrome. Neuroendocrinology. 2010, 92 (Suppl 1): 6-10.

    Article  CAS  PubMed  Google Scholar 

  16. Bilodeau S, Vallette-Kasic S, Gauthier Y, Figarella-Branger D, Brue T, Berthelet F, Lacroix A, Batista D, Stratakis C, Hanson J, et al: Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 2006, 20: 2871-2886.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Drouin J, Bilodeau S, Vallette S: Of old and new diseases: genetics of pituitary ACTH excess (Cushing) and deficiency. Clin Genet. 2007, 72: 175-182.

    Article  CAS  PubMed  Google Scholar 

  18. Davis SW, Castinetti F, Carvalho LR, Ellsworth BS, Potok MA, Lyons RH, Brinkmeier ML, Raetzman LT, Carninci P, Mortensen AH, et al: Molecular mechanisms of pituitary organogenesis: In search of novel regulatory genes. Mol Cell Endocrinol. 2010, 323 (1): 4-19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Kelberman D, Rizzoti K, Lovell-Badge R, Robinson IC, Dattani MT: Genetic regulation of pituitary gland development in human and mouse. Endocr Rev. 2009, 30: 790-829.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Nieman LK: Difficulty in the diagnosis of Cushing disease. Nat Clin Pract Endocrinol Metab. 2006, 2: 53-57. quiz following 57

    Article  PubMed  Google Scholar 

  21. Tabarin A, Perez P: Pros and cons of screening for occult Cushing syndrome. Nat Rev Endocrinol. 2011, 7 (8): 445-455.

    Article  PubMed  Google Scholar 

  22. Hopkins RL, Leinung MC: Exogenous Cushing's syndrome and glucocorticoid withdrawal. Endocrinol Metab Clin North Am. 2005, 34: 371-384. ix

    Article  CAS  PubMed  Google Scholar 

  23. Newell-Price J, Trainer P, Perry L, Wass J, Grossman A, Besser M: A single sleeping midnight cortisol has 100 % sensitivity for the diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf). 1995, 43: 545-550.

    Article  CAS  Google Scholar 

  24. Guignat L, Bertherat J: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective. Eur J Endocrinol. 2010, 163: 9-13.

    Article  CAS  PubMed  Google Scholar 

  25. Findling JW, Raff H: Screening and diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am. 2005, 34: 385-402. ix-x

    Article  PubMed  Google Scholar 

  26. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, et al: Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003, 88: 5593-5602.

    Article  CAS  PubMed  Google Scholar 

  27. Newell-Price J, Trainer P, Besser M, Grossman A: The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr Rev. 1998, 19: 647-672.

    CAS  PubMed  Google Scholar 

  28. Carroll T, Raff H, Findling JW: Late-night salivary cortisol for the diagnosis of Cushing syndrome: a meta-analysis. Endocr Pract. 2009, 15: 335-342.

    Article  PubMed  Google Scholar 

  29. Nunes ML, Vattaut S, Corcuff JB, Rault A, Loiseau H, Gatta B, Valli N, Letenneur L, Tabarin A: Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients. J Clin Endocrinol Metab. 2009, 94: 456-462.

    Article  CAS  PubMed  Google Scholar 

  30. Yaneva M, Mosnier-Pudar H, Dugue MA, Grabar S, Fulla Y, Bertagna X: Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome of various causes. J Clin Endocrinol Metab. 2004, 89: 3345-3351.

    Article  CAS  PubMed  Google Scholar 

  31. Tirabassi G, Papa R, Faloia E, Boscaro M, Arnaldi G: Corticotrophin-releasing hormone and desmopressin tests in the differential diagnosis between Cushing's disease and pseudo-Cushing state: a comparative study. Clin Endocrinol (Oxf). 2011, 75: 666-672.

    Article  CAS  Google Scholar 

  32. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK: Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005, 90: 4955-4962.

    Article  CAS  PubMed  Google Scholar 

  33. Boscaro M, Arnaldi G: Approach to the patient with possible Cushing's syndrome. J Clin Endocrinol Metab. 2009, 94: 3121-3131.

    Article  CAS  PubMed  Google Scholar 

  34. Chrousos GP, Schulte HM, Oldfield EH, Gold PW, Cutler GB Jr, Loriaux DL: The corticotropin-releasing factor stimulation test. An aid in the evaluation of patients with Cushing's syndrome. N Engl J Med. 1984, 310: 622-626.

