I. What every physician needs to know

Each adrenal gland (also known as suprarenal gland) is essentially two separate and distinct endocrine glands – the cortex and the medulla. The adrenal cortex consists of three concentric zones. The outer zone is the glomerulosa, which secretes mineralocorticoid; the intermediate zone is the fasciculata, which secretes glucocorticoids, most importantly cortisol; and the innermost zone is the reticularis, which secretes androgens. The adrenal medulla is part of the sympathetic nervous system and produces the catecholamines epinephrine and norepinephrine (also known as adrenaline and noradrenaline).

Adrenal adenomas are benign tumors of the adrenal glands, which can be either functioning or non-functioning. Though the majority are clinically silent, functional adenomas from either the cortex of medulla can lead to overproduction of any of their associated hormones.

Eponymous names are associated with syndromes of adrenal cortical hyperfunction. Cushing’s syndrome is a clinical condition resulting from excessive levels of circulating glucocorticoids and can be caused by adrenocortical adenomas. Likewise, Conn’s syndrome is primary hyperaldosteronism (PH), either from an aldosterone-producing adenoma or bilateral idiopathic hyperplasia. Excess production of androgens from adrenal adenomas is rare, but can occur.

Adenomas derived from the medulla of the adrenal gland are called pheochromocytomas and may result in overproduction of one or both catecholamines.

II. Diagnostic Confirmation: Are you sure your patient has adrenal adenoma?

The work-up for adrenal adenomas usually results from one of two clinical scenarios. The first, and most common, is the incidental finding of an adrenal mass on imaging for unrelated reasons (see Figure 1 for the approach to adenoma identified on imaging). The second occurs when a clinician identifies a clinical syndrome that might be suggestive of adrenal hyperfunction.

Adenoma versus malignancy

Distinguishing adenoma from carcinoma or metastatic lesion (i.e., benign lesion from malignant lesion) is imperative as the management of malignant disease necessitates surgical removal for primary tumors and treatment of the primary malignancy in the case of metastatic disease. Though no definitive test can distinguish between adenoma and malignancy, imaging is the most useful modality, with computed tomography (CT) being the preferred imaging test.

Tumor size and attenuation value in Hounsfield units (HU) are the imaging characteristics that are most useful in differentiating between adenomas and non-adenomas, including adrenocortical cancers, metastases and pheochromocytomas (see Table I). Tumors smaller than 4 cm with an attenuation value of 10HU or less are highly likely to be adenomas. As size increases, the likelihood of malignancy rises. Up to 25% of tumors larger than 6 cm in size are malignant.

Benign features	Suspicious features
Size <6 cm	Size >6 cm
<10 HU on unenhanced CT	>10 HU on unenhanced CT
Smooth margins	Irregular margins
Homogenous or hypodense appearance	Heterogeneous appearance
CT contrast-medium washout >50% at 10 minutes	CT contrast-medium washout <50% at 10 minutes

HU: Hounsfield units

CT: computed tomography

Functional versus non-functional lesions

The second major branch point in the evaluation of an adrenal tumor found on imaging is the determination of whether or not it is functional. In general, all patients should undergo hormonal evaluation for Cushing’s syndrome and pheochromocytoma. Hormonal testing for hyperaldosteronism should be strongly considered in those patients with hypertension. Various recommendations exist for the evaluation of incidentally found adrenal masses; see Figure 1 for one approach.

Clinical syndromes suggestive of adenoma

The second clinical scenario where work-up of an adrenal adenoma is indicated is after identification of a clinical syndrome that is suggestive of adrenal hyperfunction. The primary hormone found in excess, as many adenomas arise from a discrete zone of the adrenal cortex and may overproduce a single hormone, delineates these syndromes.

A. History Part I: Pattern Recognition

Perturbations of adrenal function can occur with any of the hormones released from the gland, including cortisol, aldosterone, catecholamines, and steroid hormones.

