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Cushing syndrome, also referred to as hypercortisolism, is a condition characterized by the excessive production of cortisol in the body. This can be triggered by either the overproduction of cortisol by the body itself or by the administration of glucocorticoid medications.
Cortisol, often known as the “stress hormone,” is a steroid hormone produced by the body. It plays a crucial role in various physiological processes, particularly during stressful situations.
During periods of stress, your body releases excess cortisol, which aids in:
- Elevating your heart rate.
- Raising your blood pressure.
- Regulating your blood glucose levels.
- Controlling your respiration.
- Heightening your muscle tension.
Cortisol is temporarily suppressing some non–essential bodily functions during times of stress.
Cushing syndrome can result in excessive blood pressure, bone loss, and sometimes lead to type 2 diabetes. A fatty hump between the shoulders, a rounded face, and pink or purple stretch marks on the skin are among the common symptoms of Cushing syndrome. Possible treatment options encompass pharmaceuticals, radiation therapy, and surgical intervention.
Symptoms
Cushing syndrome has several symptoms that are unique to it, as well as some that could indicate a range of other conditions. Not everyone experiences the same symptoms as it varies depending on the level of excess cortisol.
Cushing syndrome symptoms include:
- Rapid weight increase in the abdomen, face (moon face), back of the neck (buffalo hump), and chest, with thin arms and legs
- Stretch marks that are pink or purple on the stomach, hips, thighs, breasts, and underarms
- Acne
- Wounds that do not heal normally
- Skin that is thin and weak, prone to bruising
In some cases, symptoms may also include:
- Fatigue
- Muscle weakness
- Difficult–to–control emotions
- Difficulties concentrating or remembering
- Anxiety, depression, and irritability
- Sleeplessness
- Slow growth in children
- Dizziness and hazy vision
- Bone loss, which can lead to fractures
- Hypertension
- Headache
- Infections
- Darkening of the skin
There are symptoms of Cushing syndrome that are more common in men than in women, and vice versa. Men may experience lower sex drive, lower fertility, and difficulty getting an erection. Women may experience hirsutism or excessive hair growth and irregular menstrual cycle.
If any signs and symptoms persist, it is important to seek medical attention from a healthcare provider for an accurate diagnosis and appropriate treatment. Individuals who are prescribed glucocorticoid medication for conditions like asthma, arthritis, or inflammatory bowel disease should remain vigilant for any symptoms indicative of Cushing syndrome. While Cushing syndrome can cause discomfort, it is a treatable condition with the use of appropriate medications.
Causes
Cortisol, a hormone synthesized by the adrenal glands, plays a central role in developing Cushing syndrome when present in excessive amounts. Elevated levels of cortisol can be attributed to various underlying factors, including the use of glucocorticoid medications, the presence of tumors, and, in rare cases, genetic predisposition.
- Exogenous Cushing syndrome: Exogenous Cushing syndrome occurs when a person takes glucocorticoid medicines to treat a disease. Taking significant dosages of this medication over an extended period can lead to Cushing syndrome. It can be taken orally, as a shot, rubbed into the skin, or inhaled into the lungs via an inhaler.
Glucocorticoids can be used to relieve back or joint pain, as well as various skin rashes. Glucocorticoid drugs, such as prednisone are commonly used to treat a variety of autoimmune disorders, including persistent asthma, rheumatoid arthritis, lupus, sarcoidosis, and many others that cause chronic inflammation. Glucocorticoids may also be used to prevent the body from rejecting a new organ following a transplant.
- Endogenous Cushing syndrome: Adrenocorticotropic hormone (ACTH) is the hormone that tells the adrenal glands to produce cortisol. Some tumors produce ACTH, which increases cortisol levels and can lead to Cushing syndrome.
- ACTH–producing pituitary adenoma: It is the most common kind of endogenous Cushing syndrome and occurs more frequently in women. Pituitary adenomas are typically discovered at the base of the brain and are not cancerous. These tumors that form in the pituitary gland can produce an excessive amount of ACTH which is responsible for 8 out of 10 cases of Cushing syndrome. Cushing syndrome is known as Cushing disease when it manifests in this manner.
- Ectopic ACTH–producing tumor: In this case, tumors form outside of the pituitary gland and produce ACTH. These tumors, commonly discovered in the lungs, pancreas, thyroid, and thymus gland may or may not be malignant. Small cell lung cancer is the most prevalent form. Ectopic ACTH production causes the body to produce an excessive amount of cortisol.
- Adrenal gland tumors or disease: Adrenal gland problems can result in excessive cortisol production. Adrenal adenoma is the most prevalent type of tumor in the outer region of the adrenal gland. These tumors are not cancer, and only a few produces excessive cortisol. Adrenal nodular hyperplasia occurs when several cortisol–producing tumors form in the adrenal glands and causes Cushing syndrome. Adrenocortical carcinoma, which refers to cancerous tumors located in the outer region of the adrenal glands, is an infrequent occurrence. Adrenocortical carcinoma can produce cortisol and cause Cushing syndrome.
- Familial Cushing syndrome: Cushing syndrome can occur if certain tumors produce ACTH or cortisol. Infrequently, individuals may genetically acquire a predisposition to develop tumors in one or multiple of their endocrine glands, responsible for hormone production.
Diagnosis
Diagnosing Cushing syndrome typically requires a thorough and comprehensive evaluation to eliminate other possible causes. This process can be intricate and time–consuming. It often involves in–depth discussions regarding symptoms, careful examination of medications being taken, and a comprehensive physical examination.
