Cushing's Syndrome Overview
Cushing's syndrome is a disorder caused by prolonged exposure of the body's tissues to high levels of corticosteroids (glucocorticoids).
Corticosteroids are powerful steroid hormones produced by the adrenal glands, located above each kidney. They regulate the metabolism of proteins, carbohydrates, and fats. They reduce the immune system's inflammatory responses and help to maintain blood pressure and heart function. A vital function of corticosteroids is to help the body respond to stress.
Corticosteroid production by the adrenal glands follows a sequence of events. The hypothalamus (see Anatomy of the Endocrine System) releases corticotropin-releasing hormone (CRH), which causes the pituitary gland to secrete adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal glands to produce corticosteroid. When the corticosteroid level is low, more CRH and ACTH are produced; when the corticosteroid level is high, less CRH and ACTH are produced. Under normal conditions, the corticosteroid level and CRH/ACTH levels are in dynamic balance; Cushing's disease occurs when that balance is disturbed.
Excess corticosteroids have detrimental effects on many of the tissues and organs of the body. All of these effects together are called Cushing's syndrome.
Overproduction of corticosteroids can be caused by a tumor in the pituitary gland, which produces excess ACTH, thereby stimulating the adrenal gland to produce excess corticosteroids. This condition is called Cushing's disease because the origin is in the hypothalamic pituitary system. Cushing's syndrome is a qcollection of symptoms which look and act like Cushing's disease but is not the result of pituitary ACTH overproduction.
Endogenous Cushing's syndrome is the result of autonomous, unregulated production of corticosteroids by a tumor within one or both of the adrenal glands themselves. The most common cause of Cushing's syndrome, however, is exogenous Cushing's syndrome, which results from taking excessive amounts of corticosteroid drugs.
Cushing's Syndrome Causes
- Exogenous administration of corticosteroids
- Endogenous (produced by the body) corticosteroid overproduction
- Adrenal gland tumors: Overproduction of corticosteroid may be due to an adrenal tumor, which could be cancerous or noncancerous.
- ACTH-producing pituitary tumors: Pituitary tumors produce excess ACTH, which acts on the adrenal gland to produce excess corticosteroid.
- Some lung tumors or other tumors outside the pituitary gland may produce ACTH, which in turn stimulate the adrenal glands to produce excess corticosteroid.
Cushing's Syndrome Symptoms
- Weight gain, especially in the face, neck region, upper back, and torso (see Images 1-2)
- Changes in skin, including purple stretch marks, easy bruising, and other signs of skin thinning
- Proximal muscle weakness causing difficulty in climbing stairs, getting out of a low chair, and raising arms
- Psychological problems such as depression, cognitive dysfunction, and emotional lability
- New onset or worsening of high blood pressure and diabetes mellitus
- Polyuria or polydipsia (increased thirst) from diabetes mellitus or diabetes insipidus
- Reduced bone mass and fractures caused by weakened bones (steroid-induced osteoporosis)
- Impaired wound healing or predisposition to infections because of impaired immune function
- Irregular menses, amenorrhea, and hirsutism (overabundance of hair) in women
- Decreased libido, infertility, and impotence in men
- Persons with ACTH-producing pituitary tumor (Cushing's disease) may develop headaches, polyuria (increased frequency of urination) and nocturia (increased voiding of urine at night), visual problems, or galactorrhea (breasts produce milk in a woman who is not pregnant or breastfeeding an infant).
- If sufficient pressure from the tumor is present on the anterior pituitary (front part of the pituitary), hyposomatotropism (decreased production of growth hormone), hypothyroidism (decreased production of thyroid hormone), and hypogonadism (defective development of reproductive organs) may develop.
- When rapid onset of corticosteroid excess occurs, virilization in women or feminization in men may be seen. This suggests adrenal carcinoma as the underlying cause of Cushing's syndrome.
Exams and Tests for Cushing's Syndrome
- Measurement of 24-hour cortisol levels: The amount of cortisol excreted in the urine during a 24-hour time period is measured. Values higher than three to four times the upper limit of normal are suggestive of Cushing's syndrome.