Pheochromocytoma and adrenal hyperandrogenism are covered in detail elsewhere, but excess cortisol (Cushing’s syndrome) and PH (Conn’s syndrome) will be discussed here.

Cushing’s syndrome

Patients with Cushing’s syndrome caused by a hypersecretory adenoma usually have central obesity with thin extremities and weight gain is almost always present. The skin becomes thin and bruises easily and many patients develop striae, typically red to purple in coloration and greater than 1 cm wide.

Classically, patients were described as having a plethoric appearance and a proximal myopathy involving the lower limbs and shoulder girdle. The association with facial rounding (“moon face”) and supraclavicular and dorsocervical fat pads (“buffalo hump”) is less strong as these can be seen in obesity from other causes.

Additional skin complaints include adult onset of acne, poor wound healing or multiple recent skin infections. Libido is often decreased in both sexes and women may describe irregular menses due to the cortisol effects on other endocrine systems. Men may describe erectile dysfunction. Though virilization may be somewhat more common in adrenal carcinoma, increased hair growth in women has been reported in adenomas as well. In addition, patients may describe thirst and polyuria, even in the absence of glycosuria. Non-specific, fatigue and generalized weakness are frequent complaints.

Finally, neuropsychiatric symptoms have been reported, with depression and lethargy being the most common. Insomnia is also a common finding, while paranoia and psychosis are rare manifestations.

Signs that may be seen include hypertension and osteopenia or osteoporosis (sometimes with avascular bone necrosis). Impaired glucose tolerance or overt diabetes mellitus is common, as is hyperlipidemia. Hypokalemia can be present but is more common in adrenocorticotropic hormone (ACTH) secreting tumors than as a result of excess cortisol from an adrenal adenoma. In some cases, the uninvolved adrenal gland will atrophy and a size discrepancy between the left and right adrenal glands may develop. Finally, some patients will develop renal calculi due to hypercalciuria and reduced renal tubular reabsorption of phosphate.

Of note, subclinical Cushing’s syndrome from adrenal adenomas is becoming increasingly recognized. These patients may have fewer (if any) of the signs and symptoms described above, but will have subtle aberrations in glucocorticoid regulation (i.e., abnormal biochemical testing). The significance of this clinical state is still under investigation.

Primary hyperaldosteronism (Conn’s syndrome)

Excess aldosterone increases sodium retention and suppresses plasma renin while increasing renal potassium excretion, leading to hypertension and hypokalemia. Symptoms from this condition are generally attributable to those effects.

Patients may complain of headaches, nocturia, polyuria, muscle cramps, and palpitations. Edema is rarely seen.

Hypertension is the predominant sign and is present in most patients. The hypertension may be moderate and some patients have been reported to only have diastolic dysfunction. The blood pressure is generally relatively resistant to conventional antihypertensive agents, but rarely results in malignant hypertension. Left ventricular hypertrophy may be seen and typically is out of proportion to the degree of hypertension.

B. History Part 2: Prevalence

Cushing’s syndrome

Adrenal tumors are incidentally found in up to 5% of patients undergoing CT of the abdomen and have been reported to have a prevalence of 9% on post-mortem autopsies in unselected populations. However, of adrenal “incidentalomas”, only about 5% will have associated Cushing’s syndrome.

Endogenous Cushing’s syndrome is considerably less common than Cushing’s syndrome resulting from exogenous steroid use. However, among those with an endogenous source of cortisol production, approximately 10-30% will have an adrenal tumor as the cause. Though some of these will be adrenocortical carcinoma, the vast majority will be from adenomas.

Cushing’s disease from adrenal adenomas affects women five times more often than men with the average age of onset around 40 years old.

Primary hyperaldosteronism (Conn’s syndrome)

Of adrenal masses found inadvertently on CT imaging, only about 1-3% will have associated hyperaldosteronism. In the general population, however, hyperaldosteronism may be more prevalent than once believed. Some studies have put the rate as high as 13% among patients with hypertension. When only patients with resistant hypertension are considered, the prevalence approaches 20%.

