Endogenous Cushing Syndrome 

Updated: Oct 18, 2018
Author: Ha Cam Thuy Nguyen, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP 

Overview

Background

Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids. Exogenous use of glucocorticoids should always be considered and excluded in the etiology of Cushing syndrome. This article focuses on endogenous Cushing syndrome. Endogenous glucocorticoid overproduction, or hypercortisolism, can be dependent on or independent of adrenocorticotropic hormone (ACTH).[1, 2]

Individuals with Cushing syndrome can develop moon facies, facial plethora, supraclavicular fat pads, buffalo hump, truncal obesity, and purple striae, as shown in the image below.

Physical findings in Cushing syndrome. Physical findings in Cushing syndrome.

Individuals often complain of proximal muscle weakness, easy bruising, weight gain, hirsutism, and, in children, growth retardation. Hypertension, osteopenia, diabetes mellitus, and impaired immune function may occur.

Also see Glucocorticoid Therapy and Cushing Syndrome and Iatrogenic Cushing Syndrome.

Pathophysiology

Endogenous glucocorticoid overproduction or hypercortisolism that is independent of ACTH is usually due to a primary adrenocortical neoplasm (most commonly an adenoma and rarely a carcinoma). Bilateral micronodular hyperplasia (primary pigmented nodular adrenocortical disease) and macronodular hyperplasia are rare causes of Cushing syndrome.

Ectopic cortisol secretion from a case of ovarian carcinoma has been reported as a cause of ACTH-independent Cushing syndrome.[3]

ACTH level in ACTH-independent Cushing syndrome is low due to the negative feedback to pituitary corticotroph cells from a high level of serum cortisol. ACTH-dependent Cushing syndrome is characterized by elevated ACTH levels. Elevated ACTH levels are usually due to an anterior pituitary tumor, which is classic Cushing disease (60-70%). Nonpituitary ectopic sources of ACTH, such as small-cell lung carcinoma (oat cell carcinoma), carcinoid tumor, medullary thyroid carcinoma, or other neuroendocrine tumors can result in high ACTH levels and sequentially hypercortisolism.

Ectopic corticotropin-releasing hormone (CRH) secretion leading to increased ACTH secretion comprises a very rare group of cases of Cushing syndrome.[4]

A study by Tatsi et al indicated that in children with endogenous Cushing syndrome, the absolute lymphocyte count is abnormally low, while the total white blood cell (WBC) and absolute neutrophil counts are abnormally high, with a correlation found between these changes and the severity of Cushing syndrome. It was also found that successful treatment of the syndrome returns the WBC count to normal.[5]

Etiology

The following conditions may cause endogenous glucocorticoid overproduction:

ACTH-independent Cushing syndrome

See the list below:

  • Primary adrenal lesions

    • Overproduction of glucocorticoids may be due to an adrenal adenoma, adrenal carcinoma, or macronodular or micronodular adrenal hyperplasia. The zona fasciculata and zona reticularis layers of the adrenal cortex normally produce glucocorticoids and androgens. Glucocorticoid-secreting tumors are derived from these cells and, thus, may secrete both glucocorticoids and androgens.

    • In general, excess androgen secretion is suggestive of an adrenal carcinoma rather than an adrenal adenoma. These glucocorticoid-producing tumors do not usually secrete aldosterone, which is produced in the zona glomerulosa layer of the adrenal cortex.

    • The Carney complex is a familial form of micronodular hyperplasia of the adrenal gland. It is an autosomal dominant disorder and ACTH-independent cause of Cushing syndrome. Pigmented skin lesions and mesenchymal and endocrine tumors characterize this disorder. Cushing syndrome may be overt, subclinical, cyclical, or periodic.

    • Primary bilateral macronodular adrenal hyperplasia is uncommon and characterized by multiple nonpigmented nodules that are greater than 10 mm in diameter and enlarged adrenal glands. The exact etiology of this condition is not quite clear, however, genetic mutations, paracrine ACTH secretion, and aberrant hormone receptors have been reported to play a role in its pathogenesis.

    • McCune-Albright syndrome is a rare cause of precocious puberty. It is associated with hyperfunction of the adrenal glands that may lead to Cushing syndrome.[6]

  • Ectopic cortisol secretion from a case of ovarian carcinoma has been reported as a cause of ACTH independent Cushing syndrome.[3]

ACTH-dependent Cushing syndrome

See the list below:

  • ACTH-producing pituitary adenoma

    • Pituitary adenomas that secrete ACTH are derived from corticotroph cells in the anterior pituitary.

    • ACTH secreted by corticotroph cells is released into the circulation and acts on the adrenal cortex to produce hyperplasia and stimulate the secretion of adrenal steroids.

    • These adenomas, if large, can result in loss of production of other anterior pituitary hormones (TSH, FSH, LH, growth hormone, and prolactin).

    • Nelson syndrome has been described as corticotroph tumor progression seen in patients who had bilateral adrenalectomy as radical treatment for Cushing disease. In a retrospective study looking at 53 Cushing disease patients who underwent bilateral adrenalectomy without pituitary irradiation,[7] corticotroph tumor progression was noted to be present in half of the patients, mostly within 3 years of surgery. Patients with a shorter duration of Cushing disease and a high plasma ACTH concentration in the year after adrenalectomy were more likely to develop Nelson’s syndrome. Enlarging corticotroph tumor can manifest clinically with compressive symptoms such as headache, vision change, ocular palsy and hyperpigmentation due to very high ACTH concentrations.

  • Ectopic ACTH secretion is caused by small-cell lung tumors, carcinoid tumors, or other tumors with neuroendocrine origin. These tumors themselves can secrete ACTH, which subsequently stimulates the adrenal glands to make more cortisol.

