Cushing Syndrome

What Causes Cushing Syndrome?

CS may be caused by the long-term use of corticosteroid medications. These medications are used to treat a wide variety of medical conditions, including:

• Asthma
• Rheumatoid arthritis
• Lupus
• Organ transplants
• Joint pain or back pain

CS may also result from a disease or tumor that causes a person’s body to produce too much cortisol. Some of these conditions affect the adrenal glands, small glands near the kidneys that produce cortisol, but the tumors may occur elsewhere in the body.

As many as 80% of CS cases not caused by medication are caused by a type of tumor called a pituitary adenoma. Pituitary adenomas are tumors that affect the pituitary, a small gland in the skull underneath the brain and behind the nose. Pituitary adenomas are common, but most grow slowly and don’t spread to other parts of the body, meaning they are non-cancerous. However, some pituitary tumors produce adrenocorticotropic hormone (ACTH). ACTH causes the adrenal glands to produce too much cortisol, leading to the symptoms of Cushing syndrome.

Scientists don’t know what causes pituitary adenomas. The root cause of a tumor is a mutation or damage in the genes that control the growth of affected cells. The specific cause of the gene damage that triggers a tumor’s formation is usually not identifiable. In a healthy cell, these genes prevent the cell from growing or reproducing too rapidly, and the genes can also determine the cell’s expected lifespan. In a tumor’s cells, the damage to the genes causes the cells to grow and reproduce rapidly, and the cells may live longer than usual. As this rapid growth and reproduction continue, the cells grow into an abnormal mass.

Is Cushing Syndrome Hereditary?

Most cases of Cushing syndrome do not appear to be linked to inherited traits. However, some cases have been associated with inherited syndromes that produce tumors in various parts of the body, including the pituitary or adrenal glands. These syndromes include:

• Multiple endocrine neoplasia, type I (MEN1)
• Primary pigmented micronodular adrenal disease

How Is Cushing Syndrome Detected?

CS may be difficult to detect in its early stages because its symptoms, such as fatigue or weight gain, can resemble those of other disorders.

Some warning signs of Cushing syndrome may include:

• Rounding of the face
• Accumulation of fat between the shoulders
• Thinning skin
• Easy bruising
• Purple stretch marks

How Is Cushing Syndrome Diagnosed?

Doctors may take several different diagnostic steps when they suspect a patient may have a pituitary tumor.

• Laboratory tests. Blood tests and urine tests may be able to detect abnormal hormone levels that could be an indication of a pituitary tumor. 
• Saliva test. High levels of cortisol in a saliva sample taken late at night may be an indication of Cushing syndrome.
• Imaging. Imaging technologies are non-invasive ways to look for tumors of the pituitary, adrenal glands, or other parts of the body. They may also be used to judge the tumor’s size, location, and growth. Magnetic resonance imaging (MRI) uses a strong magnetic field to produce images of the brain and other organs. Computerized tomography (CT) scans may also be used to look for tumors.
• Petrosal sinus sampling. This test examines blood drawn from vessels that drain away from the pituitary gland. High levels of ACTH in this blood can indicate an ACTH-secreting pituitary adenoma.

How Is Cushing Syndrome Treated?

Treatment of Cushing syndrome depends on the disorder’s underlying cause. If CS is caused by corticosteroid medications, changing the dosage may improve symptoms. However, patients should never discontinue the use of medications on their own without the advice and supervision of a doctor.

Surgery

When CS is caused by a tumor, surgical removal of the tumor is usually the preferred course of treatment. Some small pituitary tumors may be removed using a technique called endoscopic transnasal transsphenoidal surgery. In this procedure, the surgeon makes a small incision inside the nasal cavity and removes the tumor via the nose and sinuses.

Larger tumors may require a procedure called a craniotomy. In this case, the surgeon makes an incision in the scalp and removes part of the skull to reach the tumor.

Tumors of the adrenal glands or elsewhere can often be removed using minimally invasive surgical techniques. In some cases, complete removal of the adrenal glands may be necessary.

Medication to maintain normal levels of cortisol is generally required after surgery.

Radiation Therapy

Radiation therapies involve using high-energy x-rays to target and kill tumor cells directly. The radiation is typically focused on the tumor to prevent damage to healthy cells. Radiation therapy is often used when the tumor can’t be entirely removed with surgery or when the tumor is in a location that is not safely accessible. It may also be used if the tumor begins to grow again after surgery.

Medications

Medications such as ketoconazole, mitotane, or metyrapone can sometimes successfully control excess cortisol production. These medications may be used when surgery or radiation treatments don’t improve symptoms.

How Does Cushing Syndrome Progress?

Untreated, Cushing syndrome can eventually lead to serious complications, including:

• High blood pressure
• Type 2 diabetes
• Blood clots
• Infections
• Bone loss and fractures
• Cholesterol problems
• Depression
• Problems with memory or concentration

How Is Cushing Syndrome Prevented?

There is no known way to prevent the tumors that are common causes of Cushing syndrome.