During the physical examination, healthcare providers will assess for specific symptoms associated with Cushing syndrome, including a rounded face, a hump on the back of the neck, and thin, easily bruised skin with stretch marks.
If there is suspicion that glucocorticoid medications may be responsible for inducing the syndrome, healthcare providers will carefully examine the various forms of medication, such as pills, injections, creams, and inhalers, to determine if any of them could potentially trigger the condition.
In cases where healthcare providers have confirmed that glucocorticoid medications are the cause of Cushing syndrome, further testing may not be required. However, if the cause is not evident or additional confirmation is needed, laboratory tests are typically conducted to confirm the presence of hypercortisolism. These tests may include:
- Blood and urine tests: A blood test will determine the level of ACTH in the blood. If the levels are low, an adrenal tumor may be present. If the levels are normal or high, a pituitary or ectopic tumor may exist.
The 24–hour urinary cortisol test measures the level of cortisol in the urine in micrograms (mcg). This requires collecting the urine during a 24–hour period for the urine test. Generally, these tests assess hormone levels and determine whether the body produces too much cortisol.
- Saliva test: This test measures cortisol levels between 11 pm and midnight. Normally, cortisol levels are very low late at night, but with Cushing syndrome, cortisol levels will be unusually high throughout that hour.
- Imaging tests: A CT scan or an MRI may be performed to look for a tumor in the pituitary and adrenal glands.
- Inferior petrosal sinus sampling: During the procedure, drugs to keep the patient calm and comfortable is given intravenously. ACTH levels will be compared between the two sample locations. The first sample will be obtained through a tiny tube inserted into the groin or neck area and threaded to the petrosal sinuses. A second blood sample is drawn from the forearm. Medication to induce the tumor to produce more ACTH is given. After which, blood samples from the same regions are obtained again.
Generally, this test identifies the site of ACTH secretion. The pituitary gland secretes ACTH and other pituitary hormones into the bloodstream. If the ACTH level in the sinus sample is higher, the problem is pituitary. If the ACTH levels in the sinuses and forearm are comparable, the problem is not with the pituitary gland. This test has an accuracy rating of 95% to 98%.
Treatment
The treatment approach for Cushing syndrome depends on the underlying cause of the elevated cortisol levels. The primary goal is to reduce cortisol levels in the body. If the use of glucocorticoids is responsible, the healthcare provider may recommend reducing the dosage or finding alternative medications. Additional treatment options include medication therapy, surgical intervention, or radiation therapy, depending on the specific circumstances and individual needs of the patient.
- Reducing glucocorticoid use: Symptoms of Cushing syndrome may be managed by lowering the dosage of glucocorticoid medicine. This is done gradually while still controlling the disease that requires this medication. Decreasing the medication gradually permits the body to produce a healthy quantity of cortisol. Stopping these medications too early can result in low cortisol levels in the body.
- Surgery: Surgical removal of pituitary, adrenal, and ectopic tumors is effective, but the patient must adapt to new, lower cortisol levels. Cortisol drugs or cortisol replacement medicine in the form of hydrocortisone pills is necessary after Cushing syndrome surgery. Most of the time, usually after six to 18 months, the doctor can gradually reduce the replacement medication.
Pituitary tumors are frequently removed through the nose. ACTH–producing tumors in other regions of the body can be removed through traditional surgery or through less invasive procedures with smaller incisions. Adrenal gland tumors can be removed through a midsection or back incision using a minimally invasive procedure.
If an ACTH–producing tumor is not detected, or if it cannot be completely removed, and Cushing syndrome persists, bilateral adrenalectomy may be recommended. This method immediately prevents the body from producing excessive cortisol. After both adrenal glands are removed, lifetime medication to replace cortisol and another adrenal hormone called aldosterone is necessary.
- Radiation therapy: A six–week period of radiation, or a single large dose may be recommended for those who are unable to undergo surgery, or if the tumor was not completely removed after the surgery. The treatment may be designed to minimize radiation exposure to other tissues. Discuss with the doctor all possible side effects.
- Medications: While treatment options for Cushing syndrome, such as medication, surgery, or radiation therapy, are not universally effective in completely eliminating all symptoms associated with excess cortisol, their primary aim is to control and manage cortisol levels in the body. The goal is to bring cortisol levels within a normal range, thereby alleviating symptoms and minimizing the adverse effects of cortisol excess. These medications are prescribed prior to surgery in individuals with severe Cushing syndrome, or if other treatments are not possible or failed to work.
Certain medications used to treat hypercortisolism can have significant side effects on the brain and nervous system, as well as the potential for liver damage. In addition, common side effects of these medications include fatigue, gastrointestinal disturbances (such as upset stomach and vomiting), headaches, muscle aches, elevated blood pressure, low potassium levels, and edema. It is important for healthcare providers to closely monitor and manage these potential side effects during the course of treatment.
Typical medications prescribed for Cushing syndrome include:
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- Mifepristone. This does not reduce the quantity of cortisol produced by the body, but it does prevent the effect of cortisol on tissues. This medication is approved for Cushing syndrome patients who have type 2 diabetes or high blood sugar levels.
- Pasireotide. Cortisol levels are reduced by decreasing the amount of ACTH produced by the tumor. This medication is administered as an injection twice a day.
- Other drugs. Ketoconazole, osilodrostat, mitotane, levoketoconazole, and metyrapone are medications used to regulate cortisol production in the adrenal gland.
