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40 years!
Last updated:
August 09, 2021
Years published: 1986, 1987, 1988, 1989, 1991, 1992, 1994, 1995, 1997, 1998, 1999, 2002, 2007, 2012, 2017, 2021
NORD gratefully acknowledges Cushing’s Support and Research Foundation, Inc., Edward R. Laws, MD, FACS, Professor of Neurosurgery, Harvard Medical School, Director, Pituitary/Neuroendocrine Center, Brigham and Women’s Hospital, Sherry Iuliano, NP, Jack Kilgallon and Peter Gentry, Pituitary/Neuroendocrine Center, Brigham and Women’s Hospital; Lynnette Nieman, MD, FACP, Senior Investigator, Section of Reproductive Endocrinology, NIH Intramural Research Program and Constantine A. Stratakis, MD, D(med)Sci, Chief, Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, for assistance in the preparation of this report.
Summary
Cushing syndrome is a rare endocrine disorder, characterized by a variety of symptoms and physical abnormalities that occur as a result of excessive amounts of the hormone cortisol, a vital glucocorticoid. Glucocorticoids are a class of steroid hormones that are important in the regulation of the metabolism of glucose, and also modulate the response to stress. Although it may occur in children, Cushing syndrome most commonly affects adults between the ages of 25 to 40. It can be caused by prolonged exposure to elevated levels of glucocorticoids produced within the body (endogenous) or introduced from outside the body (exogenous). Symptoms can include weight gain, obesity, a rounded face, thin purple streaks (purple striae) which occur on the skin, increased fat around the neck and slender arms and legs. Children with Cushing syndrome are typically obese and have delay in growth.
Introduction
In 1912, Harvey Cushing described a patient who had typical features of hypercortisolemia, but assumed it to be a “polyglandular” disorder. The cause was disputed for almost 40 years. Cushing disease, which is pituitary adrenocorticotropin hormone (ACTH) dependent Cushing syndrome produced by a benign pituitary tumor, was first definitively described by Dr. Cushing in 1932. Although pituitary surgery was introduced in the early 20th century, it was not until 1933 that pituitary neurosurgery began to be performed on patients with Cushing disease.
People with Cushing syndrome gain an excessive amount of weight. Obesity extends to include fat deposits around the face causing a “moon-shaped” or rounded appearance. Fat also accumulates around the neck (supraclavicular) and upper back (dorsal cervical) areas. Obesity also occurs in the trunk of the body (“centripetal obesity”), but the arms and legs remain slender. People with Cushing syndrome may have skin that is reddened, thin, fragile and slow to heal. The connective tissue may also become weak, resulting in the appearance of reddish-blue stretch marks on the arms, breasts, underarms (axillae), abdomen, buttocks and/or thighs.
Women with Cushing syndrome may have excessive body hair (hirsutism) on the face, neck, chest, abdomen and/or thighs. Acne affecting the face, chest and back may also develop. Some people have thinning and loss of the hair on the head, and some women may develop menstrual irregularities (oligoamenorrhea, amenorrhea). Men and women with this disorder may experience a decrease in fertility and a diminished or absent sex drive (loss of libido).
Children and adolescents with Cushing syndrome may experience delayed growth with or without weight gain and/or hypertension. Growth does not always stop entirely; it may be slower than before or only partially affected; however, Cushing syndrome in growing children always affects growth in one way or another.
Abnormally high blood pressure (hypertension) occurs in approximately 85 percent of people with Cushing syndrome. Bones may become brittle and break easily. This occurs as a result of progressive bone thinning (osteoporosis). Other features often include abnormally high blood sugar (diabetes mellitus, hyperglycemia), increased thirst and urination, impaired immune function leading to frequent bacterial and fungal infections, severe weakness, fatigue, easy bruising and muscle wasting (lower limbs muscle atrophy). Mild to severe psychic disturbances, including anxiety, depression and irritability, occur in many patients. Headache may also be present. Sleep disorders and sleep apnea are frequent in advanced cases. Some patients note cognitive difficulties and troubles with work performance and interpersonal relationships.
Cushing syndrome is a rare endocrine disorder caused by abnormally excessive amounts of the hormone cortisol.
