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Cushing's syndrome

Cushing's syndrome, also known as hypercortisolism, occurs when a person's tissues are exposed to an excess of the hormone cortisol.

When the appropriate amount of cortisol is released by the adrenal glands, it helps regulate blood pressure, energy production, the ability to fight disease, and how the body maintains itself and responds to stress. But too much cortisol can alter the normal function of these processes, resulting in the symptoms of Cushing's syndrome.

Causes

The body produces too much cortisol. Too much cortisol is produced when the pituitary and adrenal glands are not working properly. This can be caused by:

Growths on the adrenal glands, that may or may not be cancerous, can cause the adrenal glands to release extra cortisol.

1. Use of exogenous steroids: Steroid hormone therapy for a long time as treatment for another disorder or disease, for example, taking a steroidal anti-inflammatory for arthritis.

2. Endogenous:

   • Adrenocortical tumors:

• A noncancerous tumor of the pituitary gland that produces increased amounts of the hormone adrenocorticotropin (ACTH). This, in turn, prompts the adrenal glands to produce too much cortisol. This form of Cushing's syndrome is known as "Cushing's disease."
• Adrenocortical cancer
• Certain types of cancerous tumors in other parts of the body can produce ACTH, causing the adrenal glands to produce extra cortisol.

• ACTH secreting pituitary adenomas
• Ectopic ACTH production by nonpituitary tumors.

Clinical suspicion

Hypertension (especially young individuals) and diabetes and overweight (centripetal) particularly in the presence of :

1. Proximal muscle weakness.

2. Pigmented striae.

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Symptoms and signs

Cushing's syndrome is fairly rare. For every one million people, 2-5 new cases are diagnosed each year, with about 10 percent of these being children and teenagers.

Symptoms include

• weight gain, particularly of the trunk and face with sparing of the limbs, 'moon' face,
• excess sweating,
• thin and easily bruised skin, purple striae on the trunk and legs,
• proximal muscle weakness (hips, shoulders),
• hirsutism.
• The excess cortisol may also affect other endocrine axes and cause, for example, reduced libido, impotence, and infertility.
• Patients frequently suffer various psychological disturbances.

Signs include

• persistent hypertension and
• impaired ability to regulate glucose (typically hyperglycaemic and often with frank diabetes)

Most children and teenagers with Cushing's syndrome will show several of the following:

• extreme weight gain
• growth retardation
• missed periods in teenage girls
• excess hair growth
• acne
• reddish-blue streaks on the skin
• high blood pressure
• tiredness and weakness
• either very early or late puberty

Adults with the disease may also have symptoms of extreme weight gain, excess hair growth, high blood pressure, and skin problems. In addition, they may show:

• muscle and bone weakness
• moodiness, irritability, or depression
• sleep disturbances
• high blood sugar
• menstrual disorders in women and decreased fertility in men

Diagnosis

Doctors review the patient's medical records and do a physical exam. If these suggest Cushing's syndrome, more tests are done. A definite diagnosis involves:

• Seeing if there is too much cortisol in the body, and
• Discovering the cause of extra cortisol. A urine test measures how much cortisol is being produced. If the level indicates Cushing's syndrome, the doctor will order other tests to discover the cause. These may include:
  • Biochemistry tests. The dexamethasone suppression test involves taking a man-made cortisol by mouth for several days during which time cortisol levels in the blood and urine are measured. The CRH stimulation test involves receiving an injection of the corticotropin-releasing hormone (CRH) followed by a blood test to see if there is a rise in the levels of ACTH and cortisol.
  • Scans. This may include computerized tomography (CT) and magnetic resonance imaging (MRI) scans of the pituitary and adrenal glands, chest, and abdomen; ultrasound imaging of the adrenal glands; chest x-rays; and perhaps a radioisotope procedure called an iodocholesterol scan.
  • Catheterization procedures. Samples of the blood leaving the pituitary gland are tested to see if the pituitary is causing the high level of ACTH.

Confirm the diagnosis by any of the following methods.

1. 24hr urinary cortisol
2. Overnight dexamethazone suppression test.
3. Other screening tests include cortisol circadian rhythm & low dose dexamethasone suppresion test but require the patient to be admitted.

After establishing the diagnosis with one of the tests above a high dose dexamethasone suppression test suppresses pituitary Cushing's but not other causes. A plasma ACTH level will then determine if ACTH plays a role in the pathogenesis. CT or MRI of the pituitary or adrenal gland to search for an adenoma. A chest x-ray is essential to exclude bronchial carcinoma or carcinoid.

N.B. Cushing's disease refers to hypercorticism secondary to ACTH secreting pituitary adenoma.

Treatment

Whatever the underlying cause, cortisol hypersecretion should be controlled prior to surgery or radiotherapy to decrease the morbidity and mortality associated with operating on unprepared patients.

If an adrenal adenoma is identified it may be removed by surgery. Post-operatively most patients will require steroid replacement at least in the interim as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed replacement with hydrocortisone or prednisolone is imperative.

In those patients not suitable for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol sythesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy. In iatrogenic Cushing's, dose adjustment may be sufficient or it may be necessary to change to another type of immunosuppresive medication.

The drug of choice is metyrapone. The mean level of plasma cortisol during the day should be reduced to 11-15 ug/dL. Alternatively ketokonazole or aminoglutethamide may be used.

The definitive treatment is surgical removal of the source of hypersecretion, whether it be pituitary, adrenal or of ectopic origin.

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