Health Questions and Answers


Differentiate Cushing’s syndrome from Cushing’s disease.
Cushing’s syndrome refers to hypercortisolemia and its associated signs and symptoms due to any cause. Cushing’s disease refers specifically to hypercortisolemia due to ACTH overproduction by a pituitary adenoma. The most common cause of Cushing’s syndrome is iatrogenic due to exogenous steroid treatment for a variety of conditions (rheumatologic, organ transplant, reactive airway disease). If one excludes iatrogenic hypercortisolemia, the most common cause of Cushing’s syndrome is Cushing’s disease, which accounts for approximately two thirds of all cases.

What are the signs and symptoms of Cushing’s disease?

  • Atrophic, thin skin, easy bruising, purple striae (abdomen, axilla, hips, thighs)
  • Weight gain or central obesity
  • Dorsocervical (buffalo hump) and supraclavicular fat accumulation
  • Moon facies
  • Menstrual irregularities
  • Hirsutism
  • Diabetes or insulin resistance
  • Muscle weakness
  • Hypertension
  • Increased susceptibility to infection
  • Osteoporosis (or osteopenia)
  • Psychiatric symptom (depression, mood changes, even psychosis)
  • Hypercoagulable state

List the four steps involved in evaluating a patient for Cushing’s syndrome.
Step 1: Screen for and document Cushing’s syndrome (hypercortisolemia).
Step 2: Differentiate between ACTH-dependent and ACTH-independent causes.
Step 3: Distinguish pituitary Cushing’s disease from ectopic ACTH secretion.
Step 4: Anatomic imaging and surgical resection of the tumor once identified.

Who should be considered for Cushing’s syndrome screening?
This is a difficult question because many people have symptoms that could be associated with Cushing’s syndrome, such as weight gain, hypertension, diabetes, and depression. Consider screening adults with weight gain and an abnormal fat distribution, proximal muscle weakness, large (> 1 cm wide) purple striae, and new cognitive/depression complaints; children with linear growth failure and continued weight gain; and young people with nontraumatic bone fractures, cutaneous atrophy, or hypertension. Patients with multiple clinical features should be screened particularly if the symptoms become more severe over time.

How should one screen for Cushing’s syndrome?
First-line screening tests include the low-dose (1 mg) overnight dexamethasone test and 24-hour urine free cortisol levels.

How is the low-dose dexamethasone suppression test performed?
Give 1 mg of dexamethasone at 11 pm the night before. This dose should suppress 8 am cortisol to < 1.8 μg/dL if a sensitive assay is used (the old cutoff value was < 5 μg/dl).

How is the 24-hour urine free cortisol test done?
This test should be normal in patients without Cushing’s syndrome (most assays define normal as = < 100 mg/24 h). This test may be repeated up to three times if the first test is normal and there is a high index of suspicion. It must always be performed with a creatinine level to ensure adequacy of the urine collection. What is the late evening salivary cortisol test? Some clinicians advocate this test because it is easy to perform and salivary and plasma cortisol levels are highly correlated. Patients are instructed to obtain late night (11 pm) salivary samples. Cortisol levels should be low and confirm normal diurnal variation. Cushing’s patients have abnormally high late-night levels. This test can be considered as a screening test, particularly in patients with episodic hypercortisolemia, but it has not replaced the other two tests as first-line modalities. Normal ranges are assay-dependent and must be validated for each laboratory. Once hypercortisolemia has been documented, what is the next step in evaluating a patient with Cushing’s syndrome? After ruling out ingestion of exogenous steroids, the next step is to differentiate between ACTH-dependent (80%) and ACTH-independent (20%) disease. ACTH-dependent disease is associated with pituitary adenoma (80%), ectopic ACTH (20%), and corticotropin-releasing hormone (CRH) hypersecretion (rare). ACTH-independent disease is associated with adrenal adenoma (40-50%), adrenal carcinoma (40-50%), nodular dysplasia (rare), and McCune-Albright syndrome (rare). What is the best way to make this distinction? The best method is simultaneous measurement of ACTH and cortisol. If the ACTH is >10 pg/mL, the patient most likely has an ACTH-dependent cause of Cushing’s syndrome. Additionally, an ACTH value > 10 pg/mL following peripheral CRH administration suggests ACTH dependency.

Once ACTH-dependent Cushing’s syndrome has been confirmed, what is the final step in making the biochemical diagnosis?
The final step involves differentiating between a corticotrope adenoma and an ectopic ACTH-secreting tumor. A high-dose (8-mg) dexamethasone test can be performed. Patients with a pituitary source of ACTH retain suppressibility of cortisol to high-dose dexamethasone, whereas patients with ectopic ACTH tumors do not.

