Endocrinology Metabolism

Cushing's Syndrome

Are You Sure the Patient Has Cushing's Syndrome?

Cushing's syndrome results from chronic exposure to excess endogenous or exogenous glucocorticoids. It has significant long-term sequelae, so timely diagnosis and treatment are needed. Cardiovascular, infectious, and thrombotic disorders are the main causes of death if hypercortisolemia is left untreated.

Signs and Symptoms

The clinical phenotype caused by endogenous or exogenous cortisol excess includes a constellation of signs and symptoms, the majority of which, such as obesity, are nonspecific and commonly seen in the more prevalent pseudo-Cushing states. Prolonged exposure to excess cortisol negatively affects nearly all organ systems. Key features are weight gain, central adipose tissue deposition, and dorsocervical, supraclavicular, and temporal fat pads.

Other features of hypercortisolism include severe fatigue, hypertension, diabetes, hirsutism, reproductive system abnormalities (such as menstrual irregularity, amenorrhea, and decreased libido), easy bruising, decreased bone mineral density, and pathologic bone fractures. Nonspecific psychiatric disease such as irritability, decreased memory and concentration, depression, and emotional lability are common. Some of the more specific signs and symptoms of hypercortisolemia include violaceous striae more than 1 cm in diameter, plethora, and proximal myopathy. Predisposition to hypertension and diabetes and the adverse metabolic profile in Cushing's disease are major contributors to long-term morbidity and mortality. The hypercoagulable state of hypercortisolism is manifested by an increased predisposition for deep venous thrombosis, pulmonary embolism, and stroke. However, some patients have a nonclassic presentation with few clinical features, often in the setting of mild or cyclic hypercortisolism.

In children, growth retardation in the context of weight gain is the most sensitive marker of the disease.

Exposure to exogenous glucocorticoids must be excluded before the diagnosis of endogenous Cushing's syndrome can be entertained. Such exposure may include prescription medications given orally, via inhaler, per rectum, or via parenteral routes. Occasionally, nonprescription glucocorticoid-containing topical agents may by absorbed sufficiently to cause Cushing's syndrome, especially if the skin is broken over a large area (e.g., in psoriasis) and if a higher-potency glucocorticoid is used.

Cushing's syndrome is an uncommon condition, with a reported incidence of 2-3 cases per 1 million people per year. Cushing's syndrome is most likely when the patient has features that are atypical for age (such as fracture in a young person) or has features that are more specific for the syndrome (such as wide purple striae) or the patient has been accumulating features over time. Because many of the signs and symptoms of Cushing's syndrome are common in the general population, it may be difficult to establish the diagnosis based on the clinical presentation.

What Else Could the Patient Have?

The diagnosis of Cushing's syndrome is straightforward if the patient has a florid presentation. However, common disorders in the general population such as obesity and depression can mimic Cushing's syndrome. These conditions are sometimes referred to as pseudo-Cushing's states and show cortisol levels that are normal or only slightly increased. Psychiatric disorders such as depression, anxiety, anorexia, and bulimia, as well as alcoholism, alcohol withdrawal, uncontrolled diabetes mellitus, partial acquired lipodystrophy, and obesity, are common disorders in the general population that can raise questions of endogenous Cushing's syndrome. When cortisol levels are increased in these individuals, it is thought that higher brain centers stimulate CRH release with subsequent activation of the hypothalamic-pituitary-adrenal (HPA) axis and mildly increased urine cortisol excretion. However, negative inhibition by cortisol on the hypothalamic CRH neurons and pituitary corticotropes restrains excessive increase in cortisol levels, so that urine free cortisol (UFC) remains less than 3 times the upper normal range and overlaps that of some patients who have true Cushing's syndrome.

Physicians should be aware that even though screening tests for Cushing’s syndrome have a high specificity and sensitivity, they can have an unacceptably high false-positive rate if applied to unselected patients. Only individuals with more specific and discriminatory signs of Cushing's syndrome should be screened. On the other hand, the spectrum of Cushing's syndrome presentation is broad and diagnosing mild cases can be challenging. Unusual features for age, such as osteoporosis or hypertension, finding of an adrenal incidentaloma suggestive of adenoma, or multiple or progressive features of hypercortisolism (especially if they are more predictive of pathologic hypercortisolism, such as easy bruising, facial plethora, proximal myopathy, and wide purple striae), should prompt the clinician to test further.