- Overnight 1-mg dexamethasone suppression test: For this test, 1mg of dexamethasone (exogenous corticosteroid) is administered at 11 pm, with measurement of serum cortisol the next morning at 8 am. In healthy individuals, the serum cortisol should be less than 2-3 mcg/dL. Cushing's syndrome may be excluded with a cortisol level less than 1.8 mcg/dL.
- The 48-hour low-dose dexamethasone suppression test: In many persons, overnight 1mg dexamethasone suppression test may be inconclusive. In such persons, 48-hour low-dose dexamethasone suppression test is performed. In this test, 0.5mg dexamethasone is administered every six hours for eight doses and serum cortisol levels are measured.
- Corticotropin-releasing hormone (CRH) stimulation test: This test can detect mild corticosteroid excess. It combines the 48-hour low-dose dexamethasone suppression test with CRH stimulation. CRH is administered intravenously two hours after the eighth dose of 0.5mg dexamethasone. Corticosteroid levels are measured 15 minutes after CRH administration. A level of greater than 1.4 mg/dL is suggestive of Cushing's syndrome.
- Brain CT scan: In persons with pituitary adenoma, enlarged pituitary gland can be seen on brain CT scan.
- Abdominal CT scan: It is recommended if a primary adrenal problem is suggested by the symptoms and clinical examination. The presence of an adrenal mass larger than 4-6 cm in the CT scan raises the possibility that the mass is an adrenal carcinoma.
- Chest and abdominal CT scans: They should be performed in patients with suspected ACTH production from tumors present elsewhere in the body (for example, lung).
- Magnetic resonance imaging (MRI) of the brain: If a pituitary source of excess ACTH is suspected, MRI of the brain is performed.
Treatment of Cushing's syndrome depends on the primary cause of the syndrome. The aim of treatment is to reduce the corticosteroid secretion to normal. The treatment may include surgical removal of the tumor, radiation, or the use of corticosteroid-inhibiting drugs.
If the cause of Cushing's syndrome is long-term use of corticosteroids to treat another disease (for example, asthma or arthritis), your health care provider will gradually reduce the dose of corticosteroids to the lowest dose required for the control of that disease.
The primary therapy for pituitary tumors is trans-sphenoidal (through the sphenoid bone present at the base of the skull) surgery, and the primary therapy for adrenal tumors is adrenalectomy (surgical removal of the adrenal glands). When surgery is not successful or cannot be performed, treatment with medication may be attempted, however, medication failures are common. Pituitary radiation may be useful if pituitary surgery fails.
Drugs that inhibit the synthesis of corticosteroid, such as mitotane, ketoconazole, metyrapone, aminoglutethimide, trilostane, and etomidate, have been used to cause medical adrenalectomy. These medications are used rarely and often are toxic at the doses required to reduce corticosteroid secretion. Thus, medical treatment is initiated cautiously. Persons receiving the medications may require corticosteroid replacement to avoid adrenal insufficiency.
Drugs that decrease CRH or ACTH release have also been studied for the treatment of Cushing's disease. Such agents include bromocriptine, cyproheptadine, valproic acid, and octreotide. Currently, use of these drugs is investigational.
Metyrapone (Metopirone) blocks the final step in corticosteroid synthesis. Side effects are high blood pressure, acne, and hirsutism (overabundance of hair). This is the only drug that can be used during pregnancy.
Ketoconazole (Nizoral) is probably the most popular and effective drug for long-term use and is usually the drug of choice. It blocks several key enzymes in the body that are essential for the production of corticosteroids. Side effects of ketoconazole include headache, sedation, nausea, irregular menses, decreased libido, impotence, gynecomastia (excessive development of the male mammary gland), and impaired liver function tests. The drug is contraindicated during pregnancy. Additionally, ketoconazole interacts with numerous drugs, typically increasing other drugs' blood levels and causing toxicity. H2 blockers, such as cimetidine (Tagamet), ranitidine (Zantac), or famotidine (Pepcid) decrease ketoconazole's effectiveness. Proton pump inhibitors, such as omeprazole (Prilosec), lansoprazole (Prevacid), or pantoprazole (Protonix) also decrease effectiveness of ketoconazole.
Aminoglutethimide (Cytadren) blocks one of the steps in corticosteroid production. It is a relatively weak enzyme inhibitor at doses that can be tolerated. Side effects of aminoglutethimide include increased sleepiness, headache, a generalized itchy rash, hypothyroidism, and increased size of the thyroid gland. In rare cases, it may cause bone marrow suppression.