How is the dexamethasone test confirmed?
Many clinicians confirm the diagnosis with inferior petrosal sinus sampling (IPSS). This test takes advantage of the concentration gradient between pituitary venous drainage via the inferior petrosal sinus (IPS-central) and peripheral venous values of ACTH to further determine whether an ACTH-producing corticotroph adenoma is present in the pituitary; the inclusion of CRH stimulation adds greater sensitivity to the test.

Explain how the IPSS is done.
Samples of ACTH and cortisol are obtained simultaneously from the IPS (central) and from a peripheral site (e.g., inferior vena cava [IVC]). In patients with Cushing’s disease, the central/peripheral ratio (C/P = IPS/IVC ratio) of ACTH is > 2. In patients with ectopic ACTH, the ratio is < 2 and selective venous sampling (e.g., of the pulmonary, pancreatic, or intestinal beds) may localize the ectopic tumor. How does the inclusion of CRH increase diagnostic accuracy? Administration of CRH during bilateral IPS sampling has increased the diagnostic accuracy of the test by eliciting an ACTH response in the few patients with pituitary tumor who did not have a diagnostic C/P gradient in the basal samples. All patients with Cushing’s disease have had a C/P ratio > 3 after CRH, whereas patients with ectopic ACTH or adrenal disease have had C/P ratios < 3 after CRH.

What is the most significant limitation of IPSS with or without CRH?
It is important to note that IPSS with or without CRH has not been extensively performed in normal subjects. Thus correct interpretation of the results requires that the patient be hypercortisolemic at the time of the study so that the response of normal corticotropes to CRH is suppressed. One approach is represented in Fig. 2-2. If results indicate an ectopic source, a CT or MRI of the chest is usually performed first since most are due to small cell carcinoma or bronchial or thymic carcinoid tumors.

What is pseudo-Cushing’s syndrome?
This is a clinical state characterized by mild overactivity of the hypothalamic-pituitary-adrenal axis that is not associated with true Cushing’s syndrome (hypercortisolemia). It is typically seen in a variety of psychiatric states (depression, anxiety), alcoholism, uncontrolled diabetes, and severe obesity. The dexamethasone-CRH stimulation test can be used to help distinguish this disorder from true Cushing’s syndrome. Alternatively, an elevated midnight plasma cortisol level rules out pseudo-Cushing’s because, unlike patients with true Cushing’s syndrome, patients with pseudo-Cushing’s retain the diurnal rhythym of cortisol secretion.

What is Nelson’s syndrome?
Nelson’s syndrome occurs in up to 30% of patients following bilateral adrenalectomy and is due to corticotrope hyperplasia/adenoma. Patients often present with mass effects associated with the adenoma and hyperpigmentation due to high levels of ACTH (with resultant high levels of melanocyte-stimulating hormone).

Define adrenal insufficiency.
As the name suggests, this disorder is caused by insufficient release of adrenal hormones (typically hormones of the adrenal cortex: cortisol and aldosterone).

What causes adrenal insufficiency?
The causes can be divided into two categories: primary and central. Primary adrenal insufficiency (Addison’s disease) is due to adrenal gland dysfunction. Central adrenal insufficiency includes both secondary (pituitary) and tertiary (hypothalamic) causes.

List the causes of primary adrenal sufficiency.
Autoimmune destruction (70-80%), tuberculosis (20%), adrenal destruction by bilateral hemorrhage or infarction, tumor, infections (other than tuberculosis), surgery, radiation, drugs, amyloidosis, sarcoidosis, hyporesponsiveness to ACTH, and congenital abnormalities.

List the cause of central adrenal insufficiency.
Withdrawal of exogenous steroids (common), following cure of Cushing’s syndrome, pituitary adenoma/infarction, and hypothalamic abnormalities (rare).

Summarize the differences in treatment of primary and central adrenal insufficiency.
In terms of treatment, patients with Addison’s disease typically require replacement of both glucocorticoids (prednisone or hydrocortisone) and mineralocorticoids (Florinef), whereas patients with central adrenal insufficiency typically need only glucocorticoids. Patients with central disease do not usually require mineralocorticoids because aldosterone secretion is largely unaffected. All patients should be instructed to increase steroid replacement during times of illness and should wear medical alert jewelry. The goal of treatment is to ameliorate the signs and symptoms of adrenal insufficiency without causing Cushing’s syndrome due to exogenous glucocorticoid replacement. Always use the lowest possible doses that control symptoms to avoid side effects.

What is the gold standard test to assess adequacy of the hypothalamic-pituitary-adrenal axis?
Although a number of tests are available to assess function of the hypothalamic-pituitary-adrenal axis, the insulin tolerance test (ITT) is the gold standard. The principle of the test is to induce hypoglycemia (plasma glucose < 40 mg/dL) with IV insulin, which acts as a major stressor to stimulate production of ACTH, cortisol, and GH.