  • Ectopic CRH secretion leading to increased ACTH secretion comprises a very rare group of cases of Cushing syndrome.[4]

Epidemiology

Identifying the exact incidence of Cushing syndrome is challenging because patients can present with a wide spectrum from subclinical, mild, cyclic, to severe Cushing syndrome. Therefore, the true incidence might be underestimated. In a European population based study, the annual incidence of endogenous Cushing syndrome was reported to be 1.2-1.7 per million per year (Cushing disease), 0.6 per million per year (adrenal adenoma), and 0.2 per million per year (adrenal carcinoma).[8]

The female-to-male incidence ratio is approximately 5:1 for Cushing syndrome due to an adrenal or pituitary tumor. Ectopic ACTH production is more frequent in men than in women because of the higher incidence of lung tumors in this population.

The peak incidence of Cushing syndrome due to either an adrenal or pituitary adenoma is in persons aged 25-40 years. Ectopic ACTH production due to lung cancer occurs later in life.

Prognosis

Mortality in patients with Cushing syndrome was reported to be twice that of persons without the disease.[9]  A systematic review and meta-analysis indicated that Cushing disease patients with persistent disease after surgery have higher mortality than those with initial remission and Cushing syndrome due to a benign adrenal adenoma.[9]

Morbidity and mortality associated with Cushing syndrome are related primarily to the effects of excess glucocorticoids. Exposure to excess glucocorticoids results in multiple medical problems, including hypertension, cardiovascular disease, obesity, osteoporosis, fractures, impaired immune function, impaired wound healing, glucose intolerance, and psychosis. A large primary pituitary tumor may also cause panhypopituitarism and visual loss. Prognosis is favorable if surgery is curative. The rare adrenocortical carcinomas are associated with a 5-year survival rate of 30% or less. Catastrophic medical crises such as perforated viscera[10] and opportunistic fungal infections[11] can occur in glucocorticoid excess states. High levels of endogenous glucocorticoids may mask the abdominal symptoms associated with catastrophic abdominal events such as perforated bowel.

Lack of cortisol leading to an adrenal crisis may occur in patients with endogenous Cushing syndrome who have undergone resection of an ACTH-producing or cortisol-producing tumor or who are taking adrenal steroid inhibitors.

Other potential complications associated with Cushing syndrome include the following:

  • Osteoporosis

  • Increased susceptibility to infections

  • Hirsutism

  • Diabetes mellitus

  • Hypertension

  • Risk for adrenal crisis

  • Panhypopituitarism

  • Diabetes insipidus 

A study by Davi' et al found that in ectopic Cushing syndrome, prognosis is influenced by the type of neuroendocrine tumor causing it, as well as by grading, the presence of distant metastases, the severity of the hypercortisolism, the existence of hypokalemia, and the presence of diabetes mellitus. The investigators also determined that survival and surgical cure rates are better for bronchial carcinoids than for occult tumors and pancreatic neuroendocrine tumors.[12]  

Patient Education

Patients should be educated about adrenal crisis.

Instruction on specific medication use is indicated.

 

Presentation

History

Patients with Cushing syndrome may complain of weight gain, especially in the face, supraclavicular region, upper back, and torso. Frequently, patients notice changes in their skin, including purple stretch marks, easy bruising, and other signs of skin thinning. Because of progressive proximal muscle weakness, patients may have difficulty climbing stairs, getting out of a low chair, and raising their arms.

Menstrual irregularities, amenorrhea, infertility, and decreased libido may occur in women related to inhibition of pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which likely is due to interruption of luteinizing hormone-releasing hormone (LHRH) pulse generation. In men, inhibition of LHRH and FSH/LH function may lead to decreased libido and impotence.

Psychological problems such as depression, cognitive dysfunction, and emotional lability may develop. New-onset or worsening of hypertension and diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and osteoporotic fractures may occur.

Signs and symptoms specifically associated with endogenous Cushing syndrome include the following:

  • Patients with an ACTH-producing pituitary tumor: Headaches, polyuria, nocturia, visual problems, or galactorrhea

  • Patients with tumor mass effect on the anterior pituitary: Hyposomatotropism, hypothyroidism, hyperprolactinemia or hypoprolactinemia, hypogonadism

  • Patients with an adrenal carcinoma as underlying cause of Cushing syndrome: Rapid onset of symptoms of glucocorticoid excess in conjunction with hyperandrogenism presenting as virilization in women or feminization in men

Physical Examination

Obesity

Patients may have increased adipose tissue in the face (moon facies), upper back at the base of neck (buffalo hump), and above the clavicles (supraclavicular fat pads).

Central obesity may also appear as increased adipose tissue in the mediastinum and peritoneum, increased waist-to-hip ratio greater than 1 in men and 0.8 in women; and, upon CT scan of the abdomen, increased visceral fat is evident.

Skin

Facial plethora may be present, especially over the cheeks. Violaceous striae, often wider than 0.5 cm, are observed most commonly over the abdomen, buttocks, lower back, upper thighs, upper arms, and breasts. Ecchymosis may be present. Patients may have telangiectasia and purpura, cutaneous atrophy with exposure of subcutaneous vasculature tissue and tenting of skin may be evident. Glucocorticoid excess may cause increased lanugo facial hair. If glucocorticoid excess is accompanied by androgen excess, as occurs in adrenocortical carcinomas, hirsutism and male pattern balding may be present in women. Steroid acne, consisting of papular or pustular lesions over the face, chest, and back, may be present.

Acanthosis nigricans, which is associated with insulin resistance and hyperinsulinemia, may be present. The most common sites are axilla and areas of frequent rubbing, such as over elbows, around the neck, and under the breasts.

Cardiovascular and renal

Hypertension and possibly edema may be present due to cortisol activation of the mineralocorticoid receptor leading to sodium and water retention. Cushing syndrome is also associated with cardiac structural and functional changes. Left ventricular (LV) hypertrophy and impaired LV diastolic function have been described in patients with Cushing syndrome; however, these changes are reversed upon normalization of corticosteroid excess.[13]

Gastroenterologic

Peptic ulceration may occur with or without symptoms. Particularly at risk are patients given high doses of glucocorticoids (rare in endogenous hypercortisolism).

Endocrine

Galactorrhea may occur when anterior pituitary tumors compress the pituitary stalk, leading to elevated prolactin levels.

Signs of hypothyroidism, such as slow deep tendon reflex relaxation, may occur from an anterior pituitary tumor whose size interferes with thyroid-stimulating hormone (TSH) synthesis and release. Similarly, other pituitary function may be impacted as well.