Cushing Syndrome Caregiver Tips

Some people with pituitary tumors also suffer from other brain and mental health-related issues in addition to Cushing syndrome, a condition called co-morbidity. Here are a few of the disorders commonly associated with these tumors:

• People with brain tumors often experience depression or anxiety.
• Personality changes resembling bipolar disorder are sometimes an indication of a brain tumor.

Cushing Syndrome Brain Science

The pea-sized pituitary is sometimes called the “master gland” because it helps control the action of other glands throughout the body. Glands are organs that produce chemicals called hormones which regulate bodily functions.

The pituitary works in conjunction with a part of the brain called the hypothalamus, to which the pituitary is directly connected. The hypothalamus produces several different hormones and passes them on to the pituitary, where they’re stored, released, or used to control the function of other glands. Together, the hypothalamus and pituitary monitor and regulate some of the body’s most basic and essential systems.

Some of the functions controlled or impacted by the hypothalamus and pituitary include:

• Growth
• Reproduction
• Metabolism
• Regulation of water and sodium in the body
• Blood pressure
• Labor, childbirth, and lactation
• Stress responses

Cushing Syndrome Research

Title: Glucocorticoid Withdrawal Syndrome in Patients With Treated Cushing Syndrome

Stage: Recruiting

Principal investigator: Irina Bancos, MD

Mayo Clinic

Rochester, MN

Cushing syndrome (CS) is an endocrine disorder caused by chronic glucocorticoid exposure (GC). Endogenous CS has an estimated incidence of 0.2 to 5.0 cases per million per year and a prevalence of 39 to 79 cases per million in various populations. CS usually affects young women, with a median age at diagnosis of 41.4 with a female-to-male ratio of 3:1. Following a curative surgery for CS, patients develop adrenal insufficiency and require GC replacement postoperatively until the hypothalamic-pituitary-adrenal (HPA) axis recovery occurs. Factors such as age, gender, BMI, subtypes of CS, duration of symptoms, clinical and biochemical severity, and postoperative GC dose have been reported to affect HPA recovery in small retrospective studies. Glucocorticoid withdrawal syndrome (GWS) is a withdrawal reaction due to a decrease in supraphysiological GC concentrations, which occurs after a successful surgery of CS. Glucocorticoid withdrawal syndrome (GWS) is an under-recognized entity in patients undergoing curative surgery for endogenous Cushing syndrome.

In this study, researchers aim to determine pre- and post-surgical predictors of the duration and severity of glucocorticoid withdrawal in patients undergoing curative surgery for cortisol excess, and assess the effect of MUSE intervention on GWS severity in patients undergoing curative surgery for CS as compared to standard of care.

Title: SPI-62 as a Treatment for Adrenocorticotropic Hormone-dependent Cushing’s Syndrome (RESCUE)

Stage: Recruiting

Study Director: Frank Czerwiec, MD

Sparrow Pharmaceuticals

Portland, OR  

This is a multicenter, randomized, placebo-controlled, Phase 2 study to evaluate the pharmacologic effect, efficacy, and safety of SPI-62 in subjects with ACTH-dependent Cushing’s syndrome. Each subject who provides consent and meets all inclusion and exclusion criteria will participate in 3 periods: a 28-day screening period (Days -35 to -8), a 7-day baseline period (Days -7 to -1), and a 24-week treatment period (Day 1 of Week 1 to Day 168 ± 3 days of Week 24). Up to 26 subjects will be enrolled with the aim that 18 subjects with Cushing’s disease will complete the study. Subjects will receive each of the following 2 treatments for 12 weeks: SPI-62 and a matching placebo.

Title: Corticotrophin-releasing Hormone (CRH) Stimulation for 18F-FDG-PET Detection of Pituitary Adenoma in Cushing Disease

Stage: Not Yet Recruiting

Principal investigator: Prashant Chittiboina, MD

National Institute of Neurological Disorders and Stroke (NINDS)

Bethesda, MD

Cushing disease is caused by a pituitary gland tumor. As a result, patients with Cushing disease suffer from obesity, diabetes, osteoporosis, weakness, and hypertension. The cure is surgery to remove the pituitary tumor. Currently, MRI is the best way to find these tumors. But not all tumors can be seen with an MRI. Researchers hope giving the hormone CRH before a PET scan can help make these tumors more visible.

Objective: To test whether giving CRH before a PET scan will help find pituitary gland tumors that might be causing Cushing disease.

Eligibility: People ages eight and older with Cushing disease caused by a pituitary gland tumor that cannot be reliably seen on MRI

Design: Participants will be screened with their medical history, a physical exam, an MRI, and blood tests.

Participants will have at least one hospital visit. During their time in the hospital, they will have a physical exam and a neurological exam. In addition, they will have a PET scan of the brain. A thin plastic tube will be inserted into an arm vein. A small amount of radioactive sugar and CRH will be injected through the line. Participants will lie in a darkened room for about an hour and be asked to urinate. Then they will lie inside the scanner for about 40 minutes. After the scan, they will be asked to urinate every 2-3 hours for the rest of the day. Finally, blood will be drawn through a needle in the arm.

Participants will have surgery to remove their tumor within three months after the scan.

Participants will then continue regular follow-up in the clinic.