What test do most clinicians use to assess adrenal insufficiency?
Because the ITT is cumbersome and requires close monitoring, most clinicians perform an ACTH stimulation test. In the classic test, a baseline cortisol is drawn and 250 μg of IV synthetic ACTH (Cortrosyn) is given. Blood samples for cortisol are collected at 30 and 60 minutes. A normal response is a stimulated cortisol value of > 20 μg/dL. A normal response rules out adrenal insufficiency in the majority of cases. A rare exception is the patient with acute central adrenal insufficiency (i.e., pituitary apoplexy or head trauma); since the adrenal glands have not had sufficient time to become atrophic and unresponsive to ACTH. Lack of a normal response indicates decreased adrenal reserve but does not differentiate between primary and central adrenal insufficiency.

How do you distinguish between primary and central adrenal insufficiency?
An ACTH level is used to determine whether the adrenal insufficiency is primary (high ACTH) or central (low or normal ACTH). More recently, clinicians have considered the 250-μg ACTH test less accurate in detecting patients with mild adrenal insufficiency (since it is a supraphysiologic dose) and have recommended a 1-μg ACTH stimulation test. The test is performed the same way as the higher dose test but requires dilution of the ACTH. ACTH (Cortrosyn) is available only in a 250-μg vial and must be diluted for this low-dose test. Therefore, careful attention must be given to ensure proper administration of the drug to avoid a high false-positive rate.

Why is it important to rule out adrenal insufficiency in pituitary patients with central hypothyroidism?
Pituitary patients with central hypothyroidism metabolize cortisol more slowly than euthyroid patients. Thyroid hormone replacement increases cortisol metabolism and can precipitate adrenal crisis in a patient with undiagnosed central adrenal insufficiency. It is important to detect and treat adrenal insufficiency before starting thyroid hormone replacement to avoid this complication.

Describe the clinical presentation of pheochromocytoma. What is the “classic triad” of symptoms?
Patients with pheochromocytomas present with signs and symptoms attributable to catecholamine excess. These symptoms include the classic triad (episodic headache, diaphoresis, and tachycardia) with or without hypertension (may be paroxysmal hypertension). Other symptoms may include anxiety/psychiatric disturbances, tremor, pallor, visual changes (papilledema, blurred vision), weight loss, polyuria, polydipsia, hyperglycemia, dilated cardiomyopathy, and arrhythmias. Most patients have two of the three symptoms of the classic triad. If the patient is hypertensive and has the classic triad of symptoms, the sensitivity and specificity for pheochromocytoma are both > 90%.

What other diagnoses should be considered?
It is important to consider other potential diagnoses, including anxiety/panic attacks, alcoholism (or alcohol withdrawal), sympathomimetic drugs (cocaine, amphetamines, phencyclidine, epinephrine, phenylephrine, terbutaline, phenylpropanolamine [a popular over-the-counter decongestant]), combined ingestion of MAO inhibitor and tyramine-containing food, hyperthyroidism, menopause, hypoglycemia, and abrupt discontinuation of short-acting sympathetic antagonists (e.g., clonidine).

What is the “rule of 10” for pheochromocytomas?

  1. 10% are extra-adrenal
  2. 10% are bilateral
  3. 10% are familial
  4. 10% are malignant

How do you evaluate a patient with suspected pheochromocytoma?
The most important strategy is to make a biochemical diagnosis before embarking on radiographic imaging. This step is crucial because people can have incidental adrenal tumors that do not hypersecrete catecholamines.

Describe the two main screening tests for pheochromocytoma.
Some clinicians recommend plasma-free normetanephrine and metanephrine levels as the initial biochemical test. If these values are more than four-fold higher than the upper limit of the normal reference range, proceed to radiographic imaging (CT of abdomen initially) to localize the tumor. Unfortunately, these tests are not always widely available. In such cases, obtain measurements of 24-hour urine normetanephrine and metanephrine.

What other tests may be helpful?
Other helpful tests include 24-hour urine fractionated catecholamines and catecholamine metabolites homovanillic acid and vanillylmandelic acid as well as plasma catecholamines. A clonidine suppression test may also be used to confirm the diagnosis. In borderline cases, multiple tests need to be performed or repeated.

How is the 24-hour urine test performed?
Since catecholamine hypersecretion may be episodic, it is best to collect the urine samples when the patient is symptomatic. If possible, testing should be performed after discontinuing medications. Caffeine, alcohol, and tobacco should be avoided during testing.

