Patient education: Cushing syndrome treatment (Beyond the Basics)

CUSHING SYNDROME OVERVIEW — Cushing syndrome occurs when there is an excess of cortisol, a hormone produced by the adrenal glands (figure 1). This can happen because the pituitary gland releases too much of the hormone corticotropin (ACTH), which stimulates the adrenal glands to make cortisol. It can also happen if an adrenal gland tumor makes too much cortisol or if a person takes large doses of a cortisol-like medication ("glucocorticoid") for a long time.

The treatment of Cushing syndrome depends upon the underlying cause. Treatment can reverse most of the symptoms of Cushing syndrome, although treatment must be managed carefully to minimize the possibility of permanent hormone deficiency and treatment-related side effects.

This article discusses the treatment of Cushing syndrome. The causes, symptoms, and diagnosis of Cushing syndrome are discussed separately. (See "Patient education: Cushing syndrome (Beyond the Basics)".)

CUSHING SYNDROME DUE TO MEDICATIONS — When Cushing syndrome is caused by glucocorticoids (like prednisone) that are taken for another medical condition (eg, asthma or rheumatoid arthritis), stopping the glucocorticoids resolves symptoms. However, in most cases, the body has adapted to the presence of the glucocorticoids, and they must be tapered off gradually to allow the pituitary and adrenal glands to resume normal function.

Some conditions require long-term glucocorticoid therapy. In this situation, an alternate plan for managing the signs and symptoms of Cushing syndrome is necessary.

TREATMENT OF CUSHING DISEASE — When Cushing syndrome results from a corticotropin (ACTH)-producing tumor of the pituitary gland (Cushing disease), treatment may include surgery, radiation, or medication to lower cortisol levels.

Surgery — Surgical removal of a small pituitary adenoma (benign tumor) is called "transsphenoidal adenomectomy." The pituitary is located at the base of the brain. It is possible to access this area through the gums above the upper front teeth or the nose (figure 2).

Using special instruments, the surgeon makes an incision in one of these areas (figure 3). The incision is extended through the sphenoid sinus, allowing the surgeon to see and remove the adenoma with aid of a microscope or endoscope (a thin tube with a light and camera on the end). This type of surgery permanently cures Cushing syndrome in 60 to 70 percent of people.

Sometimes an adenoma cannot be identified; in these cases, some surgeons remove half of the pituitary gland (hemihypophysectomy); other surgeons remove most of the pituitary gland (85 to 90 percent, subtotal hypophysectomy), to be certain that the tumor has been removed.

The downside of removing the gland is that it can result in reduced pituitary function and interfere with ovulation (in females) and sperm production (in males). These problems may cause infertility (trouble getting pregnant or getting a partner pregnant). Lifelong replacement of one or more hormones also may be necessary after this surgery.

Medical therapy — When pituitary surgery is unable to restore normal cortisol production, several drugs can be used to control cortisol production. Cabergoline, a drug used mostly to treat prolactin-secreting pituitary tumors, can normalize ACTH and cortisol production in approximately 30 percent of people. Similarly, pasireotide can normalize ACTH and cortisol in 20 to 25 percent of people with Cushing disease.

Mifepristone is a medication that can decrease the effects of excess cortisol on glucose, but its role in long-term therapy of Cushing disease is not well known. Other drugs that block production of cortisol, such as ketoconazole, metyrapone, or mitotane, also can be used to reduce high levels of cortisol while waiting for more definitive treatment.

Radiation — Radiation can be a useful treatment when pituitary tumors cannot be completely removed by surgery, if surgery is not possible, or if Cushing disease recurs. Radiation of pituitary tumors reduces cortisol levels in up to 80 percent of adults and most children with Cushing disease (pituitary adenoma that makes ACTH). Because this cortisol-lowering effect takes time (3 months to 10 years), medications that lower adrenal cortisol production may be given while waiting for the effects of radiation. These medications include ketoconazole and metyrapone.

Adrenalectomy — Surgical removal of the adrenal glands (adrenalectomy) is a final measure that is sometimes recommended if other treatments are not successful. It may be chosen earlier if the person with Cushing disease is extremely ill and the high cortisol levels need to be normalized quickly. Adrenalectomy stops excess cortisol production but requires immediate initiation of lifelong, daily adrenal hormone replacement therapy with glucocorticoid and mineralocorticoid. (See "Patient education: Adrenal insufficiency (Beyond the Basics)", section on 'Hormone deficiencies'.)

