Target Pituitary

What are Cushing's syndrome and Cushing's disease?

When too much cortisol is present in the body, it is called Cushing’s syndrome, regardless of the cause. Cortisol is made by the adrenal glands which are stimulated by ACTH, which is produced in pituitary gland. When the cause of the excess cortisol is excess ACTH made by a pituitary tumor, the condition is called "Cushing’s disease". Rarely, excess ACTH can be produced by a tumor elsewhere in the body, which is referred to as "ectopic" production of ACTH. Another cause of Cushing's syndrome can be taking excess steroid medications. Finally, excess production of cortisol by an adrenal tumor can lead to Cushing's syndrome.

These conditions result in prolonged exposure of the body's tissues to high levels of the hormone cortisol. Features of excess cortisol include weight gain, especially centrally, fatigue, easy bruisability, excess facial and body hair growth in women (termed hirsutism), susceptibility to infection, depression, menstrual irregularities in women, decreased libido and erectile dysfunction in men, high blood pressure, diabetes mellitus, and weak and brittle bones (osteoporosis). Many of these are non-specific, meaning that people who have them usually do not have Cushing's syndrome. Most patients who do have Cushing's syndrome have some, but not all, of these features. There is a characteristic appearance in many patients who have excess cortisol which includes a round, reddened face, excess fat pad in the back of the neck ("buffalo hump"), excess fat in the collarbone area, central weight gain, primarily in the abdomen, with relative thinning of the arms and legs, and abdominal stretch marks. In the majority of cases, it can be cured, with improvement in all of these features.

Cushing's Syndrome - A Patient's Story
Cushings Before Surgery

Before surgery

Cushings After Surgery

After successful surgery

Cushing's Information

Target Pituitary

  • What are the symptoms?
    Cushing's Disease (ACTH secreting adenoma)

    Symptoms vary, but most people have central (upper body) obesity, rounded face, increased fat around the neck, and thinning arms and legs. Children tend to be obese with slowed growth rates.

    Other symptoms appear in the skin, which becomes fragile and thin. It bruises easily and heals poorly. Purplish pink stretch marks (striae) may appear on the abdomen, thighs, buttocks, arms and breasts. The bones are weakened, and routine activities such as bending, lifting or rising from a chair may lead to backaches, rib and spinal column fractures.

    Many people have severe fatigue, weak muscles, high blood pressure and high blood sugar. Irritability, insomnia, anxiety and depression are common. Patients with Cushing's disease are also at increased risk for blood clots and infections.

    Women usually have excess hair growth on their faces, necks, chests, abdomens, and thighs. Their menstrual periods may become irregular or stop. Men have decreased fertility with diminished or absent desire for sex.

  • What are the causes?
    Cushing's Disease (ACTH secreting adenoma)

    Cushing's syndrome occurs when the body's tissues are exposed to excessive levels of cortisol for long periods of time. Many people suffer the symptoms of Cushing's syndrome because they take glucocorticoid hormones such as prednisone for asthma, rheumatoid arthritis, lupus or other inflammatory diseases

    Others develop Cushing's syndrome because of overproduction of cortisol by the body. Normally, the production of cortisol follows a precise chain of events. First, the hypothalamus, a part of the brain which is about the size of a small sugar cube, sends corticotropin releasing hormone (CRH) to the pituitary gland. CRH causes the pituitary to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals, which are located just above the kidneys, receive the ACTH, they respond by releasing cortisol into the bloodstream.

    Cortisol performs vital tasks in the body. It helps maintain blood pressure and cardiovascular function, reduces the immune system's inflammatory response, balances the effects of insulin in breaking down sugar for energy, and regulates the metabolism of proteins, carbohydrates, and fats. One of cortisol's most important jobs is to help the body respond to stress, which can cause high levels of the hormone. People suffering from depression, alcoholism, malnutrition and panic disorders also have increased cortisol levels.