Describe the clonidine suppression test.
Plasma catecholamines are measured before and 3 hours after oral administration of 0.3 mg of clonidine. Failure to suppress plasma catecholamines suggests the diagnosis of pheochromocytoma. This test must not be performed in hypovolemic patients or patients taking diuretics, beta blockers, or tricyclic antidepressants.

After the biochemical diagnosis is made, how is the tumor localized?
The tumor is localized by using CT or MRI (first of the adrenals, then of the chest, abdomen, and pelvis). If the tumor cannot be localized with standard imaging, peform an 123I metaiodobenzylguanidine (MIBG) scan to localize functional catecholamine-rich tissue.

What is the treatment of choice for patients with pheochromocytomas?
After tumor localization, the treatment of choice is surgery. All patients must be preoperatively treated with alpha-adrenergic (phenoxybenzamine) and beta-adrenergic (atenolol) blockade to avoid stress-induced catecholamine excess and hypertensive crisis during surgery. It is critical to avoid beta-adrenergic blockade in the presence of unopposed alpha agonists because it may lead to peripheral vasoconstriction and an exacerbation of the patient’s hypertension.

What is an adrenal incidentaloma?
Approximately 1% of all abdominal CT scans reveal a previously unsuspected adrenal mass, termed adrenal incidentaloma. These tumors fall into three categories: nonfunctioning mass, hyperfunctioning mass, and pseudoadrenal mass. Since approximately 10% are hormonally active and < 3% are adrenocortical carcinomas, it is important to assess hormonal hyperfunction and malignant potential.

How do you evaluate an adrenal incidentaloma?
Although there are numerous approaches, evaluations should be individualized. It is important to perform a careful history and physical exam, looking for signs and symptoms of hormone excess. It is usually recommended that patients be screened for Cushing’s syndrome (24-hour urine free cortisol and/or 1-mg overnight dexamethasone suppression test) and pheochromocytoma (24-hour urine metanephrines/catecholamines or plasma metanephrines). One can consider screening for hyperaldosteronism, particularly if the patient is hypertensive and has a serum potassium < 3.9. Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) may be used to test for an aldosterone-secreting tumor, looking for an PAC:PRA ratio > 20-25. Nonfunctioning tumors < 4 cm are typically observed for growth. Functional tumors or tumors > 4 cm (or growing) are typically removed by surgery.

What is primary hyperaldosteronism?
Primary hyperaldosteronism is excessive production of aldosterone independent of the renin-angiotensin system. It is observed in approximately 0.5-2% of the population, and the differential diagnosis includes solitary aldosterone-producing adenoma (65%), bilateral or unilateral adrenal hyperplasia, adrenal carcinoma, and glucocorticoid remediable aldosteronism.

How do patients with primary hyperaldosteronism present?
Patients present with hypertension, hypokalemia (weakness, muscle cramping, paresthesias, headaches), low magnesium levels, and metabolic alkalosis.

How should patients with primary hyperaldosteronism be evaluated?
The first step is assess upright plasma aldosterone concentration and PRA in the absence of drugs that alter the renin-aldosterone axis (such as most antihypertensives: spironolactone, ACE inhibitors, and diuretics). A ratio of plasma aldosterone concentration (ng/dL) to PRA (ng/mL/h) of > 20-25 makes the diagnosis likely.

How is the diagnosis of primary hyperaldosteronism confirmed?
Confirmation requires a high 24-hour urine aldosterone level in the presence of normokalemia and adequate volume status or inadequate suppression of aldosterone levels using the saline suppression or salt-loading test. As always, biochemical diagnosis should precede diagnostic imaging. Treatment depends on the etiology but usually includes surgery except in cases of adrenal hyperplasia or glucocorticoid-remediable hyperaldosteronism.

The Endocrine Society:
Uptodate Reference: (Web-based source of information about endocrine diseases directed to physicians)
American Association of Clinical Endocrinologists:
Pituitary Society:


  • Aron DC (ed): Endocrine incidentalomas. Endocrinol Metab Clin North Am 29:69-186, 2000.
  • Pacek K, et al: Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 134:315-329, 2001.
  • Arnaldi G, Angeli A, Atkinson AB, et al: Diagnosis and complications of Cushing’s syndrome: A consensus statement. J Clin Endocrinol Metab 88(12):5593-5602, 2003.
  • Larson PR, et al: Williams Textbook of Endocrinology, 10th ed. Philadelphia, W.B. Saunders, 2003.
  • Pickett CA: Diagnosis and management of pituitary tumors: Recent advances. Prim Care Clin Office Pract 30:765-789, 2003.
  • Wierman ME (ed): Diseases of the Pituitary: Diagnosis and Treatment. Totowa, NJ, Humana Press, 1997.

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