Key Screening Laboratory Tests

Because the symptoms and signs of Cushing's syndrome are rarely pathognomonic, an appropriate biochemical evaluation is key to establishing the diagnosis.

The diagnosis of Cushing's syndrome rests on the demonstration of elevated cortisol levels in body fluids and on the demonstration of impaired negative feedback inhibition of the corticotropes by glucocorticoid. Three tests (UFC, late night salivary cortisol, and dexamethasone suppression) are recommended, and the choice of tests should be individualized for each patient, taking into account the caveats for each test.

The 24-hour UFC represents the daily integrated production of cortisol. The limitations to this test are that it requires an ability to collect a complete 24-hour specimen and to avoid overcollection or undercollection. Generally, the patient discards the first morning urine void and collects all subsequent voids until and including the next morning's first void, hopefully at about the same time of day. Falsely elevated results may occur in association with high fluid intake (>4-5 liters daily) or with overcollection. Falsely low results may occur in association with renal failure (especially with a glomerular filtration rate of <60 ml/min) or with undercollection. The completeness of the collection may be evaluated by measuring the total volume of the collection as well as the creatinine excretion, which should remain within 10%-15% among multiple collections.

Structurally based assays, such as tandem mass spectrometry, are most often used to measure urine cortisol. These structurally based assays measure cortisol only and do not measure cross-reacting precursors or metabolites that are recognized as "cortisol" in antibody-based assays. Thus, the upper limit of the normal range is lower, and it is possible that some patients with mild Cushing's syndrome are not identified through the use of structurally based assays. The upper limit of normal is used to characterize UFC as normal or not, recognizing that some patients without Cushing's syndrome will have mild elevations in UFC, which reduces the specificity of the test. At least two specimens should be collected, to ensure accuracy and to evaluate for cyclicity.

Measurement of late night salivary cortisol may be very useful if two or more samples are obtained. The circadian rhythm of adrenocorticotropin (ACTH) and cortisol is blunted in patients with Cushing's syndrome, who lose the nadir of cortisol that occurs just after sleep onset in healthy individuals. While measurement of midnight serum cortisol can establish hypercortisolism, this is a cumbersome and potentially expensive test. Salivary cortisol represents the free fraction of cortisol in blood and is a convenient way to assess the late night nadir of cortisol. Samples are stable when frozen as well as at room temperature. The pitfalls for this test include possible inhibition of the enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD-2, which converts cortisol to inactive cortisone in the salivary gland) by licorice or tobacco, which may falsely elevate cortisol levels. False elevations in salivary cortisol also occur if the sample collection is not timed properly relative to sleep. As a result, the test is not reliable in shift workers, individuals with unusual sleep patterns, or patients who travel across time zones. One must also consider contamination with blood (and hence bound cortisol) from mouth sores, gingivitis, or aggressive tooth brushing, although this possibility is not well documented.

The other recommended screening test for hypercortisolism is the 1 mg overnight dexamethasone suppression test, which can be performed on an outpatient basis. Patients with Cushing's syndrome do not suppress cortisol appropriately to this large dose of glucocorticoid, which in healthy individuals would decrease ACTH and hence cortisol by virtue of negative feedback inhibition of CRH and ACTH. The test is performed by administering dexamethasone, 1 mg orally, between 11 p.m. and midnight, and measuring cortisol the next morning between 8 and 9 a.m. Measurement of a simultaneous dexamethasone level allows evaluation of whether the dose was taken and whether the patient metabolizes the agent more quickly or slowly than normal. Variability in metabolism underlies many false-positive and false-negative results. Because a serum cortisol concentration <1.8 μg/dl is the criterion for a normal response, one must use an assay with a functional detection limit below that level and must avoid the test in individuals with a high corticosteroid-binding globulin (CBG) (such as those on oral estrogen) or low CBG (e.g., nephrotic syndrome), which may alter total cortisol values.

If the results of screening tests are equivocal or conflicting, they should be repeated at intervals, especially if the patient develops additional signs of the syndrome. Further testing with the 2-mg 2-day low-dose dexamethasone suppression test followed by a CRH stimulation test may help to distinguish Cushing's syndrome from pseudo-Cushing’s states in individuals with normal dexamethasone suppression but abnormal urine or salivary cortisol measurements.