    Causes of Cushing's syndrome include:

    • Pituitary Adenomas - When the cause of excess cortisol is a pituitary adenoma, this is called "Cushing's disease". The excess ACTH produced by the pituitary tumor stimulates the adrenal to secrete excess cortisol. Adenomas are benign, or non-cancerous, tumors of the pituitary gland which can secrete increased amounts of ACTH. Women are affected 5 times as often as men.
    • Ectopic ACTH Syndrome - Some benign or malignant (cancerous) tumors that arise outside the pituitary can produce ACTH, which leads to excess cortisol production by the adrenal glands. This condition is known as ectopic ACTH syndrome. The most common forms of ACTH-producing tumors are carcinoid tumors, which can be benign or malignant and small cell lung cancer, which accounts for about 25 percent of all lung cancer cases. Other less common types of tumors that can produce ACTH are thymomas, pancreatic islet cell tumors, and medullary carcinomas of the thyroid.
    • Adrenal Tumors - Sometimes, an abnormality of the adrenal glands, most often an adrenal tumor, causes Cushing's syndrome. The average age of onset is about 40 years. Most of these cases involve non-cancerous tumors of adrenal tissue, called adrenal adenomas, which release excess cortisol into the blood.
    • Adrenocortical carcinomas, or adrenal cancers, are the least common cause of Cushing's syndrome. Cancer cells can secrete excess levels of several adrenal cortical hormones, including cortisol and adrenal androgens. Adrenocortical carcinomas usually cause very high hormone levels and rapid development of symptoms.
    • Familial Cushing's Syndrome - Most cases of Cushing's syndrome are not inherited. Rarely, however, some individuals have special causes of Cushing's syndrome due to an inherited tendency to develop tumors of one or more endocrine glands. In Primary Pigmented Micronodular Adrenal Disease, children or young adults develop small cortisol-producing tumors of the adrenal glands. In Multiple Endocrine Neoplasia Type I (MEN I), hormone secreting tumors of the parathyroid glands, pancreas and pituitary occur. Cushing's syndrome in MEN I may be due to pituitary, ectopic or adrenal tumors. These conditions are extraordinarily uncommon.

  • Complications
    Cushing's Disease (ACTH secreting adenoma)

    Cushing's disease affects multiple organ systems. Patients with Cushing's may develop diabetes mellitus, high blood pressure, muscle weakness, clotting disorders, infections and obesity. Bone loss with pathologic fractures can occur. Many patients with Cushing's experience skin changes, including thinning, fragility, easy bruising and striae (wide, purple stretch marks). Psychologic effects, including depression, anxiety and/or insomnia, are common and can be disabling.

  • Preparing for your appointment
    Write down questions to ask your doctor.

    The evaluation and treatment of Cushing's syndrome is often difficult and require special expertise.

    Special Instructions (If available, please bring):

    • Copies of your medical records/discharge summary/physician notes.
    • A copy of your MRI or CT on a CD.
    • A copy of your lab reports.
    • Bring any medications you are taking with you to your appointment.
    • Please make sure your MGH registration is accurate and up-to-date.

    Our clinic assistants will help you update your hospital registration and insurance information.

    Thank you.

  • How is Cushing's syndrome diagnosed?
    Cushing's Disease (ACTH secreting adenoma)

    Diagnosis is based on a review of the patient's medical history, physical examination and laboratory tests. These tests help to determine if excess levels of cortisol are present and, if so, from what source.

    • 24-Hour Urinary Free Cortisol Level - The patient's urine is collected over a 24-hour period and tested for the amount of cortisol. Levels higher than 50-100 micrograms a day for an adult suggest Cushing's syndrome. The normal upper limit varies in different laboratories, depending on which measurement technique is used.

    • Late-night Salivary Cortisol Level - The patient spits into a salivette or chews a cotton swab between 11 pm and midnight. Normally, cortisol levels at this time of the day are particularly low. Elevated levels late at night are often the first measurable abnormality in patients with early Cushing's disease.