Low testosterone levels in men may lead to decreased testicular volume from inhibition of LHRH and LH/FSH function. In women, low level of LHRH and LH/FSH lead to menstrual irregularities or amenorrhea.

Skeletal/muscular

Proximal muscle weakness may be evident. Osteoporosis may lead to incident fractures and kyphosis, height loss, and axial skeletal bone pain. Avascular necrosis of the hip is also possible from glucocorticoid excess.

Neuropsychological

Patients may experience emotional liability, fatigue, and depression.

Visual-field defects, often bitemporal, and blurred vision may occur in individuals with large ACTH-producing pituitary tumors that impinge on the optic chiasma.

Adrenal crisis

Patients with cushingoid features may present to the emergency department in adrenal crisis. Adrenal crisis may occur in patients on steroids who stop taking their glucocorticoids or neglect to increase their steroids during an acute illness. It may also occur in patients who have recently undergone resection of an ACTH-producing or cortisol-producing tumor or who are taking adrenal steroid inhibitors.

Physical findings that occur in a patient in adrenal crisis include hypotension, abdominal pain, vomiting, and mental confusion (secondary to low serum sodium or hypotension). Other findings include hypoglycemia, hyperkalemia, hyponatremia, and metabolic acidosis

 

DDx

Diagnostic Considerations

Diagnosis of Cushing syndrome can sometimes be very challenging, especially in cases of pseudo-Cushing, subclinical, mild or cyclic Cushing syndrome.

A pseudo-Cushing is defined as having some of the clinical features and biochemical evidence of Cushing syndrome. However, resolution of the primary condition results in disappearance of the cushingoid features and biochemical abnormalities.

In patients who chronically abuse alcohol, clinical and biochemical findings suggestive of Cushing syndrome are often encountered. Discontinuation of alcohol causes disappearance of these abnormalities, and, therefore, this syndrome is often specifically referred to as alcohol-induced pseudo-Cushing syndrome. Patients with depression often have perturbation of the HPA axis, with abnormal cortisol hypersecretion. These patients rarely develop clinical Cushing syndrome. Because excess glucocorticoids can lead to emotional liability and depression, distinguishing between depression and mild Cushing syndrome is often a diagnostic challenge.

See Pseudo-Cushing Syndrome. 

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of Cushing syndrome due to endogenous overproduction of cortisol requires the demonstration of inappropriately high serum cortisol or urine cortisol levels, as shown in the algorithm below. Currently, 4 methods are accepted for the diagnosis of Cushing syndrome: urinary free cortisol level, low-dose dexamethasone suppression test, evening serum and salivary cortisol level, and dexamethasone–corticotropin-releasing hormone test.

Imaging studies for Cushing syndrome should be performed after the biochemical evaluation has been performed. Ideally, the biochemical abnormalities should reconcile with the anatomic abnormalities before definitive therapy is offered.

Laboratory Studies

The diagnosis of Cushing syndrome requires demonstration of inappropriately high level of cortisol in the serum or urine. The levels should be measured when cortisol, according to its physiologic circadian rhythm, is supposed to be suppressed, that is, late evening or when a patient is given exogenous glucocorticoids.

This concept gives rise to the following tests, which have been recommended as screening tests for Cushing syndrome:

  • Midnight serum or salivary cortisol
  • 24-hour urine free cortisol
  • Low dose dexamethasone suppression test

Exogenous glucocorticoid use around time of testing must be addressed and excluded to ensure the accuracy of the test result's interpretation.

Urinary free cortisol (UFC) determination has been widely used as an initial screening tool for Cushing syndrome because it provides measurement of cortisol over a 24-hour period. A valid result depends on adequate collection of the specimen. Urinary creatinine excretion can be used to assess the reliability of the collection. 24-Hour urine creatinine excretion should be 20-25 mg/kg (lean body weight) in adult males younger than 50 years of age and 15-20 mg/kg (lean body weight) in adult females younger than 50 years. However, in elderly patients, creatinine excretion gradually declines over time, which makes this estimation less accurate than that for younger individuals. Urine free cortisol values higher than 3 times the upper limit of normal are highly suggestive of Cushing syndrome. Values higher than the normal reference range but less than 3times the upper limit of normal are inconclusive. Values within this range may indicate pseudo–Cushing syndrome or Cushing syndrome and require further testing. Multiple collections are necessary because patients with disease may have values that fall within the normal range.

The rationale for the dexamethasone suppression test is based on the normal physiology of the hypothalamic-pituitary-adrenal axis; glucocorticoids inhibit secretion of hypothalamic CRH and pituitary ACTH. Since cortisol production is controlled by ACTH, decrease in ACTH lead to decrease in plasma and urine cortisol. The overnight 1-mg dexamethasone suppression test requires administration of 1 mg of dexamethasone at 11 PM with subsequent measurement of cortisol level at 8 am.[14]  To enhance the sensitivity of the test, a cutoff value of less than 1.8 mcg/dL (50 nmol/L) excludes Cushing syndrome.[15]  Its ease of administration makes the 1-mg dexamethasone suppression test a widely used screening tool.

Dexamethasone is metabolized through the liver via the CYP3A4 pathway. Thus, liver disease or drugs that induce CYP3A4 enzymes can interfere with dexamethasone metabolism and affect the final test result. To help recognizing any problems with dexamethasone metabolism, dexamethasone level should be measured in the blood at the same time that the cortisol level is measured in early morning.[16]  Please refer to each specific laboratory reference for expected value of dexamethasone in this setting..

Late-night serum and salivary cortisol levels take advantage of the alterations in circadian rhythm of cortisol secretion in patients with Cushing syndrome. Normally, cortisol values are at their lowest level late at night. In patients with Cushing syndrome, an elevated serum cortisol at 11 PM can be an early, but not definitive, finding. Measuring serum cortisol levels requires hospitalization, with blood samples obtained within 5-10 minutes of waking a patient, and is not a practical test.

