Cushing’s syndrome is a disorder that develops due to long-term exposure to high levels of the hormone cortisol. Excess cortisol can lead to symptoms such as irritability, depression, mood swings, anxiety, memory loss, poor sleep, fatigue, weakness, and signs such as weight gain, a rounded or “moon” face, a fatty hump at the back of the neck, muscle loss, bone fractures, and easy bruising of the skin. Women may also experience excess hair growth and irregular menstrual periods and men may experience a decrease in sex drive. Blood pressure and blood sugar levels can rise, leading to new diagnoses of hypertension and diabetes or difficulty controlling these conditions.

There are two types of Cushing’s syndrome. The most common type, exogenous Cushing’s syndrome, results from prolonged use of medications that are similar to the cortisol the body produces naturally, called glucocorticoids. Some common examples of these are prednisone, dexamethasone, and cortisone. In rare cases, Cushing’s syndrome can result from the body’s own overproduction of cortisol.

Cushing’s syndrome can be serious if not recognized and treated. With accurate diagnosis and appropriate management, many people can recover or experience significant improvement in their symptoms and quality of life.

Cushing’s syndrome develops after prolonged and excessive exposure to cortisol. Cortisol helps regulate many important functions, including blood pressure, blood sugar, metabolism, the body’s response to stress, and inflammation. The adrenal glands produce cortisol in response to signals from the pituitary gland, which releases a hormone called adrenocorticotropic hormone (ACTH) to control how much cortisol is made.

When cortisol levels remain high for prolonged periods, it can affect many parts of the body, including the skin, muscles, bones, heart, blood vessels, and brain.

The two main types of Cushing’s syndrome are:

• Exogenous Cushing’s syndrome develops from excessive exposure to corticosteroid medications.
• Endogenous Cushing’s syndrome results from the body’s own overproduction of cortisol, often due to tumors of the pituitary or adrenal glands.

Cushing’s syndrome can affect people of any age, including children, but it is most often diagnosed in adults between the ages of 30 and 50. Because the symptoms can develop slowly and may resemble those of other health problems, diagnosis is sometimes delayed.

The most common cause of Cushing’s syndrome is glucocorticoids (a class of corticosteroids), which are often prescribed to treat conditions such as asthma, rheumatoid arthritis, lupus, or to prevent organ rejection after a transplant. When used in high doses for a long time, these drugs can lead to Cushing’s syndrome.

Endogenous Cushing’s syndrome can be caused by several conditions:

• Pituitary tumors: Noncancerous tumors in the pituitary gland can produce too much ACTH, which signals the adrenal glands to make more cortisol. This is the most common endogenous cause of Cushing’s syndrome. When caused by pituitary tumors, Cushing’s syndrome is called Cushing’s disease.
• Adrenal tumors: Tumors on the adrenal glands can make too much cortisol. These tumors are usually benign but can sometimes be cancerous.
• Ectopic ACTH-producing tumors: These tumors occur outside the pituitary gland and make ACTH, resulting in higher-than-normal cortisol levels. These may occur in the lungs, pancreas, thyroid, or thymus.

Risk factors for Cushing’s syndrome include:

• Long-term use of glucocorticoids
• Presence of tumors in the pituitary gland, adrenal glands, or other organs such as the lungs, pancreas, thyroid, or thymus
• History of organ transplant requiring immune-suppressing medications
• Certain genetic syndromes or family history of endocrine tumors

Signs and symptoms of Cushing’s syndrome may include:

• Weight gain, especially in the face, upper back, and abdomen
• Rounded, full face (“moon face”)
• Increased fat at the back of the neck and between the shoulders
• Loss of fat on the arms and legs
• Wide purple stretch marks (called striae) on the abdomen, thighs, breasts, or under the arms
• Thin skin or easy bruising
• Muscle weakness, especially in the hips and shoulders
• Bone loss or fractures
• High blood pressure
• High blood sugar or diabetes
• Tiredness
• Depression, anxiety, or mood changes
• Difficulty thinking clearly or memory problems
• Slow growth or obesity in children
• Excess hair growth on the face, neck, chest, abdomen, or thighs (in women)
• Irregular or absent menstrual periods (in women)
• Decreased interest in sex and erectile dysfunction (in men)
• Increased frequency of infections
• Headache

The presence of a number of signs and symptoms at the same time raises suspicion of Cushing’s syndrome.