    • 1 mg Overnight Dexamethasone Suppression Testing - The patient takes a 1 mg dexamethasone tablet between 11 pm and midnight and goes to the lab to have a cortisol level checked the next morning at 8 a.m. If the cortisol level is not adequately suppressed by the dexamethasone, this may indicate that the patient has Cushing's disease or Cushing's syndrome. The dexamethasone suppression test can produce false-positive results in patients with depression, alcohol abuse, high estrogen levels, acute illness, stress, and a number of other causes. Conversely, drugs such as phenytoin and phenobarbital may cause false-negative results in response to dexamethasone suppression. For this reason, patients are usually advised by their physicians to stop taking these drugs at least one week before the test, and the diagnosis of Cushing's disease is not usually made solely on the basis of this test.

    • The Dexamethasone-CRH Test - Some individuals have high cortisol levels, but do not develop the progressive effects of Cushing's syndrome, such as muscle weakness, fractures and thinning of the skin. These individuals may have Pseudo Cushing's syndrome, which was originally described in people who were depressed or drank excess alcohol, but is now known to be more common. Pseudo Cushing's does not have the same long-term effects on health as Cushing's syndrome and does not require treatment directed at the endocrine glands. Although observation over months to years will distinguish Pseudo Cushing's from Cushing's, the dexamethasone-CRH test was developed to distinguish between the conditions rapidly, so that Cushing's patients can receive prompt treatment. This test combines the dexamethasone suppression and the CRH stimulation tests. Elevations of cortisol during this test suggest Cushing's syndrome.

      Once Cushing's syndrome has been diagnosed, other tests are used to find the exact location of the abnormality that leads to excess cortisol production. Usually, an ACTH level is measured as a first step. If it is not very low, the most likely causes are a pituitary or, less commonly, an ectopic source. If the ACTH is very low, an adrenal tumor or use of steroid-containing medications is more likely. If the biochemical testing points to a pituitary source, the next step is usually an MRI of the pituitary gland. If a relatively large tumor is observed, generally surgery by a pituitary surgeon is the next step. For smaller tumors, which may or may not be the cause of Cushing's syndrome in the patient, and in cases in which no tumor is seen, additional testing is generally required.

    • Petrosal Sinus Sampling - This test is not always required, but in many cases, it is the best way to separate pituitary from ectopic causes of Cushing's syndrome. Samples of blood are drawn from the petrosal sinuses, veins which drain the pituitary, by introducing catheters through a vein in the upper thigh/groin region, with local anesthesia and mild sedation. X-rays are used to confirm the correct position of the catheters. Often CRH, the hormone which causes the pituitary to secrete ACTH, is given during this test to improve diagnostic accuracy. Levels of ACTH in the petrosal sinuses are measured and compared with ACTH levels in a forearm vein. ACTH levels higher in the petrosal sinuses than in the forearm vein indicate the presence of a pituitary adenoma; similar levels suggest ectopic ACTH syndrome.

    • CRH Stimulation Test - This test helps to distinguish between patients with pituitary adenomas and those with ectopic ACTH syndrome or cortisol-secreting adrenal tumors. Patients are given an injection of CRH, the corticotropin-releasing hormone which causes the pituitary to secrete ACTH. Patients with pituitary adenomas usually experience a rise in blood levels of ACTH and cortisol. This response is rarely seen in patients with ectopic ACTH syndrome and practically never in patients with cortisol-secreting adrenal tumors.

  • How is Cushing's syndrome treated?
    Cushing's Disease (ACTH secreting adenoma)

    Treatment depends on the specific reason for cortisol excess and may include surgery, radiation, or the use of cortisol-inhibiting drugs. If the cause is long-term use of glucocorticoid hormones to treat another disorder, the doctor will usually gradually reduce the dosage to the lowest dose adequate for control of that disorder.