Measuring salivary cortisol level has gained interest, as it is a simple and convenient way of obtaining a nighttime sample. This measurement allows patients to collect their own samples at home. Most physicians who use this test obtain readings over several evenings to increase accuracy. It is convenient and useful in patients with mild or cyclic Cushing syndrome in whom diagnosing Cushing syndrome can be extremely hard. Patients can have several samples collected at home over a period of time. Salivary cortisol sample is simple to handle because cortisol in saliva stays stable at room temperature for many days.

Results from a metaanalysis of 7 studies related to late-night salivary cortisol testing in the diagnosis of Cushing syndrome (947 patients aged >18 years, including 339 persons with Cushing syndrome) indicated that such testing has a sensitivity of 92% and a specificity of 96%.[17]  Positive likelihood ratio range was between 8.8 and 21 and negative likelihood ratio was between 0.07 and 0.08 in 2 metaanalysis studies[17, 18] . These analyses suggest that late night salivary cortisol is an excellent test in diagnosing Cushing syndrome. Factors that can make interpretation of results complicated are a change in the sleep-wake rhythm, shift work, sample contamination or acute stress or illness. Recent studies have suggested that late night salivary cortisol might have better performance than urinary free cortisol.[19]

The dexamethasone-CRH test is intended to distinguish patients with Cushing syndrome from those with pseudo-Cushing states.[20]  It combines a 48-hour low-dose dexamethasone suppression test with CRH stimulation. Dexamethasone (0.5 mg q6h) is given 8 times starting at about 8 AM, CRH is administered  2  hours after the last dose of dexamethasone and plasma cortisol and ACTH levels are obtained at 15-minute intervals for 1 hour. A cortisol value at 15 minutes after CRH greater than 38 nmol/L (1.4 mcg/dL) identifies Cushing syndrome. The test has a sensitivity of 90-100% and a specificity of 67-100%.[21, 22]  This test is reserved for patients with high clinical suspicion for Cushing syndrome but equivocal results on other diagnostic tests.

Unfortunately, mild Cushing syndrome is often difficult to distinguish from normal cortisol secretion or pseudo-Cushing states. The aforementioned tests can produce both false-positive and false-negative results. False-positive results are associated with obesity, alcoholism, chronic renal failure, affective disorders, strenuous exercise, or eating disorders. Other potential confounders in the interpretation of tests include the following:

  • Medications that increase corticosteroid-binding globulin, such as estrogen and tamoxifen, may cause appropriate increases in serum cortisol levels.

  • Medications that facilitate the metabolism of dexamethasone, such as phenobarbital, phenytoin, and rifampin, may cause false-positive results with the dexamethasone suppression test.

A study by Wester et al indicated that analysis of hair cortisol content using a single scalp hair sample provides diagnostic accuracy in Cushing syndrome similar to that of current first-line tests. Using a cutoff of 31.1 pg/mg, hair cortisol content had a diagnostic sensitivity and specificity of 93% and 90%, respectively.[23]

Once the diagnosis is established, the next step requires determining the etiology of Cushing syndrome. See the flow chart below. The logical first step involves identifying if the hypercortisolism is an ACTH-dependent or ACTH-independent disorder.

Etiology of Cushing syndrome. Etiology of Cushing syndrome.

Etiology workup

In a patient in whom the diagnosis of Cushing syndrome has been established, an undetectable plasma ACTH with a simultaneously elevated serum cortisol level is diagnostic of ACTH-independent Cushing syndrome. ACTH-independent Cushing syndrome is most often due to a primary cortisol-producing adrenal adenoma or carcinoma, assuming exogenous glucocorticoid use has been excluded. A plasma ACTH (measured by an immunoradiometric assay) of less than 5 pg/mL is suggestive of a primary adrenal tumor. An ACTH level greater than 20 pg/mL (4.4 pmol/L) is consistent with ACTH-dependent Cushing syndrome. An ACTH level between 5 and 20 pg/mL is equivocal.

The 8-mg overnight dexamethasone suppression test and the 48-hour high-dose dexamethasone test may be useful when baseline ACTH levels are indeterminate. These studies also help in determining whether a patient who has ACTH-dependent disease has pituitary-dependent or ectopic ACTH disease. In the 8-mg overnight dexamethasone suppression test, individuals ingest 8 mg dexamethasone orally at 11 PM, with measurement of an 8 am cortisol level the next day. A baseline 8 am cortisol measurement is also obtained the morning prior to ingesting dexamethasone. Suppression of serum cortisol level to less than 50% of baseline is suggestive of a pituitary source of ACTH rather than ectopic ACTH or primary adrenal disease. However, the diagnostic accuracy is only 70-80%.

With the 48-hour high-dose dexamethasone suppression test, patients ingest 2 mg dexamethasone every 6 hours for 8 doses. A decrease in urinary free cortisol of greater than 50% is suggestive of an anterior pituitary adenoma rather than ectopic ACTH or a primary adrenal tumor.[24]  Unfortunately, the sensitivity of this test is only 81%, with a specificity of 66.7% as reported in one study.[25]  Although more patients with Cushing disease than those with ectopic ACTH had a positive suppression test, there was significant overlap as the rate of suppression was 0-99% for each diagnosis. The more stringent criterion of a 90% decrease in urinary free cortisol levels excludes the diagnosis of ectopic ACTH and has almost 100% specificity for anterior pituitary disease.

Testing with CRH is used in the differential diagnosis of ACTH-dependent Cushing syndrome. In most patients with pituitary ACTH secretion, the intravenous administration of CRH causes a rise in plasma ACTH and cortisol levels. In patients with ectopic secretion of ACTH, CRH does not affect ACTH or cortisol levels. ACTH and cortisol samples are obtained before administration of ovine CRH (oCRH), and subsequently at 15, 30, 45, 60, 90, and 120 minutes after administration of 1 mcg/kg of CRH. A rise of more than 20% in mean increase plasma cortisol level at 30 and 45 minutes or a rise of more than 35% in mean ACTH level at 15 and 30 minutes after oCRH is consistent with pituitary ACTH-dependent Cushing syndrome. Sensitivity and specificity are 91% and 88%, respectively, for cortisol measurements and 93% and 100% for ACTH measurements.[26]

In another study, a value of ACTH percentage increment of 50% gave the best diagnostic value (sensitivity 86% [72.6-94.8] and specificity 90% [55.5-98.3]).[27]  However, the best cut off point for cortisol percentage increment (30%) yielded inferior results with sensitivity 61% (45.5-75.6) and specificity 70% (34.8-93.0).