    Article  CAS  PubMed  Google Scholar 

  35. Tsagarakis S, Tsigos C, Vasiliou V, Tsiotra P, Kaskarelis J, Sotiropoulou C, Raptis SA, Thalassinos N: The desmopressin and combined CRH-desmopressin tests in the differential diagnosis of ACTH-dependent Cushing's syndrome: constraints imposed by the expression of V2 vasopressin receptors in tumors with ectopic ACTH secretion. J Clin Endocrinol Metab. 2002, 87: 1646-1653.

    CAS  PubMed  Google Scholar 

  36. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH: Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med. 1994, 120: 817-820.

    Article  CAS  PubMed  Google Scholar 

  37. Batista D, Gennari M, Riar J, Chang R, Keil MF, Oldfield EH, Stratakis CA: An assessment of petrosal sinus sampling for localization of pituitary microadenomas in children with Cushing disease. J Clin Endocrinol Metab. 2006, 91: 221-224.

    Article  CAS  PubMed  Google Scholar 

  38. Castinetti F, Morange I, Dufour H, Jaquet P, Conte-Devolx B, Girard N, Brue T: Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing's syndrome. Eur J Endocrinol. 2007, 157: 271-277.

    Article  CAS  PubMed  Google Scholar 

  39. Kaskarelis IS, Tsatalou EG, Benakis SV, Malagari K, Komninos I, Vassiliadi D, Tsagarakis S, Thalassinos N: Bilateral inferior petrosal sinuses sampling in the routine investigation of Cushing's syndrome: a comparison with MRI. AJR Am J Roentgenol. 2006, 187: 562-570.

    Article  PubMed  Google Scholar 

  40. Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, Cutler GB Jr, Loriaux DL: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med. 1991, 325: 897-905.

    Article  CAS  PubMed  Google Scholar 

  41. Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, et al: Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008, 93: 2454-2462.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Tritos NA, Biller BM, Swearingen B, Medscape: Management of Cushing disease. Nat Rev Endocrinol. 2011, 7: 279-289.

    Article  CAS  PubMed  Google Scholar 

  43. Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Muller OA, Fahlbusch R: Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. J Neurosurg. 2008, 108: 9-18.

    Article  PubMed  Google Scholar 

  44. Hoybye C, Grenback E, Thoren M, Hulting AL, Lundblad L, von Holst H, Anggard A: Transsphenoidal surgery in Cushing disease: 10 years of experience in 34 consecutive cases. J Neurosurg. 2004, 100: 634-638.

    Article  PubMed  Google Scholar 

  45. Shimon I, Ram Z, Cohen ZR, Hadani M: Transsphenoidal surgery for Cushing's disease: endocrinological follow-up monitoring of 82 patients. Neurosurgery. 2002, 51: 57-61. discussion 61–52

    Article  PubMed  Google Scholar 

  46. Jagannathan J, Sheehan JP, Jane JA: Evaluation and management of Cushing syndrome in cases of negative sellar magnetic resonance imaging. Neurosurg Focus. 2007, 23: E3.

    Article  PubMed  Google Scholar 

  47. Atkinson AB, Kennedy A, Wiggam MI, McCance DR, Sheridan B: Long-term remission rates after pituitary surgery for Cushing's disease: the need for long-term surveillance. Clin Endocrinol (Oxf). 2005, 63: 549-559.

    Article  Google Scholar 

  48. Esposito F, Dusick JR, Cohan P, Moftakhar P, McArthur D, Wang C, Swerdloff RS, Kelly DF: Clinical review: Early morning cortisol levels as a predictor of remission after transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab. 2006, 91: 7-13.

    Article  CAS  PubMed  Google Scholar 

  49. Valero R, Vallette-Kasic S, Conte-Devolx B, Jaquet P, Brue T: The desmopressin test as a predictive factor of outcome after pituitary surgery for Cushing's disease. Eur J Endocrinol. 2004, 151: 727-733.

    Article  CAS  PubMed  Google Scholar 

  50. Pereira AM, van Aken MO, van Dulken H, Schutte PJ, Biermasz NR, Smit JW, Roelfsema F, Romijn JA: Long-term predictive value of postsurgical cortisol concentrations for cure and risk of recurrence in Cushing's disease. J Clin Endocrinol Metab. 2003, 88: 5858-5864.