Tests to Determine the Cause of Cushing's Syndrome

Tests for the differential diagnosis of Cushing's syndrome should be undertaken only after the clinical and biochemical diagnosis of hypercortisolemia has been unequivocally confirmed. Both normal corticotropes and corticotrope tumors respond to negative feedback and to CRH stimulation. Thus, without a firm diagnosis of pathologic hypercortisolemia, further testing can lead to misdiagnosis of a normal person as having Cushing's disease, with a subsequent risk of unnecessary interventions, such as transsphenoidal surgery (TSS).

Once Cushing's syndrome is proved, one can proceed with evaluation of its cause, which involves dynamic endocrine testing and imaging. Testing to establish the differential diagnosis of Cushing's syndrome must be conducted when the patient has had sufficient glucocorticoid exposure to suppress ACTH secretion from normal corticotropes. In this setting, measurable ACTH reflects tumoral production. Thus, interpretation of tests for the differential diagnosis may be difficult in cases of mild or cyclic Cushing's syndrome, in which normal corticotropes may respond.

The causes of Cushing’s syndrome can be divided into ACTH-dependent (caused by excess ACTH) or ACTH-independent processes (caused by autonomous adrenal cortisol production). ACTH-dependent Cushing’s syndrome is further divided into Cushing’s disease, in which a pituitary corticotrope tumor produces excess ACTH, and ectopic ACTH production, in which a nonpituitary tumor produces excess ACTH. When normal corticotropes are suppressed by endogenous hypercortisolism, ACTH concentrations are low (<15 pg/ml or undetectable) in patients with primary adrenal disorders and are inappropriately normal or increased in Cushing's disease or ectopic ACTH syndrome.

When the plasma ACTH concentration is low or undetectable, the adrenal glands should be imaged to determine the site(s) of abnormality and whether there is a bilateral or unilateral process. The most common cause of ACTH-independent Cushing's syndrome is a unilateral benign adrenal adenoma. Adrenal carcinoma is also unilateral. While an adenoma is homogeneous on CT scanning, with smooth borders and a density of <10 Hounsfield units (HU), carcinomas are heterogeneous, with irregular margins and with higher density (>20 HU). Carcinomas may produce other steroids, so that measurement of other adrenal products (testosterone, estradiol, androstenedione) may be useful.

The bilateral ACTH-independent causes of Cushing's syndrome are rare and include McCune-Albright syndrome (generally in infants and children), primary pigmented nodular adrenal disease (PPNAD), and massive macronodular adrenal disease (MMAD). McCune-Albright syndrome should be considered in patients with other features of the disorder, while PPNAD and MMAD have multiple bilateral nodules that are either small (<1 cm, PPNAD) or large (MMAD). The latter two disorders also present at different ages, with PPNAD being more common in adolescents and young adults, and MMAD more common in middle age.

Once ACTH-dependent hypercortisolemia is established, other tests are needed to discriminate between ACTH-dependent causes, as ACTH levels by themselves cannot reliably distinguish between the more common Cushing's disease (80%) and ectopic ACTH secretion. A noninvasive strategy using the 8-mg overnight dexamethasone suppression test and the CRH stimulation test may be helpful.

The 8-mg dexamethasone test takes advantage of the fact that many corticotrope tumors retain some sensitivity to glucocorticoid negative feedback, albeit requiring a higher glucocorticoid dose to suppress ACTH and cortisol secretion. A criterion of at least 50%-69% suppression of cortisol the morning after 8 mg of dexamethasone has been proposed to exclude ectopic ACTH secretion. Use of the less stringent criterion maximizes the chance of correctly diagnosing Cushing's disease but increases the risk of falsely diagnosing Cushing's disease in a patient with ectopic ACTH secretion. Use of the more stringent criterion gives about 90% sensitivity and specificity.

The CRH stimulation test takes advantage of the ability of corticotrope tumors to retain responsiveness to CRH, while ectopic ACTH-producing tumors tend not to respond. In the United States, the test involves measurement of cortisol and ACTH just before and 15, 30, and 45 minutes after intravenous administration of ovine CRH 100 mg. Different criteria have been proposed for its interpretation; use of a 20% or greater increase in cortisol (at 30 and 45 minutes) or a 34% or greater increase in ACTH (at 15 and 30 minutes) gave 90%-93% sensitivity and specificity.