Acute illness activates the HPA axis, resulting in increases in ACTH and cortisol. The laboratory workup for Cushing syndrome should not be performed when subjects are acutely ill.

Table. States of Elevated and Low Plasma Cortisol (Open Table in a new window)

States of Elevated Plasma Cortisol

States of Low Plasma Cortisol

Chronic stress

Melancholic depression

Anorexia nervosa

Obsessive-compulsive disorder

Panic disorder

Excessive exercise

Chronic active alcoholism

Alcohol and nicotine withdrawal

Diabetes mellitus

Central obesity

Sexual abuse (stress)

Hyperthyroidism

Premenstrual tension syndrome

Cushing syndrome

Pregnancy

Adrenal insufficiency

Atypical/seasonal depression

Chronic fatigue syndrome

Fibromyalgia

Hypothyroidism

Post-glucocorticoid therapy

Post-Cushing syndrome

Postpartum period

Post-chronic stress

Rheumatoid arthritis

 

If concern for adrenal carcinoma exists, measurements of adrenal androgen production, such as serum dehydroepiandrosterone sulfate (DHEAS), and 24-hour urinary 17-ketosteroid measurements may be helpful.

Imaging Studies

Imaging studies for Cushing syndrome should be performed after the biochemical evaluation has been performed. The rationale for this is that random imaging of the pituitary or adrenal glands may yield a 10% incidence of incidental nonfunctioning pituitary or adrenal adenomas, which may mislead one from proper therapy and surgery. Ideally, the biochemical abnormalities should reconcile with the anatomic abnormalities before definitive therapy is offered.

An abdominal CT scan is recommended if a primary adrenal pathology is suspected. The presence of an adrenal mass larger than 4-6 cm raises the possibility that the mass is an adrenal carcinoma.

If a pituitary source of excess ACTH is suspected, patients should undergo a contrast-enhanced magnetic resonance imaging (MRI) study of the pituitary. Unfortunately, normal-appearing pituitaries may occur in some patients with Cushing disease due to both diffuse hyperplasia of ACTH-producing cells and small microadenomas that do not appear on imaging studies. In the latter case, ACTH lateralization during an inferior petrosal sinus sampling (IPSS) study may be useful in lateralizing the occult lesion and in guiding surgical therapy.

Chest and abdominal CT scans should be performed in patients with suspected ectopic ACTH production.

Octreotide scintigraphy may be helpful in detecting ectopic ACTH tumors because some neuroendocrine tumors typically have cell surface receptors for somatostatin.

Procedures

Inferior petrosal sinus sampling (IPSS) is useful in distinguishing a pituitary source from an ectopic source of ACTH. An experienced interventional radiologist should perform this procedure to decrease the incidence of neurological complications. This study should not be used to establish the diagnosis of Cushing syndrome.

  • Bilateral IPSS and simultaneous peripheral ACTH measurements are made at baseline and 2-3 minutes, 5 minutes, and 10 minutes after intravenous administration of oCRH at 1 mcg/kg.

  • An IPS-to-peripheral ACTH ratio of greater than or equal to 2 at baseline and greater than or equal to 3 after CRH administration is consistent with Cushing disease.[28]

  • In approximately 70% of patients, a ratio of greater than 1.4 between the right and left inferior petrosal sinuses is predictive of the location of the microadenoma.

  • This study is not interpretable if pituitary venous drainage anatomy is anomalous. False negative results can be seen in catheter misplacement, asymmetric venous drainage, or anomalous venous drainage. False positive results are rare.

A study by Mulligan et al concluded that prolactin measurement during IPSS may reduce false-negative results in patients with Cushing disease who do not have an appropriate central-to-peripheral ACTH gradient.[29]

 

Treatment

Approach Considerations

Treatment of Cushing syndrome is directed by the primary cause of the syndrome. In general, therapy should reduce the cortisol secretion to normal to reduce the risk of comorbidities associated with hypercortisolism. The treatment of choice for endogenous Cushing syndrome is surgical resection of the causative tumor. The primary therapy for Cushing disease is transsphenoidal surgery, and the primary therapy for adrenal tumors is adrenalectomy.

When surgery is not successful or cannot be undertaken, as often occurs with ectopic adrenocorticotropic hormone (ACTH) or metastatic adrenal carcinoma, control of hypercortisolism may be attempted with medication. However, medication failures are common, and adrenalectomy may be indicated in ACTH-mediated Cushing syndrome. Pituitary radiation may be useful if surgery fails for Cushing disease.

In 2015, the Endocrine Society released new guidelines for Cushing syndrome:[30, 31]

  • Optimal treatment of Cushing syndrome involves direct surgical removal of the causal tumor, except in cases unlikely to cause a drop in glucocorticoids or in patients who are not candidates for surgery. Second-line therapy should be individualized.
  • Other first-line treatments include surgical resection of ectopic ACTH-secreting tumors; transsphenoidal selective adenomectomy; blocking hormone receptors in bilateral micronodular adrenal hyperplasia; and surgical removal in cases of bilateral adrenal disorders.
  • The choice of second-line treatments include medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors).
  • Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities (eg, hypertension, diabetes) by adjunctive treatments (eg, antihypertensives). Lowering cortisol levels improves hypertension, insulin resistance, dyslipidemia, and obesity.
  • In cases of benign unilateral adrenal adenoma, adrenalectomy is associated with a high cure rate in both children and adults. Adrenal carcinoma is associated with a poor prognosis; therefore, complete resection, and possibly medical treatment to stabilize cortisol levels, are necessary.
  • Long-term follow-up is recommended for osteoporosis, cardiovascular disease, and psychiatric conditions.