    • Pituitary Adenomas - Several therapies are available to treat the ACTH-secreting pituitary adenomas of Cushing's disease. The most widely used treatment is surgical removal of the tumor, known as transsphenoidal adenomectomy. Using a microscope or endoscope and very fine instruments, the surgeon approaches the pituitary gland through a nostril or an opening made below the upper lip. 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 this procedure is over 80 percent when performed by a surgeon with extensive experience. If surgery fails, or only produces a temporary cure, surgery can be repeated, often with good results. After curative pituitary surgery, the production of ACTH drops below normal. This is a natural, but temporary, drop in ACTH production, and patients are given a synthetic form of cortisol (such as hydrocortisone or prednisone). Most patients can stop this replacement therapy in less than a year.

      For patients in whom transsphenoidal surgery has failed or who are not suitable candidates for surgery, radiotherapy is another possible treatment. Radiation can often, but not always, be given in a single dose ("radiosurgery") using either proton beam, gamma knife or stereotactic LINAC. About 50% of patients are controlled within two years of their radiation treatment, and will require medications to control their cortisol levels in the interim. About one-third of patients who receive radiation will develop loss of pituitary function and may require additional hormone replacement therapy.

      There are a number of medication options that are now available to reduce abnormally high cortisol levels. These medications can be used alone or in combination and include:

      • Medications that act directly on the pituitary tumor. These medications are only effective in patients with pituitary tumors as a cause of their Cushing's syndrome) and include the somatostatin analog pasireotide. This is an injectable drug of which the primary side effect is an elevation in blood sugar in some patients. Cabergoline, is an oral medication. These medications can be useful in controlling tumor growth and cortisol levels but are only effective in a minority of patients.

      • Medications that act on the adrenal glands. These medications block cortisol production and include ketoconazole and metyrapone. They are effective at controlling cortisol levels in a majority of patients, but do not treat pituitary tumors themselves. Ketoconazole can rarely cause significant liver toxicity, and therefore liver tests must be monitored in all patients taking the medication. Metyrapone is not available in the U.S. by prescription but can sometimes be obtained from the manufacturer in emergency cases.

      • Medications that act to block the cortisol receptor. Mifepristone blocks the binding of cortisol to the receptor and inhibits the effects of excess cortisol on the body. Cortisol levels themselves do not decrease with this medication and cannot be monitored to determine its effectiveness or to titrate the dose. It is FDA-approved only for use in patients with high blood sugars.

      In cases in which other treatment modalities fail, bilateral adrenalectomy (removal of both adrenal glands, which are the source of cortisol in the body) will make it impossible for the body to produce cortisol, and the symptoms of Cushing's disease will resolve. The surgery can now often be done laparoscopicallly (through a few small incisions) with minimal recovery time. However, there are significant long-term risks of bilateral adrenalectomy, including significant growth of a preexisting pituitary tumor. In addition, patients who have undergone bilateral adrenalectomy require lifelong cortisol (e.g. prednisone or hydrocortisone) and mineralocorticoid (fludrocortisone) replacement therapy.

    • Ectopic ACTH Syndrome - To treat the overproduction of cortisol caused by ectopic ACTH syndrome, it is necessary to locate and eliminate the tumor that is secreting ACTH. The choice of treatment depends on the type of tumor. It may be difficult to locate the tumor causing the excess ACTH production. In these cases, medications to reduce cortisol production by the adrenal glands is used to control the symptoms of Cushing's syndrome, and repeat imaging is performed over time.

    • Adrenal Tumors - Surgery is the mainstay of treatment for benign as well as cancerous tumors of the adrenal glands.

  • What research is being done on Cushing's disease?
    The Neuroendocrine Clinical and Pituitary Center is committed to advance the treatment of patients with Cushing's disease through research. Current research projects are described in the Neuroendocrine Clinical and Pituitary Center Bulletin below. We welcome patient participation in the research.

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