Only about half of Cushing's disease patients have a tumor identified on conventional T1 spin echo pituitary MRI and up to 10% of healthy volunteers have an incidental lesion that is 6 mm or less in diameter. MRI should be obtained in patients in whom inferior petrosal sinus sampling (IPSS) or TSS is contemplated. Patients with a lesion 6 mm or greater are likely to have Cushing's disease, but those with smaller lesions may have ectopic ACTH secretion and a nonfunctioning incidentaloma. Patients who have a larger lesion and respond to CRH and dexamethasone almost definitely have Cushing's syndrome and can forego IPSS. In addition to potentially identifying a surgical target, MRI provides important anatomic information to the neurosurgeon.

IPSS is the gold standard test for identifying the cause of ACTH-dependent Cushing's syndrome, with 95%-99% sensitivity and sensitivity worldwide when performed by an experienced radiologist. The test involves catheterization of both petrosal sinuses and simultaneous measurement of ACTH in each and a peripheral vein, obtaining two samples at baseline and again at 3, 5, and 10 minutes after CRH administration. A central-to-peripheral gradient of >2 before CRH or >3 after CRH at any time point identifies Cushing's disease.

It is worth noting that although hypokalemia suggests ectopic ACTH secretion (EAS) over Cushing’s disease, it does not reliably discriminate between the two. Hypokalemia occurs in patients with very high cortisol levels, which then overcome the ability of renal 11β-HSD-2 to inactivate cortisol by converting it to cortisone. As a result, the excess cortisol acts as a mineralocorticoid at the kidney.

Patients with presumed ectopic ACTH secretion should undergo imaging to localize the tumor. Since most are pulmonary carcinoids, CT and MRI of the chest are good initial choices, with octreoscan being a helpful adjunctive study. However, since tumors may occur in the thyroid (medullary thyroid carcinoma), thymus (carcinoid), pancreas (carcinoid), adrenal (pheochromocytoma), and elsewhere, additional scans may be needed. Biochemical screening for these entities with calcitonin, 5-hydroxyindoleacetic acid (5-HIAA) excretion, and plasma free metanephrines may help direct these studies.

Management and Treatment of the Disease

Emergent and Long-term Therapy and Overall Management of Cushing's Syndrome

Resection of the causal tumor is the optimal treatment of Cushing's syndrome. Additionally, all patients should receive adjunctive treatment of comorbidities such as diabetes, hypertension, hyperlipidemia, osteoporosis, and depression before and after "definitive" therapy until all parameters normalize. If definitive therapy of ACTH-dependent causes cannot be achieved, generic treatment to reduce cortisol levels should be attempted, as described next, via either steroidogenesis inhibitors or bilateral adrenalectomy. Additional chemotherapeutic treatment of malignancies (e.g., metastatic ACTH-producing tumors, adrenal cancer) will not be discussed further.

Definitive treatment of the primary adrenal causes of Cushing's syndrome involves resection of the adenoma(s) or cancer. A laparoscopic approach is usually chosen for benign cases and is nearly always curative, without recurrence.

Definitive treatment of Cushing's disease involves resection of the corticotrope adenoma via TSS. This is curative in up to 95% of patients, depending on the experience of the surgeon, the size of the tumor, and whether there is infiltration of the dura or surrounding structures. In patients who have not received medical therapy that has disinhibited the normal corticotropes, remission is defined as a low serum postoperative cortisol level (usually <5 μg/dl) within the first week after surgery.

In some patients TSS is not attempted (e.g., anesthesia is precluded) or there is persistent disease after TSS or recurrence. Radiation therapy, either conventional or targeted radiosurgery, may be an option in these settings, depending on the size and location of the tumor. Radiation may achieve eucortisolism in up to 90% of patients followed long term, but there are no studies in which all patients are followed without any other intervention (such as adrenalectomy), so that the true success rate may be lower. While waiting for radiation to decrease ACTH levels, eucortisolism should be achieved by the use of steroidogenesis inhibitors (see later). After radiation therapy, patients appear more likely to develop subsequent meningioma, and perhaps cerebrovascular events, and about 50% have some degree of hypopituitarism after 10 years.

Medication directed to reducing ACTH levels is available for patients with Cushing's disease. Recently, pasireotide has been approved by the FDA for the treatment of Cushing's disease; however, it is successful in only about 20% of patients and about 73% have a worsening in glucose tolerance. Cabergoline has been shown to normalize UFC in about 40% of cases of Cushing’s disease, but experience with long-term treatment is limited. The glucocorticoid antagonist mifepristone has been approved by the FDA for the treatment of glucose intolerance and diabetes associated with Cushing's syndrome.