Pharmacotherapy

Medications used in the management of Cushing syndrome include the following:

  • Somatostatin analogs: Pasireotide

  • Adrenal steroid inhibitors: Metyrapone, ketoconazole, etomidate

  • Glucocorticoid receptor antagonist: Mifepristone

  • Adrenolytic agents: Mitotane

Pasireotide (Signifor) is a somatostatin analog that binds and activates human somatostatin receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion. It is indicated for treatment of adults with Cushing disease in whom pituitary surgery is not an option or has not been curative.

In a phase 3 trial[32]  in which 162 patients were randomly assigned to receive either 0.6 or 0.9 mg of pasireotide subcutaneously twice a day, twelve (15%) participants in the lower-dose group and 21 (26%) of the higher-dosage group met the trial's primary endpoint (free urinary cortisol levels at or below the upper limit of normal with no dose increase in 6 months). Patients with baseline levels not exceeding 5 times the upper limit of the normal range were found to achieve normal urinary free cortisol level more often than those with higher baseline levels. Other observations included improvements in systolic and diastolic blood pressure, low-density lipoprotein cholesterol, weight, and health-related quality of life. However, 48% of patients who did not have diabetes at baseline became diabetic. Seventy-three percent of the study participants experienced hyperglycemia-related adverse events, leading to 6% leaving the study and 46% requiring a new glucose-lowering medication. Cholelithiasis was also associated with its use.

In an extension treatment study of Pasireotide from an original 15-day, phase 2 study, Pasireotide was shown to maintain the effect on lowering free urinary cortisol levels in some patients up to 24 months. This supports the extended treatment of Pasireotide in some patients with Cushing’s disease.[30]

Agents that inhibit steroidogenesis, such as mitotane, ketoconazole, metyrapone, and etomidate, have been used to cause medical adrenalectomy. These medications are often are toxic at the doses required to reduce cortisol secretion. For instance, ketoconazole's prescribing information was revised to include a black box warning regarding hepatotoxicity, including fatalities and liver transplantation. Thus, medical treatment should be initiated cautiously and, ideally, in consultation with a specialist. Efficacy of these medical interventions can be assessed with serial measurements of 24-hour urinary free cortisol. Patients receiving these medications may require glucocorticoid replacement to avoid adrenal insufficiency. Patients should be counseled on the signs and symptoms of adrenal insufficiency when starting these drugs.

Metyrapone is an agent that competitively inhibits a single steroidogenic enzyme. Ketoconazole acts at several sites. In ACTH-dependent Cushing syndrome, ACTH secretion continues to stimulate steroidogenesis, which counters the actions of these medications.

Because ACTH production may persist or increase in patients with Cushing disease, radiation therapy of the pituitary is often required after unsuccessful initial therapy, either surgical or medical. These agents have higher efficacy when used in combination because they may act synergistically.

Ketoconazole has been the most popular and effective of these agents for long-term use and usually has been the agent of choice. However, the FDA has issued a warning that states clinicians should no longer prescribe ketoconazole, except to treat some life-threatening fungal infections; this is due to increased risk for severe liver injury, adrenal insufficiency, and adverse drug interactions. Ketoconazole acts on several of the P450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. A daily dose of 600-800 mg often decreases cortisol production. If this agent is ineffective at controlling hypercortisolism, the dose may be maintained while another steroid enzyme inhibitor, typically metyrapone, is initiated.

Adverse effects of ketoconazole include headache, sedation, nausea, irregular menses, decreased libido, impotence, gynecomastia, and elevated liver function tests. The drug is contraindicated during pregnancy.

Ketoconazole is less effective in patients on H2 blockers or proton-pump inhibitors because gastric acidity is required for metabolism.

Patients should be informed of the hepatotoxicity risks and monitored closely while taking this drug. Drug-to-drug interaction should also be reviewed. Certain drugs when used concurrently with Ketoconazole can increase risk of prolong QT interval or changes in drug metabolism. Concomitant use with cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, and ranolazine is contraindicated due to the possible occurrence of life-threatening ventricular arrhythmias such as torsade de pointes.

Metyrapone blocks 11-beta-hydroxylase activity, the final step in cortisol synthesis. Therapy is begun at 1 g/d divided into 4 doses and increased to a maximum dose of 4.5 g/d. Adverse effects present from increases in androgen and mineralocorticoid precursors and include hypertension, acne, and hirsutism.

Etomidate, an imidazole-derivative anesthetic agent, blocks 11-beta-hydroxylase. It is used intravenously at 0.3 mg/kg/h. Its use is limited by the requirement for administration by the intravenous route. However, it rapidly decreases cortisol concentration and may be used as an adjunct to impending surgical procedure.

Mitotane is an adrenolytic agent that acts by inhibiting 11-beta hydroxylase and cholesterol side-chain cleavage enzymes. This drug also leads to mitochondrial destruction and necrosis of adrenocortical cells in the zona fasciculata and reticularis. For this reason, it is used in treatment of adrenal cancer at doses of 2-4 g daily. Its survival benefit is unclear. It can be used in addition to radiation therapy for treatment of Cushing disease and in combination with metyrapone for treatment of ectopic ACTH secretion.

Unfortunately, mitotane is expensive, and its utility is limited by the adverse gastrointestinal and neurologic effects, including nausea, diarrhea, dizziness, and ataxia. Other adverse effects include rash, arthralgias, and leukopenia. Mitotane is taken up by adipose tissues and persists in the circulation long after discontinuation. It is a potential teratogen and can cause abortion; therefore, it is relatively contraindicated in women interested in remaining fertile.

Mifepristone (Korlym) is an antiprogestational agent, which, at high doses, competitively binds to the glucocorticoid and progesterone receptors.[33] In February 2012, the FDA approved mifepristone to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery, or are not candidates for surgery.