Women are more commonly affected than men, and the diagnosis is usually made in the 4th to 6th decade of life.

C. History Part 3: Competing diagnoses that can mimic adrenal adenoma

Cushing’s syndrome

Adrenal adenomas are only one of several causes of Cushing’s syndrome. In general, this syndrome is either ACTH-dependent or ACTH-independent (see Table II).

Adrenocorticotropic hormone dependent	Adrenocorticotropic hormone independent
Pituitary adenoma	Adrenal adenomas
Ectopic ACTH secretion	Adrenal carcinomas
Ectopic CRH secretion	Micro- and macronodular adrenal hyperplasia

ACTH: adrenocorticotropic hormone

CRH: corticotropin-releasing hormone

Cushing’s disease (pituitary adenoma), ectopic ACTH secretion and ectopic corticotropin-releasing hormone (CRH) secretion are considered ACTH-dependent causes of Cushing’s syndrome. Adrenal adenomas, adrenal carcinomas, and micro- and macronodular adrenal hyperplasia are considered ACTH-independent causes of Cushing’s syndrome. Differentiation between the ACTH-dependent and the ACTH-independent causes can be done using biochemical testing (i.e., ACTH levels), and imaging criteria can be used to help guide the distinction between the ACTH-independent causes.

The findings in Cushing’s syndrome may be subtle on initial examination and can easily be confused for the metabolic syndrome as both have characteristic hypertension, hyperlipidemia and central obesity. Biochemical testing should differentiate the two conditions. Plethora and skin findings of striae are usually not found in those with metabolic syndrome.

Other conditions that may mimic Cushing’s syndrome include alcoholism and regular use of gammahydroxybutyrate (GHB), which has been reported to cause a central Cushing’s syndrome. Depressed patients often have some degree of hypercortisolism, but should not have the physical findings. Patients with obesity may have false positive dexamethasone suppression tests, but they will usually have normal urine free cortisol tests because of the diurnal variation of serum cortisol. The virilization and irregular menses can be mimicked by polycystic ovarian syndrome in women.

Patients with lipodystrophy (i.e., patients receiving antiretroviral therapy) may have thin extremities and central obesity but should lack the biochemical abnormalities. Finally, many adolescents develop violaceous striae, but these are “striae distensae” and are not indicative of Cushing’s syndrome.

Primary hyperaldosteronism (Conn’s syndrome)

Many patients with essential hypertension will also have low plasma renin activity (PRA) levels, which can lead to a mildly elevated ratio of plasma aldosterone concentration (PAC) to PRA. However, this ratio is generally still less than 20.

Bilateral idiopathic adrenal hyperplasia can mimic PH. This condition is present in up to 30% of those with hyperaldosteronism. If not apparent from previous testing, adrenal vein sampling can help determine the laterality of aldosterone excess and distinguish between the two conditions.

Rarely, excessive ingestion of real licorice (black and derived from anise) or Sambuca (an Italian liqueur) can cause hypertension and hypokalemia. Renal vascular disease can also cause hypertension and hypokalemia, but in this condition, PRA is high. Liddle’s syndrome, a rare autosomal dominant condition of the kidney, results in excessive sodium reabsorption from the renal tubule and leads to hypertension and hypokalemia but the level of both renin and aldosterone are low.

D. Physical Examination Findings

Cushing’s syndrome

Physical exam should include body morphology, as central obesity with thin extremities is common. The “moon face” may not be readily apparent but comparison to older photographs such as a driver’s license may be revealing. In addition, a thorough skin exam looking for bruising and striae should be performed. Proximal muscle strength testing should be performed, looking for weakness; this should include the ability to rise from a chair without the use of the arms. Finally, in women, virilization (excess hair growth and acne) may be present.