    Article  CAS  PubMed  Google Scholar 

  51. Chen JC, Amar AP, Choi S, Singer P, Couldwell WT, Weiss MH: Transsphenoidal microsurgical treatment of Cushing disease: postoperative assessment of surgical efficacy by application of an overnight low-dose dexamethasone suppression test. J Neurosurg. 2003, 98: 967-973.

    Article  PubMed  Google Scholar 

  52. Valassi E, Biller BM, Swearingen B, Pecori Giraldi F, Losa M, Mortini P, Hayden D, Cavagnini F, Klibanski A: Delayed remission after transsphenoidal surgery in patients with Cushing's disease. J Clin Endocrinol Metab. 2010, 95: 601-610.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Aghi MK: Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab. 2008, 4: 560-568.

    Article  PubMed  Google Scholar 

  54. Wagenmakers MA, Netea-Maier RT, van Lindert EJ, Timmers HJ, Grotenhuis JA, Hermus AR: Repeated transsphenoidal pituitary surgery (TS) via the endoscopic technique: a good therapeutic option for recurrent or persistent Cushing's disease (CD). Clin Endocrinol (Oxf). 2009, 70: 274-280.

    Article  CAS  Google Scholar 

  55. Locatelli M, Vance ML, Laws ER: Clinical review: the strategy of immediate reoperation for transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab. 2005, 90: 5478-5482.

    Article  CAS  PubMed  Google Scholar 

  56. Nader N, Raverot G, Emptoz-Bonneton A, Dechaud H, Bonnay M, Baudin E, Pugeat M: Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J Clin Endocrinol Metab. 2006, 91: 2165-2170.

    Article  CAS  PubMed  Google Scholar 

  57. Robinson BG, Hales IB, Henniker AJ, Ho K, Luttrell BM, Smee IR, Stiel JN: The effect of o, p'-DDD on adrenal steroid replacement therapy requirements. Clin Endocrinol (Oxf). 1987, 27: 437-444.

    Article  CAS  Google Scholar 

  58. Cooper PR, Shucart WA: Treatment of Cushing's disease with o, p'-DDD. N Engl J Med. 1979, 301: 48-49.

    CAS  PubMed  Google Scholar 

  59. Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Hautecouverture M, Simon D, Laudat MH, Touitou Y, Bricaire H: Treatment of Cushing's disease by O,p'DDD. Survey of 62 cases. N Engl J Med. 1979, 300: 459-464.

    Article  CAS  PubMed  Google Scholar 

  60. Castinetti F, Morange I, Jaquet P, Conte-Devolx B, Brue T: Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease. Eur J Endocrinol. 2008, 158: 91-99.

    Article  CAS  PubMed  Google Scholar 

  61. Obinata D, Yamaguchi K, Hirano D, Yoshida T, Soma M, Takahashi S: Preoperative management of Cushing's syndrome with metyrapone for severe psychiatric disturbances. Int J Urol. 2008, 15: 361-362.

    Article  PubMed  Google Scholar 

  62. Mettauer N, Brierley J: A novel use of etomidate for intentional adrenal suppression to control severe hypercortisolemia in childhood. Pediatr Crit Care Med. 2009, 10: e37-40.

    Article  PubMed  Google Scholar 

  63. Castinetti F, Fassnacht M, Johanssen S, Terzolo M, Bouchard P, Chanson P, Do Cao C, Morange I, Pico A, Ouzounian S, et al: Merits and pitfalls of mifepristone in Cushing's syndrome. Eur J Endocrinol. 2009, 160: 1003-1010.

    Article  CAS  PubMed  Google Scholar 

  64. Vilar L, Naves LA, Azevedo MF, Arruda MJ, Arahata CM, Moura ESL, Agra R, Pontes L, Montenegro L, Albuquerque JL, Canadas V: Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing's disease. Pituitary. 2010, 13: 123-129.

    Article  CAS  PubMed  Google Scholar 

  65. Petrossians P, Thonnard AS, Beckers A: Medical treatment in Cushing's syndrome: dopamine agonists and cabergoline. Neuroendocrinology. 2010, 92 (Suppl 1): 116-119.

    Article  CAS  PubMed  Google Scholar 

  66. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, Hofland LJ, Lamberts SW, Colao A: The medical treatment of Cushing's disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab. 2009, 94: 223-230.

    Article  CAS  PubMed  Google Scholar 

  67. Arnaldi G, Boscaro M: Pasireotide for the treatment of Cushing's disease. Expert Opin Investig Drugs. 2010, 19: 889-898.