Many people develop Cushing syndrome as a result of exogenous, long-term administration of a cortisol-like drug therapy to treat another medical condition such as arthritis, lupus and other inflammatory diseases (oral medication or injection into a joint or muscle), asthma, chronic obstructive lung disease, malignant tumors or leukemia. Steroid treatment is effective for these conditions, but can cause symptoms and signs of Cushing syndrome as a side effect of such treatment.
Cushing syndrome can also be due to endogenous causes; approximately 70% of Cushing syndrome is the result of Cushing disease. Cushing disease occurs when excess adrenocorticotropin hormone (ACTH) production from a benign pituitary tumor (adenoma) causes the adrenal glands to produce excessive amounts of cortisol. Approximately 10 to 15 percent of cases of endogenous Cushing syndrome are caused by non-pituitary tumors that secrete excessive ACTH. The causes of this “ectopic ACTH syndrome” include benign or malignant tumors, most commonly in the chest cavity or abdomen. Other types of ACTH-producing tumors include medullary carcinomas of the thyroid, pheochromocytomas and pancreatic islet cell tumors. Another 10 – 15% of patients have benign or malignant tumors of the adrenal glands (adenomas) that secrete excessive cortisol. Insulin resistance can be an important factor in the evolution of Cushing syndrome.
Although most cases of Cushing syndrome are not inherited, in rare instances it results from an inherited tendency to develop tumors in one or more hormone-secreting glands. Children or young adults with primary pigmented nodular adrenocortical disease (PPNAD) develop small cortisol-producing tumors in the adrenal glands. Cushing syndrome may develop along with the genetic disorder multiple endocrine neoplasia type 1 (MEN1) that is associated with hormone-secreting tumors of the lung, pancreas, parathyroids or pituitary gland.
Many cases of Cushing syndrome are due to exogenous corticosteroid medication. It is reported that the incidence of endogenous Cushing syndrome is approximately 13 per million people annually.
Cushing syndrome caused by either an adrenal or pituitary tumor affects women five times more frequently than men. Symptoms commonly begin between 25 to 40 years of age. Men are affected 3 times more often than women by ectopic ACTH production that is caused by lung cancer, which occurs later in life. The ACTH secreting pituitary adenomas that occur in children tend to be larger, and somewhat more rapidly growing than those in adults.
The diagnosis is based upon a detailed medical history to assess for any use of exogenous glucocorticoids (oral, topical, injection, inhaled), other symptoms or signs and a thorough physical examination and a series of laboratory tests.
Usually several laboratory tests are used to confirm the diagnosis of Cushing syndrome. Tests used include: 24-hour urine test for cortisol; measurement of late-night cortisol levels in the blood and saliva; and the low dose dexamethasone suppression test (LDDST) which evaluates the cortisol response to a low dose of a synthetic glucocorticoid (dexamethasone).
The dexamethasone-corticotropin-releasing hormone (CRH) test helps to distinguish Cushing syndrome from other causes of excess cortisol, such as pseudo-Cushing syndrome. This test combines the LDDST and a CRH stimulation test. In the CRH stimulation test, an injection of CRH causes the pituitary to secrete ACTH. People with pseudo-Cushing respond to the pretreatment with dexamethasone, which prevents CRH from causing an increase in ACTH and hence cortisol. Elevated cortisol levels from this test generally indicate Cushing syndrome.
Clinical Testing and Work-up
Once Cushing syndrome has been diagnosed, the cause of excess cortisol production needs to be determined.
The first test is measurement of blood (plasma) ACTH levels. A low or undetectable level of ACTH in the blood combined with simultaneously elevated blood (serum) cortisol levels indicates that the cause of Cushing syndrome is likely due to a primary cortisol-producing adrenal adenoma or carcinoma, assuming that use of corticosteroid medication as the cause has been ruled out.
Patients with ACTH-producing tumors have measurable (normal) or high ACTH levels, and a tumor that is in the pituitary gland (Cushing disease) or elsewhere (ectopic ACTH syndrome). Radiologic imaging helps to identify these tumors. Because pituitary disease is most common, and identification of such a tumor influences the need for other testing, magnetic resonance imaging (MRI) of the pituitary is usually the next test. However, pituitary tumors are often very small (microadenomas, (10mm or less in diameter), and may not be detected with radiologic imaging in almost half of people who ultimately require surgery.