Primary hyperaldosteronism (Conn’s syndrome)

Most of the abnormalities found in PH are not readily apparent on physical exam. The presence of edema is not suggestive of this condition and may point to an alternative cause of resistant hypertension. Additionally, a thorough cardiovascular exam should be done to assess for long term changes of aldosterone excess (i.e., left ventricular enlargement, cardiomyopathy and heart failure).

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Cushing’s syndrome

On standard lab testing, those with Cushing’s syndrome may have a leukocytosis with relative lymphopenia. Hypokalemia will be variably present.

The easiest screening test for hospitalized patients is the dexamethasone suppression test. In the standard dose version of this test, dexamethasone 1mg is given orally at 11 pm and a serum cortisol level is checked the next morning at 8am. A cortisol level of less than 1.8mg/dL is a normal response (i.e., the patient’s cortisol should be suppressed) and has a low false negative rate (less than 2%). However, false positives have been reported in up to 40% of patients so confirmatory testing is needed with positive results. In the low dose dexamethasone suppression test, a dose of 0.5mg is taken orally every 6 hours starting at 6am with the last dose at midnight. Cortisol is then measured the next morning at 8am and the same cut off value of 1.8 mg/dL has been shown to have an excellent sensitivity and a specificity of 98%. Certain drugs, such as phenytoin, phenobarbital and rifampin increase the clearance rate of dexamethasone, resulting in false positives during the dexamethasone suppression test.

An alternative test is the measurement of a midnight salivary cortisol level, as the saliva and plasma should have roughly equal concentrations of cortisol. This test requires a normal sleeping pattern for interpretation, which is frequently not found in hospitalized patients.

A 24-hour urine collection for urinary free cortisol can be used as a confirmatory test when the dexamethasone suppression test is positive. If clearance is poor (low estimated glomerular filtration rate (eGFR)), urinary cortisol excretion will be decreased and may appear normal even in the presence of excessive cortisol production.

Once initial testing confirms the presence of excess cortisol, an ACTH level should be measured. A suppressed ACTH is suggestive of adrenal pathology, while an elevated ACTH level may indicate the primary lesion is in the pituitary.

Primary hyperaldosteronism (Conn’s syndrome)

Routine laboratory testing may show slightly elevated serum sodium levels (less than 147 mEq/L), a slight metabolic alkalosis and hyperglycemia. Hypokalemia is variably present (approximately 40% of patients) but may be seen spontaneously or with the addition of a thiazide diuretic. This is important to note because repletion of serum potassium is imperative prior to testing for PH.

Testing accurately for this condition is difficult as many factors may interfere with the tests. There is debate about how much effect antihypertensives have on the testing. Spironolactone, eplerenone and amiloride should be avoided (or at least held for 3 weeks prior to testing). Classical teaching is that diuretics, dihydropyridine calcium channel blockers (which can normalize aldosterone secretion) and beta-blockers (which can suppress plasma renin activity) should be discontinued for at least three weeks prior to testing. However, many investigators suggest that aside from spironolactone, eplerenone and amiloride, all other antihypertensives can be continued throughout the testing.

The patient must be on an unrestricted sodium diet during testing, should be out of bed for at least 2 hours and upright, and then seated for at least 10 minutes prior to the blood draw. The blood should be drawn between 8 and 10am for ideal measurement.

The best screening test is the ratio of the PAC to PRA. The combination of a PAC/PRA ratio of greater than 20 and a concomitant PAC greater than 10ng/dL is highly suggestive of the diagnosis. Different labs will use different units for these tests and conversion may be necessary. PRA is generally higher in all patients during therapy with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) and low or suppressed PRA in patients on these medications is suggestive of hyperaldosteronism.

Patients who have a positive initial screen should have confirmatory testing with a 24-hour urinary aldosterone level. This test is ideally done during a time of high salt intake and in a state of normal potassium and has more restrictions on antihypertensives than the PAC/PRA ratio test. Alternatively, testing of plasma aldosterone concentrations after a two-liter isotonic saline load (over 4 hours) can be suggestive if the PAC is not suppressed. This test has fallen out of favor because of the risk of volume overload in older patients.

