Pituitary Center

Diagnosis and Treatment of Cushing's Syndrome

Cushing's syndrome is a hormonal disorder caused by high levels of the hormone cortisol. Elevated levels of cortisol are also referred to as hypercortisolism. True Cushing's syndrome is uncommon, and an estimated 10 to 15 of every million people are affected each year.

Treatment at Stanford

Patients can receive an evaluation and treatment for Cushing's syndrome at the Stanford Pituitary Center.

Signs & Symptoms

The signs and symptoms of Cushing's syndrome are variable, but usually include changes in fat distribution. 

Diagnosis

Laboratory workup is performed in a patient who has signs and/or symptoms compatible with Cushing's syndrome. Tests include:

  1. 24-Hour Urinary Free Cortisol Level: This is the most specific diagnostic test. The patient will collect urine over a 24-hour period. An elevated urinary cortisol level suggests Cushing's syndrome. Usually, this test needs to be repeated several times for confirmation.
  2. 1 mg overnight dexamethasone suppression test: In this test, the patient takes 1 mg of dexamethasone and a fasting cortisol is drawn at 8 a.m. the next day. If the blood cortisol level is not suppressed, Cushing's syndrome is suggested.
  3. Late night salivary cortisol test: In this test, cortisol values in saliva are measured. Between 11 p.m. and midnight, the patient places a cotton swab in the mouth, and then places the moist cotton into a tube. An elevated salivary cortisol late at night may suggest the presence of Cushing’s syndrome.

Cause of Cushing's syndrome

Once hypercortisolism is confirmed, the next step is to determine the cause. Normally, the pituitary gland produces ACTH (Adrenocorticotropic hormone), which circulates in the blood and stimulates the adrenal glands to produce cortisol.  Right above the pituitary gland, in the base of the brain, is the hypothalamus. The hypothalamus produces CRH (Corticotropin releasing hormone), which stimulates the pituitary gland to produce ACTH. Therefore, hypercortisolism can arise from too much CRH, ACTH; or from excessive production of cortisol by the adrenal gland. 

The causes are divided into ACTH dependent and ACTH independent sources. 

Next Steps

  1. ACTH level: This test helps distinguish an adrenal source (ACTH independent) from an ACTH dependent cause. A very low ACTH level suggests the problem is coming from the adrenal glands, and not the pituitary gland.
  2. High Dose Dexamethasone Suppression Test: This test helps to distinguish patients with excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumors. Patients are given 2 mg dexamethasone by mouth every 6 hours for 2 days. A 24-hour urine collection for cortisol is performed on the second day of the test. Cortisol suppression suggests a pituitary tumor. A similar test is performed using a single dose of 8 mg at midnight, and a fasting blood draw for cortisol the next morning.
  3. Petrosal Sinus Sampling: This test may be required to separate pituitary from ectopic causes of ACTH-dependent Cushing's syndrome in patients with a normal pituitary gland on brain MRI scan. Catheters are placed through a vein in the upper thigh/groin region and are threaded through the blood vessels to the petrosal sinuses, which surround the pituitary gland. ACTH levels higher in the petrosal sinuses than in a forearm vein indicate the presence of a pituitary adenoma (Cushing's disease); similar levels suggest ectopic ACTH syndrome.

Treatment

The treatment depends on the cause of the Cushing's syndrome.  

Cushing's disease

For Cushing's disease (Cushing's syndrome due to a pituitary tumor), the treatment is surgical removal of the tumor, known as transsphenoidal surgery. Using a special microscope and very fine instruments, the surgeon approaches the pituitary gland through a nostril. Because this is an extremely delicate procedure, patients are often referred to centers specializing in this type of surgery.

The success, or cure, rate of transsphenoidal surgery procedure is over 80% when performed by a surgeon with extensive experience. If surgery fails, it can be repeated, often with good results. After curative pituitary surgery, cortisol levels may drop to very low levels. Patients are often given a synthetic form of cortisol (such as hydrocortisone or prednisone) as replacement therapy, which is usually stopped within the year. 

Ectopic Cushing's syndrome

If the evaluation suggests the presence of ectopic Cushing's syndrome, then the treatment is directed to the source. For example, if a carcinoid tumor in the lung is detected, then there are several options for therapy, including surgical excision.

Adrenal Growth

If an adrenal growth is the underlying cause, then surgical removal of the abnormal adrenal gland is necessary.

Treatment Options if the Initial Therapy is Not Effective

If the patient has Cushing’s syndrome due to excess ACTH levels and the primary tumor has not been resected, there are several next step options. Repeat surgery can be considered to try again to remove the tumor. Surgical removal of both adrenal glands (bilateral adrenalectomy) can also be performed, as this will result in normalization of the effects of Cushing’s syndrome. This therapy will lead to required replacement of adrenal gland hormones, including cortisol and a medication that controls sodium and potassium balance.

Another option is the use of medical therapy. There are several medical therapies that work by reducing adrenal gland production of cortisol. These medications include ketoconazole, metyrapone, and aminoglutethamide.

There are several new medical agents recently available that may help further with medical control of Cushing’s syndrome. Korlym (mifepristone) is a cortisol blocker. This medication, given as a pill, blocks cortisol wherever it goes, and can lead to improvement in appearance and medical consequences in the majority of people.

Another new medication, Signifor (pasireotide) is a new form of somatostatin analog that works at the primary tumor and reduces ACTH ion approximately one-third of patients.

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