The effect of Mifepristone was reported in a 24-wk multicenter, open-label trial after failed multimodality therapy at 14 United States academic medical centers and three private research centers.[34] Fifty Cushing syndrome patients were enrolled in the study. Forty-three had Cushing disease, of which 42 had prior surgery, four patients had ectopic ACTH-producing tumors and three had adrenal cancer. Response was defined as at least a 25% decrease in area under the curve for glucose on a standard oral glucose tolerance test from baseline to 24 weeks, an amount considered clinically meaningful improvement in glucose control. Twenty-nine patients enrolled in the study were glucose intolerant. Sixty percent of patients met the study’s primary endpoint. There was also a statistically significant reduction in mean HbA1c over the course of the study, from 7.43% at baseline to 6.29% at study conclusion (p< 0.001). Diastolic blood pressure response, weight reduction, and waist circumference decrease were also observed in study subjects. Overall, 87% had significant improvement in clinical status. Insulin resistance, depression, cognition, and quality of life also improved.

Patients should be monitored for adrenal insufficiency, hypokalemia, prolonged QT interval. Use of mifepristone will result in termination of pregnancy. When Mifepristone is used in women with Cushing’s syndrome, pregnancy must be excluded prior to initiation of therapy. Nonhormonal form of contraception must be used during treatment and for 1 month after stopping therapy.

Agents that decrease CRH or ACTH release have been studied for the treatment of Cushing disease. Such agents include Carbegoline, bromocriptine, Cyproheptadine, valproic acid, and octreotide.

Treatment options for patients with persistent or recurrent Cushing disease have included pituitary irradiation and repeat surgery. A small study found that a percentage of such patients respond to cabergoline therapy.[35] Longer-term follow-up and a larger number of patients are needed to confirm these encouraging preliminary results.

An ongoing phase 3 study is being conducted to confirm long-term efficacy and safety of agent LCI699 for the treatment of patients with Cushing disease.[36] LCI699 is a potent inhibitor of 11β-hydroxylase, which catalyzes the final step of cortisol synthesis. In a prior multicenter proof-of-concept 10-week study in which 12 patients were enrolled and completed the study, all 12 patients achieved urinary free cortisol level less than or equal to upper limit of normal or a 50% or greater decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. No serious side effects were reported. Common side effects were headache, fatigue, and nausea.[37]

Surgical Therapy

The treatment of choice for endogenous Cushing syndrome is surgical resection of the causative tumor. The primary therapy for Cushing disease is transsphenoidal surgery, and the primary therapy for adrenal tumors is adrenalectomy.

Other surgical interventions include the following:

  • Bilateral adrenalectomy

  • Unilateral adrenalectomy

  • Resection of carcinomas

Patients with endogenous Cushing syndrome who undergo resection of pituitary, adrenal, or ectopic tumors should receive stress doses of glucocorticoid in the intraoperative and immediate postoperative period. Typically, hydrocortisone is infused intravenously, either continuously (10 mg/h) or in boluses (80-100 mg q8h) starting prior to surgery and for the first 24 hours afterward. If the patient does well, intravenous glucocorticoid replacement may be tapered over 1-2 days and replaced with an oral formulation. The rate of steroid taper may be slowed if severe preoperative hypercortisolism was present. In the event of pituitary destruction or bilateral adrenalectomy, lifelong glucocorticoid replacement is necessary. Lifelong mineralocorticoid replacement is also necessary in those patients who undergo bilateral adrenalectomy.

Cushing disease

Treatment of choice for classic Cushing disease is transsphenoidal surgery by an experienced neurosurgeon. The goal of surgery is to remove the adenoma, preserving as much pituitary function as possible.

  • The more extensive the mass and the resulting resection, the greater the risk for loss of pituitary function. Successful amelioration of hypercortisolism occurs in 60-80% of cases. Lateralization of ACTH secretion via IPS catheterization and sampling is sometimes helpful in difficult cases.

  • Pituitary irradiation is employed when transsphenoidal surgery is not successful or not possible. The procedure is less successful than surgery in adults, with a 40-50% cure rate in adults and 85% cure rate in children. Late-onset adverse effects include hypopituitarism.

  • Bilateral adrenalectomy is an option if transsphenoidal surgery, pituitary irradiation, and medical therapy fail or if rapid normalization of cortisol levels is required. The patient then requires lifelong glucocorticoid and mineralocorticoid therapy.

  • Individuals who undergo bilateral adrenalectomy might develop Nelson syndrome, which is symptomatic enlargement of the pituitary gland and adenoma. This may occur in one quarter to one half of adults not treated with pituitary irradiation and in as many as one quarter of patients pretreated with radiation therapy.

Ectopic adrenocorticotropic production

Surgical resection of the source of ACTH production may not always be possible. Ectopic ACTH-producing tumors are often difficult to locate.

Medical therapy or bilateral adrenalectomy may be required.

Adrenal source

Adenomas may be removed with unilateral adrenalectomy, often with a laparoscopic approach.

Carcinomas should be resected for possible cure and palliation.

Micronodular or macronodular hyperplasia causing Cushing syndrome may be treated effectively by bilateral adrenalectomy. Unilateral or subtotal adrenalectomy may lead to recurrence.

Consultations

Effective diagnosis and management of Cushing disease is often facilitated by involvement of an endocrinologist and the appropriate experienced neurosurgeon.

Complications

The successful treatment of hypercortisolemia, with the accompanying recovery of the immune system, permits the subsequent manifestation of autoimmune disease. A study by Tatsi et al found that following the resolution of hypercortisolemia in 129 children with endogenous Cushing syndrome, 10 patients (7.8%) were found to have a new autoimmune disorder or related condition. Specifically, these individuals were diagnosed—6 to 19 months after treatment—with celiac disease, psoriasis, Hashimoto thyroiditis, Graves disease, optic neuritis, skin hypopigmented lesions/vitiligo, allergic rhinitis/asthma, or neuropathy (with this last responding to glucocorticoid therapy).[38]

 

Medication

Medication Summary

The goal of pharmacotherapy is to reduce morbidity and prevent complications.

Somatostatin Analogs

Class Summary

Somatostatin analogs bind and activate human somatostatin receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion.

Pasireotide (Signifor)

Pasireotide is a cyclohexapeptide somatostatin analog that binds to human somatostatin receptors (HSSTs) 1, 2, 3, 4 and 5. This action results in the inhibition of ACTH secretion, which in turn leads to decreased cortisol secretion. It is indicated for treatment of adults with Cushing disease in whom pituitary surgery is not an option or has not been curative.