People with Cushing’s syndrome are at increased risk for certain complications. These include:

• Heart disease and stroke due to high blood pressure
• Type 2 diabetes, which may require medication or insulin
• Bone density loss (osteoporosis) and weakened bones that are more likely to fracture
• Muscle weakness, especially in the hips and shoulders
• Increased infections due to a weakened immune system
• Increased risk of clots in the legs (deep vein thrombosis) or lungs (pulmonary embolism)
• Higher levels of “bad” (LDL) cholesterol and lower levels of “good” (HDL) cholesterol, which can add to the risk of heart disease or stroke
• Kidney stones
• Depression and mood changes
• Memory loss or trouble concentrating
• Cuts and injuries that take longer to heal
• Irregular menstrual periods or infertility
• Erectile dysfunction and reduced sex drive

To diagnose Cushing’s syndrome, your doctor will review your medical history, conduct a physical exam, and order one or more diagnostic tests.

Your doctor may ask about your symptoms, how long you have had them, and whether you have taken glucocorticoid medications or have other risk factors for Cushing’s syndrome. During the physical exam, your doctor will look for signs such as weight gain in specific areas, a rounded face, thin skin, easy bruising, purple stretch marks, muscle weakness, and high blood pressure.

Additional tests are necessary to make a diagnosis. They may include the following:

• 24-hour urinary free cortisol test: measures the amount of cortisol in your urine collected over a full day. High levels suggest Cushing’s syndrome.
• Late-night salivary cortisol test: checks cortisol levels in a saliva sample collected late at night, when levels should normally be low. Elevated levels may indicate Cushing’s syndrome.
• Low-dose dexamethasone suppression test: involves taking a small dose of dexamethasone (a steroid) at night, followed by a blood test for cortisol the next morning. In healthy people, dexamethasone lowers cortisol levels, but in Cushing’s syndrome, cortisol remains high.
• Blood tests for adrenocorticotropic hormone (ACTH): help determine whether the cause is related to the pituitary gland, adrenal glands, or another source.
• Computed tomography (CT) scans or magnetic resonance imaging (MRI) scans: used to look for tumors in the pituitary gland or adrenal glands.
• Inferior petrosal sinus sampling: involves blood samples taken from veins near the pituitary gland. This test can help distinguish between pituitary and other causes of excess ACTH.

Because symptoms of Cushing’s syndrome can overlap with other conditions, your doctor may need to repeat some tests or use a combination of tests to confirm the diagnosis and identify the underlying cause.

The choice of treatment for Cushing’s syndrome depends on the cause of the condition. The main goal is to lower the level of cortisol in the body. Main treatments include:

• Gradual reduction of glucocorticoid medications: If Cushing’s syndrome is caused by taking glucocorticoid medicines, the doctor will slowly decrease the dose to the lowest possible amount or switch to a different medication, if appropriate. Stopping these medicines suddenly can be dangerous, so it must be done under medical supervision.
• Surgical removal of tumors: If a tumor is causing the body to make too much cortisol, surgery to remove the tumor is often the first choice. This may involve removing a tumor from the pituitary gland, adrenal gland, or another part of the body.
• Radiation therapy: If surgery is not possible or does not fully remove the tumor, radiation may be used to destroy remaining tumor cells. Radiation can take time to work, and additional treatments may be needed while waiting for its effects.
• Medications to control cortisol: If surgery is not possible or desired, or while waiting for radiation to work, medicines can be used to lower cortisol production or block its effects. Some medicines target pituitary tumors.
• Bilateral adrenalectomy: In rare cases, both adrenal glands may be removed to stop cortisol production. People who have this surgery will need to take hormone replacement medicines for life.

Treatment is tailored to each person’s situation, and ongoing follow-up is important to monitor and manage any long-term effects.

The outlook for people with Cushing’s syndrome varies depending on the underlying cause, when the condition is diagnosed, the person’s age, overall health, and how well the condition responds to treatment. Many people experience significant improvement or even a cure when the cause of excess cortisol is identified and treated, especially if treatment begins early. However, some people may continue to have health problems related to Cushing’s syndrome that require additional treatment.

Some complications, such as high blood pressure, diabetes, bone loss, or mood changes, may improve after cortisol levels return to normal, but others can persist and require ongoing care. People with Cushing’s syndrome have a higher risk of serious health problems, including heart disease and infections, even after treatment. Lifelong follow-up to monitor for recurrence and manage any lasting effects helps ensure the best possible outcomes and quality of life for people with Cushing’s syndrome.

“Yale Medicine has a multidisciplinary team of endocrinologists, neurosurgeons, endocrine surgeons, oncologists, radiation medicine specialists, radiologists, pathologists, and the ability to do advanced endocrine testing and genetic evaluations, resulting in one of the most comprehensive programs in the world,” says Yale Medicine endocrinologist Sachin Majumdar, MD.