Definitive treatment of ectopic ACTH secretion involves resection of the tumor. When the tumor is occult or metastases are present, medical treatment with steroidogenesis inhibitors (ketoconazole, metyrapone) or the adrenolytic agent mitotane is an option, as is bilateral adrenalectomy. Medical treatment with octreotide may be effective but has not been studied extensively. The goal of medical therapy is to normalize cortisol levels or to render them undetectable and then to replace cortisol with hydrocortisone or other glucocorticoid. Two or more agents may be needed to achieve this goal. Liver function tests must be monitored during ketoconazole treatment, as it can rarely cause fatal hepatic dyscrasia. All of these agents may have gastrointestinal side effects that may limit their use. Patients should undergo surveillance to identify the ACTH-secreting tumor every 6-12 months.

Bilateral adrenalectomy is an option for patients with ACTH-dependent Cushing's syndrome. Many patients prefer to attempt other treatments first, because of the requirement for lifelong glucocorticoid and mineralocorticoid replacement after bilateral adrenalectomy. However, adrenalectomy has the advantage of providing a definitive and rapid remission of hypercortisolism and may be preferred in patients with very severe illness who are not controlled on medical therapy or in young women who wish to consider pregnancy within 5-15 years and wish to avoid panhypopituitarism.

Patients with successful tumor resection generally become hypocortisolemic postsurgery because of corticotrope suppression. The HPA axis gradually normalizes after 6-18 months, but glucocorticoid replacement is needed until that occurs. Lifelong glucocorticoid and mineralocorticoid replacement is needed after bilateral adrenalectomy.

Treatment Regimens (in order of use)

Definitive surgical resection is the optimal treatment of any cause of Cushing's syndrome. If this is not possible or if there is persistent or recurrent disease, subsequent options should be individualized based on the cause, the patient's conditions, and the patient's values and judgments.

In Cushing's disease, radiation therapy acts slowly, requires adjunctive medications, and carries a risk of hypopituitarism, other tumors, and possibly cerebrovascular disease. However, it is more likely successful than medical therapies, and there is much more known about its use. Bilateral adrenalectomy may be best for those desiring a quicker and definitive remission and for individuals who wish to avoid the adverse effects of radiation. Medical therapy with cabergoline or pasireotide is most likely to be successful in those with mild-moderate disease and may be preferred by those who wish to avoid radiation and surgery. The use of steroidogenesis inhibitors as monotherapy (i.e., without radiation treatment) is not well studied and, like other medical therapies, involves lifelong administration.

Patients with ectopic ACTH-secreting tumors that are occult or metastatic might proceed to either bilateral adrenalectomy or medical treatment, depending on the need for speedy resolution, whether they are cleared for surgery, and whether they have significant liver disease (in which case ketoconazole is not an option).

Effects of a Coexisting Disease or Medication Use on Treatment Decision

Nelson's syndrome can occur after bilateral adrenalectomy in the context of Cushing's disease. The risk of its development is not clear, although large tumors may be more likely to enlarge. Equivocal data suggest that radiation therapy may prevent this, so this option may be chosen before adrenalectomy in such patients. However, others advocate MRI surveillance for tumor enlargement after TSS and adrenalectomy, without radiation treatment. As indicated earlier, the presence of diabetes may mitigate against pasireotide treatment, and severe hepatic impairment (liver function tests >3-fold normal) precludes use of ketoconazole. Mitotane is an abortifacient with a long half-life and should not be used in women anticipating pregnancy. Hypertension and hirsutism may worsen with metyrapone use, and men may develop sexual dysfunction due to decreased testosterone production while taking ketoconazole.

When to Switch If the Treatment Is Not Proving to Be Effective and What to Substitute

The effects of TSS are usually clear within 1 week of surgery; in rare cases, cortisol continues to decrease until 6 weeks postsurgery. Some patients do not become hypocortisolemic after TSS, perhaps because of nonsuppressed corticotropes. Thus, eucortisolemic patients should be assessed using diagnostic screening tests (UFC, late night salivary cortisol, 1-mg dexamethasone suppression) to determine if they are in remission. They may not need additional treatment.