Adrenal steroid inhibitors

Class Summary

These agents inhibit key steps in the synthesis of adrenal glucocorticoids.

Metyrapone (Metopirone)

Inhibitor of endogenous adrenal corticosteroid synthesis. Inhibits 11-B-hydroxylation reaction in the adrenal cortex.

Ketoconazole

Ketoconazole is an imidazole broad-spectrum antifungal agent that inhibits cytochrome P450 enzyme system and 17,20-lyase. These enzymes are involved in the synthesis and catabolism of steroids. Ketoconazole may also inhibit the pituitary corticotroph function, which in turn inhibits ACTH secretion.

Etomidate (Amidate)

Etomidate, an imidazole-derivative anesthetic agent, decreases corticosteroid synthesis in the adrenal cortex by reversibly inhibiting 17-20 yase and 11-beta-hydroxylase at non-hypnotic doses. It is used intravenously at 0.3 mg/kg/h. Its use is limited by the requirement for administration by intravenous route. However, it rapidly decreases cortisol concentration and may be used as an adjunct to impending surgical procedure.

Antineoplastic agents, other

Class Summary

Agents in this class that decrease cortisol production and alter the peripheral metabolism of steroids may reduce morbidity.

Mitotane (Lysodren)

Mitotane is an adrenolytic agent that acts by inhibiting 11-beta hydroxylase and several cholesterol side-chain cleavage enzymes. This drug also leads to mitochondrial destruction and necrosis of adrenocortical cells in the zona fasciculata and reticularis.

Cortisol Receptor Blockers

Class Summary

Cortisol receptor blockers inhibit the effect of cortisol at the glucocorticoid receptor.

Mifepristone (Korlym, Mifeprex, Ru486)

Mifepristone is an antiprogestational agent, which, at low doses competitively binds to the intracellular progesterone receptor while, at high doses, competitively binds to the glucocorticoid receptor. It helps to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery, or are not candidates for surgery.

 

Questions & Answers

Overview

What is the clinical background of endogenous Cushing syndrome?

What is the pathophysiology of endogenous Cushing syndrome?

What are the causes of endogenous glucocorticoid overproduction in ACTH-independent Cushing syndrome?

What are the causes of endogenous glucocorticoid overproduction in ACTH-dependent Cushing syndrome?

How common is endogenous Cushing syndrome?

What is the prognosis of endogenous Cushing syndrome?

What are potential complications of endogenous Cushing syndrome?

What are the prognostic findings in ectopic Cushing syndrome?

What education should be provided to patients with endogenous Cushing syndrome?

Presentation

What is the clinical history of endogenous Cushing syndrome?

What are the signs and symptoms of endogenous Cushing syndrome?

How is obesity characterized in endogenous Cushing syndrome?

What are the skin manifestations of endogenous Cushing syndrome?

What are the cardiovascular and renal findings in endogenous Cushing syndrome?

What are the GI findings in endogenous Cushing syndrome?

What are the endocrine findings in endogenous Cushing syndrome?

What are the musculoskeletal findings in endogenous Cushing syndrome?

What are the neuropsychological findings in patients with endogenous Cushing syndrome?

Which findings suggest adrenal crisis in endogenous Cushing syndrome?

DDX

How are endogenous Cushing syndrome and pseudo-Cushing syndrome distinguished?

What are the differential diagnoses for Endogenous Cushing Syndrome?

Workup

What are the approach considerations in the workup of endogenous Cushing syndrome?

Which lab studies can provide a definitive diagnosis of endogenous Cushing syndrome?

What are the screening tests for endogenous Cushing syndrome?

What is the role of urinary free cortisol (UFC) measurement in the diagnosis of endogenous Cushing syndrome?

What is the role of the dexamethasone suppression test in the workup of endogenous Cushing syndrome?

How accurate is late-night salivary cortisol testing in the diagnosis of Cushing syndrome?

What are the possible confounders in the lab results in endogenous Cushing syndrome?

What is the next step once a diagnosis of endogenous Cushing syndrome is established?

Which lab studies are used to determine the etiology of endogenous Cushing syndrome?

Which imaging studies are indicated in the workup of endogenous Cushing syndrome?

Which clinical procedures are indicated in the workup of endogenous Cushing syndrome?

Treatment

What is the treatment approach in endogenous Cushing syndrome?

What are the Endocrine Society treatment guidelines for endogenous Cushing syndrome?

Which medications are used in the treatment of endogenous Cushing syndrome?

What is the role of pasireotide in the treatment of endogenous Cushing syndrome?

Which steroidogenesis inhibitors are indicated in the treatment of endogenous Cushing syndrome?

What are the adverse effects of ketoconazole in the treatment of endogenous Cushing syndrome?

What is the role of etomidate in the treatment of endogenous Cushing syndrome?

What is the role of mifepristone in the treatment of endogenous Cushing syndrome?

What are the treatment options for persistent or recurrent Cushing disease?

What is the treatment of choice for endogenous Cushing syndrome?

What are the surgical options for the treatment of endogenous Cushing syndrome?

What treatment is indicated in patients with endogenous Cushing syndrome who undergo tumor resection?

What is the treatment of choice for classic Cushing disease?

What are the treatment options for ectopic ACTH-producing tumors in endogenous Cushing syndrome?

What surgical treatment is indicated on the adrenal gland in endogenous Cushing syndrome?

Which specialist consultations are indicated in the treatment of endogenous Cushing syndrome?

What are the potential complications of treatment for endogenous Cushing syndrome?

Medications

What is the goal of drug treatment of endogenous Cushing syndrome?

Which medications in the drug class Cortisol Receptor Blockers are used in the treatment of Endogenous Cushing Syndrome?

Which medications in the drug class Antineoplastic agents, other are used in the treatment of Endogenous Cushing Syndrome?

Which medications in the drug class Adrenal steroid inhibitors are used in the treatment of Endogenous Cushing Syndrome?

Which medications in the drug class Somatostatin Analogs are used in the treatment of Endogenous Cushing Syndrome?