A CRH stimulation test conducted without pretreatment with dexamethasone helps to distinguish between pituitary and non-pituitary tumors. The high-dose dexamethasone suppression test (HDDST) may also be helpful. HDDST testing follows the same format as LDDST, but uses higher doses of dexamethasone.
Inferior petrosal sinus sampling (IPSS) is an effective way to confirm a pituitary etiology for Cushing syndrome, in which levels of ACTH are measured in the blood from veins that drain the pituitary (inferior petrosal sinuses). If this study indicates ectopic ACTH secretion, other imaging tests are done to find the tumor, possibly including computerized tomography (CT and MRI scans of chest and abdomen) and other nuclear medicine studies such as Octreoscan or PET studies.
Treatment
The treatment of Cushing syndrome is directly related to the cause of the cortisol overproduction.
If the cause of the elevated level of cortisol is the result of the long-term use of hormones such as prednisone for the treatment of another disorder, the dosage should gradually be reduced under medical supervision until symptoms are under control.
Pituitary tumors may be surgically removed during an operation known as a trans-nasal or sub-labial transsphenoidal adenomectomy. Specific surgical procedures and long-term results can vary greatly depending on the type and location of the tumor and the expertise of the surgeon. The success rate of this surgery is approximately 80 percent. The complication rate is generally low, and similar to that for gall bladder surgery. If surgery only produces a temporary cure, or recurrence of disease, surgery can be repeated. After successful surgery, there is an expected drop in the production of adrenocorticotrophic hormone and cortisol. Therefore, patients may require temporary administration of synthetic replacement hormone (hydrocortisone or prednisone). This drug therapy typically lasts for less than one year, while the normal glands are recovering.
Some people with Cushing disease are not good candidates for surgery and some others may have had surgery that was unsuccessful. For these affected individuals, conventional radiation therapy directed at the pituitary gland may be administered for a minimum of six weeks. Alternatively, at certain centers, a one-time, focused radiation treatment can be used (stereotactic radiosurgery, gamma knife, and Cyber knife or proton beam radiation). Improvement of symptoms over time occurs in up to 85 percent of patients.
The drug ketoconazole may be given alone or in combination with radiation therapy to help inhibit cortisol production and to speed recovery. Other drugs used to reduce adrenal gland production of cortisol include metyrapone and mitotane. Another drug, cabergoline, has occasionally shown to reduce cortisol production in about 20% of patients by acting on the pituitary tumor.
The removal or destruction of ACTH-secreting tumors is essential to reverse ectopic ACTH syndrome. Surgical removal is effective treatment of benign and some malignant tumors. Other treatments of cancers producing Cushing syndrome depend on the type of cancer and the extent to which it has spread. Such treatments may include surgery, radiation, chemotherapy and/or immunotherapy. In addition, the administration of a cortisol-inhibiting drug such as ketoconazole or mitotane can be an important part of this treatment.
Korlym (mifepristone) was approved by the FDA in 2012 as a treatment to control hyperglycemia in adults with endogenous Cushing syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery, or who have not successfully responded to surgery. Korlym works by blocking the binding of cortisol to its receptor, thus reducing the effects of excess cortisol. Another form of suppressive medical therapy is the drug Signifor (pasireotide) which may be effective but has elevated glucose levels as a side effect.
In 2020, the FDA approved Isturisa (osilodrostat) for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. This drug directly addresses cortisol overproduction by blocking the enzyme known as 11-beta-hydroxylase, thus preventing cortisol synthesis.
Because cortisol hypersecretion comes from the adrenal glands, in selected cases (usually in very ill patients who have not responded to other therapies), surgical removal of the adrenal glands can be considered. This surgery risks the development of another problem called Nelson syndrome, which can result in the activation of the underlying pituitary tumor due to a loss of inhibition from adrenal secretions.
Active investigation of novel diagnostic and therapeutic strategies for the management of Cushing syndrome and its causes are under continuing investigation in the United States and abroad.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Laws ER Jr., (ed). Cushing’s Disease: An Often Misdiagnosed and Not So Rare Disorder. New York, NY: Elsevier (Academic Press); 2017, 216pp.