Radiation therapy may take a few years to have an effect; periodic measurement of UFC and ACTH during withdrawal of steroidogenesis inhibitors can help to assess progress. Lack of response after 2 or more years suggests that adrenalectomy may be needed. Lack of effect of steroidogenesis inhibitors during this time may respond to the addition of cabergoline or pasireotide, but this has not been studied formally.

Patients who elect steroidogenesis inhibitors while awaiting tumor localization may decide on adrenalectomy because of side effects of medical therapy, a desire for a simpler medication regimen, or if cortisol levels are not controlled.

What’s the Evidence?/References

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. vol. 90. 2005. pp. 4955-62.

(A large series on presentation, biochemical responses, and treatment outcomes in patients with ectopic ACTH secretion.)

Nieman, LK, Biller, BMK, Findling, JW, Newell-Price, J, Savage, MO. "The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab. vol. 93. 2008. pp. 1526-40.

(Guidelines on diagnosis and screening from the Endocrine Society.)

Nieman, LK, Biller, BM, Findling, JW, Murad, MH, Newell-Price, J, Savage, MO, Tabarin, A. "Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab.. vol. 100. 2015. pp. 2807-31.

(Guidelines on treatment from the Endocrine Society.)

Oldfield, EH, Doppman, JL, Nieman, LK, Chrousos, GP, Miller, DL. "Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome". N Engl J Med. vol. 325. 1991. pp. 897-905.

(The largest series on the use of IPSS for the differential diagnosis of Cushing’s syndrome.)

Assié, G, Bahurel, H, Coste, J, Silvera, S, Kujas, M. "Corticotroph tumor progression after adrenalectomy in Cushing's disease: a reappraisal of Nelson's syndrome". J Clin Endocrinol Metab. vol. 92. 2007. pp. 172-9.

Colao, A, Petersenn, S, Newell-Price, J, Findling, JW, Gu, F. "A 12-month phase 3 study of pasireotide in Cushing's disease". N Engl J Med. vol. 366. 2012. pp. 914-24.

Feelders, RA, Hofland, LJ, de Herder, WW.. "Medical treatment of Cushing's syndrome: adrenal-blocking drugs and ketaconazole". Neuroendocrinology. vol. 92. 2010. pp. 111-5.

Fleseriu, M, Biller, BM, Findling, JW, Molitch, ME, Schteingart, DE, Gross, C. "Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome". J Clin Endocrinol Metab.. vol. 97. 2012. pp. 2039-49.

Invitti, C, Giraldi, FP, De Martin, M, Cavagnini, F.. "Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre study". J Clin Endocrinol Metab. vol. 84. 1999. pp. 440-8.

Jagannathan, J, Smith, R, DeVroom, H, Vortmeyer, AO, Stratakis, CA. "Outcome of using the histologic pseudocapsule as a surgical capsule in Cushing’s disease". Neurosurgery. vol. 111. 2009. pp. 531-9.

Nieman, LK, Oldfield, EH, Wesley, R, Chrousos, GP, Loriaux, DL. "A simplified morning ovine corticotropin-releasing hormone stimulation test for the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome". J Clin Endocrinol Metab. vol. 77. 1993. pp. 1308-12.

Pecori Giraldi, F, Ambrogio, AG, De Martin, M, Fatti, LM. "Specificity of first-line tests for the diagnosis of Cushing's syndrome: assessment in a large series". J Clin Endocrinol Metab. vol. 92. 2007. pp. 4123-9.

Pivonello, R, De Martino, MC, Cappabianca, P, De Leo, M, Faggiano, 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. vol. 94. 2009. pp. 223-30.

Tyrrell, JB, Findling, JW, Aron, DC, Fitzgerald, PA, Forsham, PH.. "An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing’s syndrome". Ann Intern Med. vol. 104. 1986. pp. 180-6.

Valassi, E, Biller, BM, Swearingen, B, Pecori Giraldi, F, Losa, M. "Delayed remission after transsphenoidal surgery in patients with Cushing's disease". J Clin Endocrinol Metab. vol. 95. 2010. pp. 601-10.

Zeiger, MA, Fraker, DL, Pass, HI, Nieman, LK, Cutler, GB. "Effective reversibility of the signs and symptoms of hypercortisolism by bilateral adrenalectomy". Surgery. vol. 114. 1993. pp. 1138-43.

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