Once aldosterone excess has been identified, the distinction must be made between aldosterone producing adenomas and bilateral idiopathic adrenal hyperplasia. In general, patients with adenomas usually have more severe hypertension, more pronounced hypokalemia, are younger, and have discrete tumors seen on CT scan. Additionally, a plasma 18-hydroxycorticosterone level can be obtained, which is generally greater than 100ng/dL in patients with adenomas. Posture testing can also be used. In this test, the patient is hospitalized overnight and kept recumbent. An aldosterone level is checked in this position and then after 4 hours of upright ambulation. The normal response is a decrease of aldosterone with upright posture. Lack of decrease or a paradoxical increase is suggestive of an adenoma.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Cushing’s syndrome

Imaging can be useful in lateralization of the causative adrenal lesion. A non-contrast CT is usually sufficient to identify a tumor. However, the addition of contrast (an “adrenal protocol” CT) can add additional information, primarily in determination of risk of malignancy. See Table I for important features on imaging.

Primary hyperaldosteronism (Conn’s syndrome)

Localization of the adrenal mass can sometimes be accomplished with CT imaging alone; however, the gold standard for diagnosis is adrenal vein sampling (AVS) as CT may lead to misdiagnosis in 37% of patients. AVS is a technically challenging test, but lateralization suggests ipsilateral adenoma.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis

Cushing’s syndrome

Some authors suggest checking a 24-hour urine free cortisol the day after a low dose dexamethasone suppression test. However, this adds little to the diagnostic accuracy of the baseline 24-hour urine free cortisol level and prolongs testing by an additional day.

Primary hyperaldosteronism (Conn’s syndrome)

Aldosterone and renin levels are variable throughout the day and related to position. To avoid misinterpretation, ensure the test is drawn under optimal conditions.

III. Default Management

A. Immediate Management

None

B. Physical Examination Tips to Guide Management

In PH, left ventricular hypertrophy generally improves or resolves with treatment of the hyperaldosteronism, even if the hypertension persists.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management

Following unilateral adrenalectomy for PH, patients should be monitored for hyperkalemia as well as a result of relative mineralocorticoid deficiency.

D. Long-term Management

Cushing’s syndrome

The primary treatment for Cushing’s syndrome caused by an adrenal adenoma is usually laparoscopic unilateral adrenalectomy. It is important to note that the contralateral adrenal gland is often atrophied and patients may require post-operative hydrocortisone replacement until the hypothalamic-pituitary-adrenal axis recovers, which may take anywhere from 6-18 months. Failure to give glucocorticoids post operatively can result in acute adrenal insufficiency.

Monitoring for response centers around resolution of the initial findings and symptoms. Many patients will experience significant improvement in their glucose control and/or hypertension. Weight loss is also common after successful surgery. The body changes of Cushing’s syndrome are generally reversible but may take months or longer to resolve completely and some people may not have complete resolution.

Primary hyperaldosteronism (Conn’s syndrome)

In patients with PH, there are medical and surgical treatment options. In general, surgical approaches are more successful and medical treatment is reserved for patients who are poor surgical candidates.

The preferred surgical treatment for PH due to an adenoma is laparoscopic total adrenalectomy. For the first few weeks after surgery, patients should be on a high salt diet to compensate for mild hypoaldosteronism that may occur because of chronic suppression of the renin-angiotensin system. Most patients will not require mineralocorticoid supplementation.

Medical therapy consists of spironolactone, but side effects such as painful gynecomastia, nausea and headache can lead to poor compliance. Eplerenone may be more tolerable for many patients but may be somewhat less effective.

E. Common Pitfalls and Side-Effects of Management

In patients who appear to have Cushing’s syndrome, a detailed history of exogenous steroid exposure should be undertaken prior to expensive biochemical testing. This should include exposure to topical, oral and inhaled corticosteroids.