    Article  CAS  PubMed  Google Scholar 

  68. Feelders RA, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, Zelissen PM, van Heerebeek R, de Jong FH, van der Lely AJ, et al: Pasireotide alone or with cabergoline and ketoconazole in Cushing's disease. N Engl J Med. 2010, 362: 1846-1848.

    Article  CAS  PubMed  Google Scholar 

  69. Boscaro M, Ludlam WH, Atkinson B, Glusman JE, Petersenn S, Reincke M, Snyder P, Tabarin A, Biller BM, Findling J, et al: Treatment of pituitary-dependent Cushing's disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab. 2009, 94: 115-122.

    Article  CAS  PubMed  Google Scholar 

  70. Estrada J, Boronat M, Mielgo M, Magallon R, Millan I, Diez S, Lucas T, Barcelo B: The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing's disease. N Engl J Med. 1997, 336: 172-177.

    Article  CAS  PubMed  Google Scholar 

  71. Castinetti F, Regis J, Dufour H, Brue T: Role of stereotactic radiosurgery in the management of pituitary adenomas. Nat Rev Endocrinol. 2010, 6: 214-223.

    Article  PubMed  Google Scholar 

  72. Smith PW, Turza KC, Carter CO, Vance ML, Laws ER, Hanks JB: Bilateral adrenalectomy for refractory Cushing disease: a safe and definitive therapy. J Am Coll Surg. 2009, 208: 1059-1064.

    Article  PubMed  Google Scholar 

  73. Assie G, Bahurel H, Coste J, Silvera S, Kujas M, Dugue MA, Karray F, Dousset B, Bertherat J, Legmann P, Bertagna X: Corticotroph tumor progression after adrenalectomy in Cushing's Disease: A reappraisal of Nelson's Syndrome. J Clin Endocrinol Metab. 2007, 92: 172-179.

    Article  CAS  PubMed  Google Scholar 

  74. Bush ZM, Longtine JA, Cunningham T, Schiff D, Jane JA Jr, Vance ML, Thorner MO, Laws ER Jr, Lopes MB: Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression. J Clin Endocrinol Metab. 2010, 95: E280-290.

    Article  PubMed  Google Scholar 

  75. Raverot G, Sturm N, de Fraipont F, Muller M, Salenave S, Caron P, Chabre O, Chanson P, Cortet-Rudelli C, Assaker R, et al: Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience. J Clin Endocrinol Metab. 2010, 95: 4592-4599.

    Article  CAS  PubMed  Google Scholar 

  76. Bode H, Seiz M, Lammert A, Brockmann MA, Back W, Hammes HP, Thome C: SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Exp Clin Endocrinol Diabetes. 2010, 118: 760-763.

    Article  CAS  PubMed  Google Scholar 

  77. Trementino L, Arnaldi G, Appolloni G, Daidone V, Scaroni C, Casonato A, Boscaro M: Coagulopathy in Cushing's syndrome. Neuroendocrinology. 2010, 92 (Suppl 1): 55-59.

    Article  CAS  PubMed  Google Scholar 

  78. Giordano R, Picu A, Marinazzo E, D'Angelo V, Berardelli R, Karamouzis I, Forno D, Zinna D, Maccario M, Ghigo E, Arvat E: Metabolic and Cardiovascular Outcomes in Patients with Cushing's Syndrome of Different Aetiologies during Active Disease and 1 Year after Remission. Clin Endocrinol (Oxf). 2011, 75 (3): 354-360.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  80. Cavagnini F, Pecori GF: Epidemiology and follow-up of Cushing's disease. Ann Endocrinol (Paris). 2001, 62: 168-172.

    CAS  Google Scholar 

  81. Sonino N, Fallo F, Fava GA: Psychosomatic aspects of Cushing's syndrome. Rev Endocr Metab Disord. 2010, 11: 95-104.

    Article  PubMed  Google Scholar 

Download references


The authors would like to thank the Head of the Department of Neurosurgery (Pr Dufour), La Timone Hospital, Marseille, France.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Frederic Castinetti or Thierry Brue.

Additional information

Competing interests

The authors declare that they have no competing interest.

Authors’ contributions

The authors contributed equally to this review. They read and approved the final version of the manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Authors’ original file for figure 3

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Castinetti, F., Morange, I., Conte-Devolx, B. et al. Cushing’s disease. Orphanet J Rare Dis 7, 41 (2012).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: