Cushing Syndrome

Cushing syndrome (also called hypercortisolism) is a condition that occurs when a person’s body is exposed to too much of a hormone called cortisol or a medication similar to cortisol for too long. The syndrome is usually caused by taking certain medicines that mimic cortisol. Other causes include tumors that make the body produce excess cortisol. Cushing syndrome includes a range of treatable symptoms. In most cases, the syndrome is curable. NICHD is one of the many federal agencies that support and conduct research on the causes of Cushing syndrome, ways to diagnose it earlier, and better treatments.

About Cushing Syndrome

Cushing syndrome occurs when the body’s tissues are exposed to too much of the hormone cortisol or a medication similar to cortisol for too long.1 The syndrome is named after Harvey Cushing, the brain surgeon who first described the condition.2

Cortisol is an essential hormone for life. The body’s two adrenal glands produce the hormone cortisol daily for our routine activities and a higher amount of cortisol in response to stress or when the cortisol levels in the blood are lower than they should be.

In the right amount, cortisol helps the body with several vital tasks:

  • Maintaining blood pressure and heart function
  • Controlling the immune system
  • Turning food into energy
  • Raising blood sugar levels as needed
  • Controlling bone formation

If the body makes too much cortisol or gets too much from external sources, like medications, Cushing syndrome may occur. Whether you develop Cushing syndrome depends on factors such as how much medication you take and for how long or how large a tumor grows before it is detected and treated.

Citations

  1. Stewart, P. M., & Newell-Price, J. D. C. (2016). The adrenal cortex. In S. Melmed, K. S. Polonsky, P. R. Larsen, & H. M. Kronenberg (Eds.), Williams Textbook of Endocrinology, 13th ed. (pp 490–555). Philadelphia, PA: Elsevier.
  2. Doyle, N. M., Doyle, J. F., & Walter, E. J. (2017). The life and work of Harvey Cushing 1869–1939: A pioneer of neurosurgery. Journal of the Intensive Care Society, 18(2), 157–158. Retrieved February 7, 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606407/

What causes Cushing syndrome?

Cushing syndrome can develop for two reasons:

  • Medication that contains glucocorticoid, which is similar to cortisol1,2
  • A tumor in the body that makes the adrenal gland produce too much cortisol1,2

Medications cause most cases of Cushing syndrome. Glucocorticoids, steroid drugs that are similar to cortisol, are a primary medication linked to Cushing syndrome. Healthcare providers prescribe them to treat:

  • Allergies
  • Asthma
  • Autoimmune diseases, in which the body’s immune system attacks its own tissues
  • Organ rejection, such as following an organ transplant
  • Cancer

Glucocorticoids such as prednisone are good for reducing inflammation. However, taking a high dose for a long time can cause Cushing syndrome.

Medroxyprogesterone, a form of the hormone progesterone, can also cause Cushing syndrome. Women may take it to treat menstrual problems, irregular vaginal bleeding, or unusual growth of the uterine (womb) lining, called endometriosis.

A tumor in the body can also cause Cushing syndrome. However, tumors are a much less common cause of Cushing syndrome than are medicines.

Both cancerous and noncancerous tumors can cause Cushing syndrome.2 The following list includes some of the different types of tumors.

Noncancerous (or benign)

  • Pituitary adenoma. An adenoma is a kind of tumor. A pituitary adenoma is on the pituitary gland.
  • Adrenal adenoma. An adrenal adenoma is on an adrenal gland.
  • Adrenal hyperplasia (micronodular or macronodular), or an overproduction or overgrowth of certain types of cells in the adrenal gland (tumor)
  • Adenomas in other places, such as the lungs, pancreas, thyroid, or thymus

Cancerous (or malignant)

  • Adrenal cancer
  • Pituitary carcinoma. A carcinoma is a kind of cancer. Pituitary carcinoma is very rare.
  • Cancer in places other than the pituitary or adrenal glands, mostly in the lungs, pancreas, thyroid, or thymus

How tumors can cause Cushing syndrome

Normally, the pituitary gland in the brain controls how much cortisol the body’s two adrenal glands release into the bloodstream. The pituitary gland signals the adrenal glands by releasing adrenocorticotropic hormone, also known as ACTH. When the adrenal glands sense the ACTH, they produce more cortisol. A tumor can disrupt that action. Tumors can produce either extra cortisol directly in their own tissue or extra ACTH, which triggers production of more cortisol.

Here are three ways a tumor can cause Cushing syndrome:

  • A benign tumor in the pituitary gland secretes ACTH, which causes the adrenal glands to produce too much cortisol. This tumor, called a pituitary adenoma, is the most common tumor linked to Cushing syndrome. Cushing syndrome that results from a pituitary adenoma is called Cushing disease.
  • Tumors in one or both adrenal glands produce cortisol, adding to the normal amount already produced by the glands themselves. These tumors can be adrenal adenomas, adrenal hyperplasia, or adrenal cancer.
  • A tumor in the lungs produces ACTH. The adrenal glands detect the ACTH and make more cortisol. This condition is sometimes called ectopic Cushing syndrome. The tumors may be benign or malignant.

Familial Cushing syndrome

Certain rare genetic disorders make some people more likely to get tumors in glands that influence cortisol levels. People who have one of these disorders are more likely to develop Cushing syndrome.2 Two such conditions are called multiple endocrine neoplasia type 1 and primary pigmented micronodular adrenal disease.

Physiologic/non-neoplastic hypercortisolism

In a few cases, people have symptoms and test results that suggest Cushing syndrome, but further testing reveals they do not have the syndrome. This condition is called physiologic/non-neoplastic hypercortisolism. It is very rare. The symptoms can be caused by alcohol dependence, depression or other mental health disorders, extreme obesity, pregnancy, or poorly controlled diabetes.3

Citations

  1. Nieman L. K., & Ilias, I. (2005). Evaluation and treatment of Cushing syndrome. Journal of American Medicine, 118(12), 1340–1346. PMID 16378774.
  2. Nieman, L. K., Biller, B. M. K., Findling, J. W., Newell-Price, J., Savage, M. O., Stewart, P. M., & Montori, V. M. (2008). The diagnosis of Cushing syndrome: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism, 93(5), 1526–1540. Retrieved March 2, 2017, from https://academic.oup.com/jcem/article/92/1/10/2597828 
  3. Batista, D. L., Courcoutsakis, N., Riar, J., Keil, M. F., & Stratakis, C. A. (2008). Severe obesity confounds the interpretation of low-dose dexamethasone test combined with the administration of ovine corticotrophin-releasing hormone in childhood Cushing syndrome. Journal of Clinical Endocrinology and Metabolism, 93(11), 4323-4330. PMID 18728165.

What are the symptoms of Cushing syndrome?

Cushing syndrome can cause a range of symptoms.1,2 The symptoms might also be similar to those of other conditions.3

Physically, someone with Cushing syndrome might have:

  • Overweight or obesity above the waist but thin arms and legs
  • A round, red face, sometimes referred to as a moon face
  • A fat lump between the shoulders, sometimes called a buffalo hump
  • Weak muscles or bones including osteoporosis, bone pain, and fractures
  • Skin changes, including:
    • New or worsened acne or skin infections
    • Reddish-purple stretch marks called striae (pronounced STRY-ee). These are usually about half an inch wide and can appear on the abdomen, buttocks, thighs, arms, and breasts.
    • Thin, fragile skin that bruises easily and heals poorly

Additional symptoms can include the following:

  • Children may get heavier but grow more slowly than their peers.
  • Women may have more hair on their face, neck, chest, abdomen, and thighs. They may experience menstrual problems, such as irregular or stopped periods.
  • Men may have lower sex drive, experience impotence, and become less fertile.

The following less common symptoms also may develop:

  • Mental changes such as depression, anxiety, moodiness, or behaving differently
  • Severe fatigue
  • Headaches
  • Thirst and increased need to urinate
  • High blood pressure
  • High blood sugar
  • High cholesterol and triglycerides

Overall, the symptoms that most strongly hint at Cushing syndrome are the fatty deposit on the upper back/neck, fat around the abdomen, weakness in muscles closest to the torso (such as in the shoulders and hips), wide striae (skin stripes), bruising without being bumped, unexplained osteoporosis, and—in children—slower growth in height and more weight gain that may be mistaken for obesity.2,3

Citations

  1. Batista, D. L., Riar, J., Keil, M., & Stratakis, C. A. (2007). Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics, 120(3), e575-e586. Retrieved March 14, 2017, from http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=17698579 
  2. Nieman, L. K., & Ilias, I. (2005). Evaluation and treatment of Cushing’s syndrome. Journal of American Medicine, 118(12), 1340–1346. PMID 16378774.
  3. Nieman, L. K., Biller, B. M. K., Findling, J. W., Newell-Price, J., Savage, M. O., Stewart, P. M., & Montori, V. M. (2008). The diagnosis of Cushing’s syndrome: An Endocrine Society clinical practice guideline. Retrieved March 2, 2017, from https://academic.oup.com/jcem/article/93/5/1526/2598096 

How do healthcare providers diagnose Cushing syndrome?

Diagnosing Cushing syndrome can be complex and difficult. This syndrome is easier to recognize once it develops fully, but healthcare providers try to diagnose and treat it before it gets to that point. No single test can definitively diagnose the condition, so healthcare providers often use several steps to diagnose Cushing syndrome. If you are being checked for Cushing syndrome, the tests may occur in the following order1,2:

Your healthcare provider will ask about all medications and other treatments you have taken to see whether any of them could be responsible for raising your cortisol levels. Make sure you include everything you take, including joint or nerve injections received for pain; “tonics,” dietary supplements, and herbal medications; nasal sprays; progesterone; and skin creams (including bleaching agents).1

A laboratory will check to see whether your cortisol levels are normal. This test might be one of the following:

Urine cortisol test

Urine is collected for 24 hours.

Late-night salivary cortisol test

A special device is used for collecting saliva late at night. You can mail the sample to a laboratory or deliver it to your healthcare provider.

Dexamethasone suppression test

For this test, you take dexamethasone, a drug that suppresses or stops cortisol production, by mouth, and then your blood level of cortisol is measured. The test may be done overnight or across 3 days.3

If your results are not normal, your healthcare provider may do further tests or refer you to an endocrinologist, a healthcare provider who specializes in hormones and hormone disorders, for the tests. These tests might include:

  • Another test from Step 2
  • Serum midnight cortisol test, which measures the amount of cortisol in your blood late at night
  • Dexamethasone-suppressed corticotropin-releasing hormone (Dex-CRH) test, which can help determine the cause of the symptoms

If your cortisol levels are still above normal and you receive a diagnosis of Cushing syndrome, your healthcare provider will check for the cause. Tests to find the cause might include the following:

  • A CRH stimulation test, which involves a series of blood samples
  • A high-dose dexamethasone suppression test, a variation on the dexamethasone suppression test described earlier
  • Magnetic resonance imaging (MRI) or other imaging to see the glands that might be causing symptoms
  • Petrosal sinus sampling, which is a blood test that measures levels of ACTH coming from the pituitary gland

Certain medical conditions can make some of the tests listed earlier unsafe or ineffective, so your healthcare provider may not use the tests. These conditions can include:

  • Pregnancy
  • Epilepsy
  • Renal failure
  • Cyclic Cushing syndrome, in which cortisol is sometimes normal and sometimes high

In addition, several kinds of medications unrelated to Cushing syndrome may interfere with test results. Make sure your healthcare provider knows about every drug you are taking before testing for Cushing syndrome.1

Citations

  1. Nieman, L. K., Biller, B. M. K., Findling, J. W., Newell-Price, J., Savage, M. O., Stewart, P. M., & Montori, V. M. (2008). The diagnosis of Cushing’s syndrome: An Endocrine Society clinical practice guideline. Retrieved March 2, 2017, from https://academic.oup.com/jcem/article/93/5/1526/2598096 
  2. Boscaro, M., & Arnaldi, G. (2009). Approach to the patient with possible Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism, 94(9), 3121–3131. Retrieved April 9, 2019, from https://www.ncbi.nlm.nih.gov/pubmed/19734443
  3. MedlinePlus. (n.d.). Dexamethasone suppression test. Retrieved March 2, 2017, from https://medlineplus.gov/ency/article/003694.htm

Is there a cure for Cushing syndrome?

Untreated Cushing syndrome can be life-threatening. Fortunately, most people with the syndrome are treated and cured.1

However, after successful treatment of the syndrome, some health problems may continue. For instance, your bones may continue to be weak. People who no longer have Cushing syndrome may be more likely to have high blood pressure, diabetes, and mental health issues, such as depression and anxiety.1

People whose Cushing syndrome was caused by a tumor need to have regular checkups for the rest of their lives to check for additional tumors. For many adults with Cushing disease (the term used for Cushing syndrome caused by a pituitary adenoma), surgical removal of the tumor is successful. In rare cases, some of the tumor cells are left and the adenoma can grow back.1

Citations

  1. Nieman, L. K., Biller, B. M. K., Findling, J. W., Murad, M. H., Newell-Price, J., Savage, M. O., & Tabarin, A. (2015). Treatment of Cushing’s syndrome: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism, 100(8), 2807–2831. Retrieved March 3, 2017, from https://academic.oup.com/jcem/article/100/8/2807/2836065 

What are the treatments for Cushing syndrome?

Treatment for Cushing syndrome depends on the cause of the extra cortisol in the body.1,2,3

For cases of Cushing syndrome caused by taking medicine to treat another disorder, your healthcare provider will, if possible, decrease the dose slowly and carefully and then give another medication so the body can go back to making its own cortisol.

In cases where it is not possible to stop the medication, the healthcare provider will monitor the patient closely and treat symptoms that might develop, such as high blood sugar, high cholesterol levels, bone thinning, or osteoporosis.

If a tumor is the cause of Cushing, treatments may include medication, surgery, radiation, chemotherapy, or a combination of these treatments. The treatment depends on the tumor’s location and type.

Pituitary tumors

The most common treatments for pituitary tumors are:

  • Surgery. In most cases, a surgeon removes the tumor through a cut under the upper lip or at the bottom of the nose, between the nostrils. In rare cases, the surgeon may cut through the skull to reach the pituitary tumor.
  • Radiation therapy. Radiation therapy uses X-rays to kill tumor cells or keep them from growing. It can be used if some tumor cells remain after surgery.
  • Chemotherapy. Chemotherapy uses drugs that kill tumor cells or keep them from growing. Some chemotherapy drugs are taken by mouth, and some are injected.
  • Drug therapy. Drugs can correct hormone imbalances or replace cortisol after another treatment.

To find out more about pituitary tumor treatments, visit the National Cancer Institute’s page on pituitary tumors.

Adrenal tumor or other tumors

If the tumor is in one or both of your adrenal glands, you may need surgery to remove it. Often, providers will remove the whole adrenal gland. After surgery to remove one adrenal gland, you may need to take drugs for several months to keep your cortisol levels up until the other adrenal gland is making enough by itself. After surgery to remove both adrenal glands, you will need to take medications to replace adrenal function for the rest of your life and take additional precautions during illness or surgery.

If your healthcare provider cannot remove the tumor, medications can help block the release of cortisol. Radiation therapy usually is not used for adrenal tumors.

Citations

  1. Graversen, D., Vestergaard, P., Stochholm, K., Gravholt, C. H., & Jørgensen, J. O. (2012). Mortality in Cushing’s syndrome: A systematic review and meta-analysis. European Journal of Internal Medicine, 23(3), 278–282. Retrieved April 9, 2019, from https://www.ncbi.nlm.nih.gov/pubmed/22385888
  2. MedlinePlus. (2019). Cushing’s syndrome. Retrieved April 9, 2019, from http://www.nlm.nih.gov/medlineplus/cushingssyndrome.html
  3. Nieman, L. K., Biller, B. M. K., Findling, J. W., Murad, M. H., Newell-Price, J., Savage, M. O., & Tabarin, A. (2015). Treatment of Cushing’s syndrome: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism, 100(8), 2807–2831. Retrieved March 3, 2017, from https://academic.oup.com/jcem/article/100/8/2807/2836065 
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