Trilostane (Modrastane) inhibits an enzyme required for the synthesis of corticosteroid. It is no longer available in the United States and is not as well studied. It is not a first-choice agent because it is a weak inhibitor of corticosteroid synthesis.
Etomidate (Amidate) has to be administered intravenously (into the vein); therefore, its use is limited.
Mitotane (Lysodren) causes death of adrenal cells. For this reason, it is used in the treatment of adrenal cancer. Unfortunately, mitotane is expensive, and its utility is limited by adverse gastrointestinal and neurological effects, including nausea, diarrhea, dizziness, and ataxia (an inability to coordinate muscle activity during voluntary movement). Other side effects include rash, arthralgias (pain in joints and leukopenia [decrease in white blood cells]). It is a potential teratogen (a drug that causes abnormal development of the fetus) and can cause abortion; therefore, it is relatively contraindicated in women interested in remaining fertile.
- The treatment of choice in persons with pituitary tumor is trans-sphenoidal surgery by an experienced neurosurgeon. The goal of surgery is to remove the tumor, preserving as much pituitary function as possible.
- Pituitary irradiation is used when trans-sphenoidal surgery is not successful or not possible. The procedure is less successful than surgery in adults, with a 45% cure rate in adults and 85% cure rate in children. Late-onset side effects include hypopituitarism.
- Surgical removal of both adrenal glands is an option if trans-sphenoidal surgery, pituitary irradiation, and medical therapy fail or if rapid normalization of corticosteroid levels is required. Nowadays, the removal of the adrenal glands is done laparoscopically. This has decreased both the morbidity and mortality of this procedure, and the postoperative recovery of the patients is much faster than after open surgery.
ACTH production by tumors present elsewhere in the body
- Surgical removal of the tumor producing ACTH may not always be possible because they are often difficult to locate.
- Medical therapy or surgical removal of both the adrenal glands may be required.
- The adrenal gland in which the tumor is located may be surgically removed.
- Carcinomas should be resected for cure if found early or for palliation (alleviation of symptoms without curing the underlying disease).
Persons with endogenous Cushing's syndrome who undergo surgical removal of pituitary, adrenal, or ectopic tumors should receive stress doses of corticosteroid in the intraoperative and immediate postoperative period.
In the event of damage to the pituitary gland or removal of both adrenal glands, lifelong corticosteroid replacement is necessary.
The outlook is favorable if surgery is curative.
The rare adrenal carcinomas are associated with a 5-year survival rate of 30% or less.
Two catastrophic medical crises that occur in corticosteroid excess states are perforated viscera (such as the stomach, duodenum, small intestine) and opportunistic saprophytic or fungal infections.
Exposure to excess corticosteroid results in multiple medical problems, including high blood pressure, obesity, osteoporosis, fractures, impaired immune function, impaired wound healing, glucose intolerance, and psychosis.
Exogenous steroids suppress the hypothalamic-pituitary-adrenal axis, with full recovery taking as long as a year after stopping corticosteroid medication. Thus, persons who are on or who have taken steroids are at risk for developing an adrenal crisis (a life-threatening condition caused by insufficient corticosteroid).
Support Groups and Counseling
Support groups and counseling can help you feel less alone and can improve your ability to deal with your disease. They provide you an opportunity to exchange information about the disease, take advice about managing the disease, and share your feelings with others who are undergoing a similar situation as yours.
Cushing's Help and Support provides help and hope for people whose lives are touched by Cushing's Syndrome.
For More Information
Cushing's Support and Research Foundation, Inc.
65 East India Row 22B
Boston, Massachusetts 02110
(617) 723-3824 or (617) 723-3674
Pituitary Tumor Network Association
16350 Ventura Blvd. #231
Encino, CA 91436
Fax: (805) 499-1523
Pituitary Network Association
PO Box 1958
Thousand Oaks, CA 91358
Fax: (805) 480-0633
Email: [email protected]
National Adrenal Disease Foundation
505 Northern Boulevard
Great Neck, NY 11021
Email: [email protected]
Medically reviewed by a John A. Seibel, MD; Board Certified Internal Medicine with a subspecialty in Endocrinology & Metabolism
"Overview of the treatment of Cushing's syndrome"