Cushing’s syndrome occurs when the adrenal glands produce too much cortisol for a long time. It is a rare disease; an estimated 2-3 of every million people are affected each year. Most patients are adults aged 20 to 50. Cushing’s syndrome can result from excessive production of the adrenocorticotrophin hormone (ACTH). ACTH is a hormone that is normally produced by the pituitary gland and controls the production of cortisol by the adrenal glands. In other patients with Cushing’s syndrome a tumor on the adrenal gland makes too much cortisol, and ACTH levels are not increased.

What is ectopic Cushing’s syndrome?

Excessive ACTH can be made by a tumor in the pituitary gland (called Cushing’s disease) or by a tumor located outside of the pituitary gland (called ectopic ACTH secretion). Ectopic ACTH-secreting tumors are more common in men than women. They can be benign or malignant, but malignancy risk is usually low. The most common ACTH-producing tumors are found in the chest in up to 52% of patients. ACTH can be produced by other tumors such as thymomas in 5% of patients, pancreatic islet tumors 1% of patients, and medullary carcinomas of thyroid in 2% of patients.

What are the symptoms of Cushing’s syndrome?

The symptoms of Cushing’s syndrome result from excess cortisol. The physical changes include weight gain, rounded face, increased fat around the neck, decreased strength and thinning of the arms and legs. The skin may become fragile and thin, bruise easily and heal slowly. Reddish-purple stretch marks frequently appear on the abdomen, thighs, buttocks, arms and breasts. Patients may develop infections because excess cortisol blocks the immune system. The bones become fragile and may break. Many patients complain of severe fatigue and muscle weakness. Blood pressure and blood sugar levels can increase. People with excess cortisol can develop blood clots. Many patients have psychiatric symptoms that range from loss of emotional control to depression and paranoia. Sleep disturbances are common. Women may have excess hair growth, and irregular menstrual periods. Patients have less desire for sex. The symptoms of Cushing’s syndrome caused by pituitary tumors and by ectopic ACTH-producing tumors are indistinguishable in many cases and not all patients have all of the symptoms. However, the development of severe symptoms over a few months is more likely to be caused by ectopic ACTH secretion.

How is Cushing’s disease distinguished from ectopic ACTH syndrome?

After it is clear that excess ACTH secretion is causing Cushing’s syndrome, biochemical and imaging tests are used to distinguish a pituitary tumor from ectopic ACTH-producing tumors.

Biochemical testing

Pituitary tumors tend to respond to high doses of dexamethasone and corticotropin-releasing hormone (CRH). Dexamethasone, a synthetic cortisol-like drug, normally signals the pituitary gland to reduce the secretion of ACTH.

Blood and urine levels of cortisol usually fall after taking dexamethasone in patients with Cushing’s disease but not those with ectopic ACTH production. Poor function of kidneys and/or liver, and use of certain medicines can cause a false result for this test.

The CRH stimulation test also can distinguish between patients with pituitary adenomas and those with ectopic ACTH syndrome. Patients are given an injection of CRH, a synthetic substance that stimulates a pituitary tumor to release ACTH.

Blood levels of ACTH and cortisol usually go up in patients with a pituitary tumor, but not in patients with ectopic ACTH syndrome.

Pituitary Imaging

Magnetic resonance imaging (MRI) of the pituitary gland can help make the diagnosis of Cushing’s disease if the tumor is more than 6 mm (about ¼ inch) in size. Smaller benign tumors are seen in the pituitary gland in 10% of healthy people. However, MRI does not show a pituitary tumor in about 50% of patients with Cushing’s disease.

Inferior petrosal sinus sampling (IPSS)

Petrosal sinus sampling is a standard investigation of patients with excessive ACTH production, unless all other tests point to a pituitary tumor. IPSS is done by sampling blood in the petrosal sinuses, the veins that drain the pituitary gland, using catheters put in a vein in the groin region and directed up into the petrosal sinus. For best results, blood is taken from both petrosal sinuses and another body vein before and after CRH is given. Levels of ACTH are measured and the results are compared. If ACTH levels are much higher in the petrosal sinuses than in the other vein, a pituitary adenoma is very likely; if all levels are similar, an ectopic ACTH-producing tumor is most likely. Petrosal sinus sampling correctly identifies pituitary or ectopic tumor in about 95% of patients. The success of IPSS depends on the skill of the radiologist and should be performed by an experienced radiologist in large medical centers only.

How is the tumor producing ectopic ACTH found?

Finding the exact location of the tumor making extra ACTH is necessary for successful surgical treatment. Most of these tumors are very small, and they may occur in the neck, chest, abdomen and/or pelvis. The currently available imaging studies include computed tomography (CT), MRI and octreotide imaging (Octreoscan). Octreoscan uses a radioactive compound, Indium-111 pentetreotide (octreotide), approved by the Food and Drug Administration. When octreotide attaches to a tumor it can be seen.

No single imaging modality can identify and localize every tumor that causes Cushing’s syndrome. Improved imaging techniques, including thinner slices on CT and updated MRI procedures are getting better at detecting smaller tumors. By using all imaging studies together about half of the tumors can be identified within one year, but localization may be delayed up to 12 years and repeated imaging is recommended at 6-12 month intervals. There are research studies that look to see if other kinds of imaging, using higher doses of Octreotide or various PET scans, may help in finding the tumors.

Treatment of ectopic ACTH syndrome

Surgery

If a tumor is found and can be removed, surgery is the best treatment and can cure up to 80% of cases. A cure is most likely after removal of small carcinoid tumors. Removal of the tumor leads to low cortisol levels that require cortisol replacement therapy for up to 2 years.

Medical treatment

Medicines that reduce cortisol production are used when a tumor cannot be found or cannot be removed completely. They are sometimes used before surgery to improve healing of the wound. In the United States, the available medications are ketoconazole, metyrapone and mitotane. Mifepristone is a drug that does not reduce synthesis of cortisol but blocks the action of cortisol in the body. Its use in patients with Cushing’s syndrome is currently being studied.

Adrenalectomy

Surgical removal of the adrenal glands (bilateral adrenalectomy) is an alternative to drug therapy that may be preferred by some patients. It is the treatment of choice for patients in whom all other therapies have failed and may be recommended in patients with very severe symptoms who need a fast cure. The procedure is generally safe and is performed laparoscopically. The disadvantage of this therapy is the requirement for lifelong replacement therapy with adrenal hormones.

It is essential that patients treated with medications or adrenalectomy continue with imaging studies to localize the tumor, because of the small chance of malignancy.

Conclusion

Because Cushing’s syndrome is potentially fatal if untreated, people with this condition should have regular medical care and follow their treatment plan closely. Surgery can be curative if tumor is found. If tumor is not found, Cushing syndrome should be treated with medication or adrenalectomy as needed.

Authors: Dr. Marina Zemskova and Dr. Lynnette Nieman (Spring, 2008)

Editor’s Note: Dr. Zemskova is an Associate Investigator from Reproductive Biology and Medicine Branch at National Institute of Child Health and Human Development. Dr. Nieman is a Senior Investigator from Reproductive Biology and Medicine Branch at National Institute of Child Health and Human Development.