Fung J, The Obesity Code. Greystone Books, Vancouver/Berkeley; 2015.
Swearingen B, Biller B. (eds). Diagnosis and Management of Pituitary Disorders, Totowa, NJ: Humana Press; 2008, 475.pp.
JOURNAL ARTICLES
Laws ER Jr, Catalino MP, Machine learning and artificial intelligence applied to the diagnosis and management of Cushing disease. Neurosurg Focus. 2020; 48; 1-3.
Wang,F, Catalino M, Bi WL, Dunn IF, Smith TR, Guo Y, Hordejuk D, Kaiser U, Laws, ER. Post-operative day one morning cortisol as a biomarker to predict long-term remission of Cushing disease. J Clin Endocrinol Metabol, 2020.
Burke WT, Penn DL, Repetti, CS, Iuliano, S, Laws ER. Outcomes for repeat transspnenoidal surgery for recurrent Cushings’s disease: Updated. Neurosurgery. 2019; 6:E1030-1036 PMID 31140553
Bunevicius A, Laws ER, Vance, ML, Iuliano S, Sheehan, J. Surgical and radiosurgical treatment strategies in Cushing’s disease. Journal of Neuro-Oncology. 2019 doi: 110.1007/s 11060-019-03325-6
Theodoropoulou M, Reincke M. Tumor-directed therapeutic targets in Cushing disease. J Clin Endocrinol Metab, 2019; 104:925-933.
Zaidi HA, Penn DL, Cote DJ, Laws ER Jr, Root cause analysis of diagnostic and surgical failures in the treatemnt of suspected Cushing’s disease. J Clin Neurosci. 2018; 53: 153-159.
Smith TR., Hulou MM, Huang KT, et al. Complications after transsphenoidal surgery for patients with Cushing’s disease and silent corticotroph adenomas. Neurosurg Focus 2015;38(2):E12.
Iuliano S L. and Laws, Jr. ER. Early recognition of Cushing’s disease: a case study. J Am Assoc Nurse Pract. 2013;25(8): 402-406.
Starke RM., Reames DL, Chen CJ, Laws ER and Jane JA, Jr. Endoscopic transsphenoidal surgery for cushing disease: techniques, outcomes, and predictors of remission. Neurosurgery 2013; 72(2): 240-247; discussion 247. https://www.ncbi.nlm.nih.gov/pubmed/23149974
Lodish M, Dunn SV, Sinaii N, Keil MF, Stratakis CA. Recovery of the hypothalamic-pituitary-adrenal axis in children and adolescents after surgical cure of Cushing’s disease.J Clin Endocrinol Metab. 2012;97(5):1483-91 https://www.ncbi.nlm.nih.gov/pubmed/22399509
Castinetti F, Morange I, Conte-Devolx B, Brue T. Cushing’s disease. Orphanet J Rare Dis. 2012;7(1):41. https://www.ncbi.nlm.nih.gov/pubmed/22710101
Aytug S., Laws ER Jr., and Vance ML Assessment of the utility of the high-dose dexamethasone suppression test in confirming the diagnosis of Cushing disease. Endocr Pract. 2012;18(2):152-157. https://www.ncbi.nlm.nih.gov/pubmed/21856594
Tritos NA, Biller BM. Advances in medical therapies for Cushing’s syndrome. Discov Med. 2012;13(69):171-9. https://www.ncbi.nlm.nih.gov/pubmed/22369976
Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C; SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012;97(6):2039-49. https://www.ncbi.nlm.nih.gov/pubmed/22466348
Zemskova MS, Gundabolu B, Sinaii N, et al. Utility of various functional and anatomic imaging modalities for detection of ectopic adrenocorticotropin-secreting tumors. J Clin Endocrinol Metab. 2010 Mar;95(3):1207-19. https://www.ncbi.nlm.nih.gov/pubmed/20089611
Pivonello R, De Martino MC, et al. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab. 2009;94(1):223-30. https://www.ncbi.nlm.nih.gov/pubmed/18957500
Newell-Price J. Diagnosis/differential diagnosis of Cushing’s syndrome: a review of best practice. Best Pract Res Clin Endocrinol Metab. 2009;23 Suppl 1:S5-14. https://www.ncbi.nlm.nih.gov/pubmed/20129193
Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526-40. https://www.ncbi.nlm.nih.gov/pubmed/18334580
Prevedello DM, Pouratian N, Sherman J, Jane JA Jr, Vance ML, Lopes MB, Laws ER Jr.. Management of Cushing’s disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. J Neurosurg. 2008;109(4):751-759.