ECTOPIC ACTH SYNDROME — In some people with corticotropin (ACTH)-producing, nonpituitary tumors found in other parts of the body, surgical removal of the tumor eliminates the symptoms of Cushing syndrome. These tumors are usually in the lung. When complete surgical removal is not possible, treatment with medications that reduce adrenal cortisol production (ketoconazole and metyrapone) or surgical removal of the adrenal glands (adrenalectomy) may be necessary to lower cortisol levels.

ADRENAL GLAND TUMORS — Adrenal tumors are usually treated with surgical removal of the affected adrenal gland, leaving the opposite adrenal gland for cortisol production. If the tumor is an adenoma (a benign tumor), surgery always cures the associated Cushing syndrome.

If the tumor is a carcinoma (a cancerous tumor), surgery is the only way to cure the cancer; radiation, chemotherapy, and treatment with mitotane (a medication that is toxic to cortisol-producing cells) are usually required to lower cortisol levels. After these treatments, daily adrenal hormone replacement is usually necessary. (See "Patient education: Adrenal insufficiency (Beyond the Basics)", section on 'Hormone deficiencies'.)

NODULAR ADRENAL HYPERPLASIA — Treatment of nodular adrenal hyperplasia (a very rare disorder) usually requires surgical removal of both adrenal glands. Before surgery, medications that inhibit adrenal enzymes (ketoconazole or metyrapone) can lower cortisol levels.

After surgery, daily adrenal hormone replacement is usually necessary. (See "Patient education: Adrenal insufficiency (Beyond the Basics)", section on 'Hormone deficiencies'.)

CUSHING SYNDROME DURING PREGNANCY — Cushing syndrome is rare during pregnancy. The excess cortisol production is usually caused by an adrenal tumor, most often an adenoma (a benign tumor), although some people have a pituitary tumor (Cushing disease).

Most of the excess cortisol does not cross the placenta and directly affect the fetus, but high cortisol levels can reduce placental function so that the fetus may be smaller than expected, and pregnancy loss (miscarriage) or premature birth may occur. Untreated Cushing syndrome poses a risk to a pregnant person because it can lead to pregnancy complications such as high blood pressure and gestational diabetes, which also are associated with pregnancy loss and premature birth.

When Cushing syndrome is caused by an adrenal tumor or a benign pituitary tumor (Cushing disease), surgical removal of the adrenal or pituitary gland during the middle trimester can lower the abnormal cortisol levels without affecting the pregnancy.

WHAT TO EXPECT AFTER TREATMENT — If treatment removes the source of excess cortisol, most of the symptoms of Cushing syndrome disappear within 12 months. Osteoporosis begins to improve within six months and continues to improve over several years. With successful treatment, children with Cushing syndrome can regain much of their lost bone density and growth. Some degree of high blood pressure or glucose intolerance may persist.

While cognitive symptoms (such as difficulty focusing or problems with memory) typically improve after treatment, they may not resolve completely. Talk with your health care provider if you have persistent symptoms after treatment.

WHERE TO GET MORE INFORMATION — Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our website (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Cushing syndrome (The Basics)
Patient education: Adrenal cancer (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient education: Cushing syndrome (Beyond the Basics)
Patient education: Adrenal insufficiency (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Causes and pathophysiology of Cushing syndrome
Epidemiology and clinical manifestations of Cushing syndrome
Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia
Diagnosis and management of Cushing syndrome during pregnancy
Dexamethasone suppression tests
Establishing the cause of Cushing syndrome
Establishing the diagnosis of Cushing syndrome
Overview of the treatment of Cushing syndrome
Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation
Medical therapy of hypercortisolism (Cushing's syndrome)

The following organizations also provide reliable health information.

●National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)

●Hormone Health Network

(www.hormone.org available in English and Spanish)

●National Institute of Diabetes and Digestive and Kidney Diseases

(www.niddk.nih.gov/health-information/endocrine-diseases/cushings-syndrome)

●National Adrenal Diseases Foundation

(www.nadf.us)

●Pituitary Tumor Network Association

(www.pituitary.org)

●Cushing Support & Research Foundation

(http://csrf.net/)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.