Physical signs vary, but most people have weight gain (especially in the abdomen), rounded face, increased fat around the neck, and thinning of the arms and legs. Children tend to be obese with slowed growth rates. Additionally, the skin 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.

Many people have severe fatigue, muscle weakness, 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 may have excess hair growth on their faces and body (necks, chests, abdomens, and thighs). Their menstrual periods may become irregular or stop. Men may experience erectile dysfunction.

Cushing's syndrome occurs when the body's tissues are exposed to excessive levels of cortisol for a prolonged period of time. Many people suffer the symptoms of Cushing's syndrome because they take steroid medications 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 adrenals 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.

Cushing's disease affects multiple organ systems. Patients with Cushing's may develop diabetes, high blood pressure, muscle weakness, clotting disorders, infections, and obesity. Bone loss (osteoporosis) and 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 insomnia, are common and can be disabling.

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. Multiple cortisol tests are needed in order to make a diagnosis of Cushing’s syndrome. This is important because cortisol tests may be falsely positive in a variety of conditions, including depression, alcohol use disorder, and acute stress or illness.

• 24-Hour Urinary Free Cortisol Level - The patient's urine is collected over a 24-hour period, and the amount of cortisol is measured.

• Late-Night Salivary Cortisol Level - The patient spits into a tube or chews a cotton swab between 11PM 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 11PM and midnight and goes to the lab to have a cortisol level checked the next morning at 8AM. If the cortisol level is not adequately suppressed by the dexamethasone, this may indicate that the patient has 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 the more likely cause. 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 the best way to separate pituitary from ectopic causes of Cushing's syndrome. It may not be required if a large pituitary tumor seen on MRI. The procedure is usually done by an Interventional Radiologist. Samples of blood are drawn from the petrosal sinuses, which are veins that 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. An injection of DDAVP, a hormone that stimulates the pituitary to secrete ACTH, is given during this test. 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.

• DDAVP Stimulation Test - This test helps to distinguish between patients with pituitary adenomas and those with ectopic ACTH syndrome, cortisol-secreting adrenal tumors, or non-neoplastic Cushing’s (a condition that mimics Cushing's syndrome but is not caused by a tumor). Patients are given an injection of DDAVP, a 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 or non-neoplastic Cushing’s.

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 ACTH-secreting pituitary adenomas. 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. The neurosurgeons at the MGB Pituitary Center are specialized 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, radiation treatment 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 osilodrostat, 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.

  • 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 the risk of 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. The entire adrenal gland containing the tumor is removed, usually laparoscopically. Cortisol replacement is not required long-term as the remaining adrenal gland is able to make sufficient cortisol.