Patil CG, Veeravagu A, Prevedello DM, Katznelson L, Vance ML, Laws ER Jr. Outcomes after repeat transsphenoidal surgery for recurrent Cushing’s disease. Neurosurgery. 2008 Aug;63(2):266-70; discussion 270-1.
Patil CG, Prevedello DM, Lad SP, Vance ML, Thorner MO, Katznelson L, Laws ER Jr. Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery.”. J Clin Endocrinol Metab. 2008 Feb;93(2):358-62. Epub 2007 Dec 4.
Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454-62. https://www.ncbi.nlm.nih.gov/pubmed/18413427
Lad SP, Patil CG, Laws ER Jr, Katznelson L. The role of inferior petrosal sinus sampling in the diagnostic localization of Cushing’s disease. Neurosurg Focus. 2007;23(3):E2.
Batista DL, Riar J, Keil M, Stratakis CA. Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics. 2007;120(3):e575-86. https://www.ncbi.nlm.nih.gov/pubmed/17698579
Kanter AS, Diallo AO, Jane JA Jr, Sheehan JP, Asthagiri AR, Oskouian RJ, Okonkwo DO, Sansur CA, Vance ML, Rogol AD, Laws ER Jr. Single-center experience with pediatric Cushing’s disease. J Neurosurg. 2005 Nov;103(5 Suppl):413-20.
De Tommasi C, Vance ML, Okonkwo DO, Diallo A, Laws ER Jr. Surgical management of adrenocorticotropic hormone-secreting macroadenomas: outcome and challenges in patients with Cushing’s disease or Nelson’s syndrome. J Neurosurg. 2005;Nov;103(5):825-30.
Locatelli M, Vance ML, Laws ER. Clinical review: the strategy of immediate reoperation for transsphenoidal surgery for Cushing’s disease. J Clin Endocrinol Metab. 2005 Sep;90(9):5478-82. Epub 2005 Jun 14.
Sonino N, Fava GA. Psychiatric disorders associated with Cushing’s syndrome. Epidemiology, pathophysiology and treatment. CNS Drugs. 2001;15(5):361-73. https://www.ncbi.nlm.nih.gov/pubmed/11475942
Colao A, Faggiano A, Pivonello R, et al. Inferior petrosal sinus sampling in the differential diagnosis of Cushing’s syndrome: results of an Italian multicenter study. Eur J Endocrinol. 2001;144(5):499-507. https://www.ncbi.nlm.nih.gov/pubmed/11331216
Savage MO, Lienhardt A, Lebrethon MC, et al. Cushing’s disease in childhood: presentation, investigation, treatment and long-term outcome. Horm Res. 2001;55 Suppl 1:24-30. https://www.ncbi.nlm.nih.gov/pubmed/11408758
Chrousos GP. The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes. Int J Obes Relat Metab Disord. 2000;24 Suppl 2:S50-55. https://www.ncbi.nlm.nih.gov/pubmed/10997609
Lindholm J. Cushing’s syndrome: historical aspects. Pituitary. 2000 Oct;3(2):97-104.
INTERNET
Nguyen HCD.Iatrogenic Cushing Syndrome.Medscape. Updated: Aug 26, 2020 https://emedicine.medscape.com/article/117365-overview Accessed July 22, 2021.
Cushing syndrome. MedlinePlus. Review Date 5/6/2019.
https://medlineplus.gov/ency/article/000410.htm. Accessed July 22, 2021.
Cushing’s Syndrome. National Endocrine and Metabolic Diseases Information Service. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Last Reviewed May 2018. https://www.niddk.nih.gov/health-information/endocrine-diseases/cushings-syndrome Accessed July 22, 2021.
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