|55 Kenosia Avenue
Danbury, CT 06810
Toll Free: 1.800.999.6673
The National Organization for Rare Disorders (NORD) web site, its databases, and the contents thereof are copyrighted by NORD. No part of the NORD web site, databases, or the contents may be copied in any way, including but not limited to the following: electronically downloading, storing in a retrieval system, or redistributing for any commercial purposes without the express written permission of NORD. Permission is hereby granted to print one hard copy of the information on an individual disease for your personal use, provided that such content is in no way modified, and the credit for the source (NORD) and NORD’s copyright notice are included on the printed copy. Any other electronic reproduction or other printed versions is strictly prohibited.
The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.
Copyright 1986, 1987, 1988, 1989, 1991, 1992, 1994, 1995, 1997, 1998, 1999, 2002, 2007, 2012
NORD is very grateful to Lynnette Nieman, MD, FACP, Senior Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Chief, Endocrinology Consultation Service, National Institutes of Health and Constantine A. Stratakis, MD, D(med)Sci, Scientific Director, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, for assistance in the preparation of this report.
Cushing syndrome is a rare endocrine disorder characterized by a variety of symptoms and physical abnormalities that occur due to excessive amounts of the hormone cortisol, a type of 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. 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 upper body 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 with slowed growth rates.
In 1912, Harvey Cushing described a patient with hypercorticism 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, was first described by Dr. Cushing in 1932. Though pituitary surgery was introduced in the early 20th century, it was not until 1933 that neurosurgery was performed on the first patient with Cushing disease.
People with Cushing syndrome gain an excessive amount of weight. Obesity results in fat deposits around the face causing a moon-shaped or rounded appearance. Fat also accumulates around the neck (supraclavicular) and upper back (dorsal cervical). Obesity also occurs in the trunk of the body, 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 be 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 may also develop. Some people have thinning of the hair on the head and some women may develop menstrual irregularity (oligoamenorrhea, amenorrhea). Males with this disorder may experience a decrease in fertility and a diminished or absent sex drive.
Children and adolescents with Cushing syndrome may experience growth retardation 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 symptoms may include abnormally high blood sugar (hyperglycemia), increased thirst and urination, impaired immune function, 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. Sleep disturbance is common.
Cushing syndrome is a rare endocrine disorder caused by abnormally excessive amounts of the hormone cortisol.
Most cases of Cushing syndrome are due to 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 of Cushing syndrome as a side effect of such treatment.
Cushing syndrome can also be due to endogenous causes, approximately 70% of which 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. 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.
Though most cases of Cushing syndrome are not inherited, in rare cases it results from an inherited tendency to develop tumors in one or more hormone-secreting glands. Children of young adults with primary pigmented nodular adrenocortical disease (PPNAD) develop small cortisol-producing tumors in the adrenal glands. Cushing syndrome may develop with multiple endorcrine neoplasia type 1 (MEN1) from development of hormone-secreting tumors of the lung, pancreas, or pituitary gland.
Most cases of Cushing syndrome are due to exogenous corticosteroid medication. It is reported that the incidence of endogenous Cushing syndrome is approximately 13 cases per million people annually.
Cushing syndrome caused by either an adrenal or pituitary tumor affects females five times more frequently than males. Symptoms commonly begin between 25 to 40 years of age. Men are affected 3 times more than women by ectopic ACTH production that is caused by lung cancer, which occurs later in life.
The following disorders can have symptoms similar to those of Cushing syndrome, even though people with these disorders do not have abnormally elevated cortisol levels. Comparisons may be useful for a differential diagnosis:
Polycystic ovary syndrome is characterized by absent or irregular menstruation, excessive hair on the face and/or body (hirsutism), weight gain, acne, male pattern balding, and impaired insulin action and diabetes. (For more information on this disorder, choose "polycystic ovary syndrome" as your search term in the Rare Disease Database.)
Metabolic syndrome is a combination of medical conditions related to obesity that includes excess weight around the waist, high blood pressure, high blood sugar level and abnormal levels of cholesterol and triglycerides in the blood. This cluster of problems increases the risk of heart disease, stroke, and diabetes.
Pseudo-Cushing syndrome presents with some symptoms and mildly abnormal hormone levels that overlap with those seen in Cushing syndrome. However these patients do not have the tumors of Cushing syndrome. Pseudo-Cushing syndrome has been identified in patients with alcoholism, depression, obesity, or poorly controlled diabetes. The mechanism that causes it is unclear (idiopathic).
Diagnosis is based upon a detailed medical history to assess for any use of exogenous glucocorticoids (oral, topical, injection, inhaled), a physical examination, and 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; 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 the cause of Cushing syndrome is 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 a measurable or high ACTH levels, and a tumor that is in the pituitary gland (termed 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) 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. High-dose dexamethasone suppression test (HDDST) may also be helpful. HDDST testing follows the same format as LDDST, but uses higher doses of dexamethasone.
Petrosal sinus sampling is an effective way to identify a pituitary etiology for Cushing syndrome, in which levels of ACTH are measured in the blood from veins that drain the pituitary (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, and other nuclear medicine studies such as Octreoscan or PET scans.
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 due to 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 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. If surgery only produces a temporary cure or if it fails, 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 hormone (hydrocortisone). 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 while 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 or gamma knife radiation). Improvement of symptoms occurs in up to 85 percent 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, was recently 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 cancer 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 (also known as mifepristone) by Corcept Therapeutics 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.
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
For information about clinical trials sponsored by private sources, contact:
Contacts for additional information about Cushing syndrome:
Lynnette Nieman, MD, FACP
Intramural Research Program on Reproductive and Adult Endocrinology
The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Chief, Endocrinology Consultation Service
National Institutes of Health
Building 10, CRC, 1 East, Rm 1-3140
10 Center Dr, MSC 1109
Bethesda, MD 20892-1109
Constantine A. Stratakis, MD, D(med)Sci
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institutes of Health
31 Center Dr, Room 2A46, MSC 2425
Bethesda, MD 20892-2425
PO Box 4121
Brick, NJ 08723
Phone #: N/A
800 #: N/A
Home page: N/A
60 Robbins Rd
Plymouth, MA 02360
Phone #: 617-723-3674
800 #: --
Home page: http://www.csrf.net
1-3 rue de Chantepoulet
Geneva, CH 1211 Switzerland
Phone #: 410-229-080484
800 #: N/A
Home page: http://www.esid.org
PO Box 8126
Gaithersburg, MD 20898-8126
Phone #: 301-251-4925
800 #: 888-205-2311
Home page: http://rarediseases.info.nih.gov/GARD/
505 Northern Bloulevard
Great Neck, NY 11021 USA
Phone #: 516-487-4992
800 #: --
Home page: http://www.nadf.us/
31 Center Dr
Building 31, Room 2A32
Bethesda, MD 20892
Phone #: N/A
800 #: 800-370-2943
Home page: http://www.nichd.nih.gov/
Office of Communications & Public Liaison
Bldg 31, Rm 9A06
31 Center Drive, MSC 2560
Bethesda, MD 20892-2560
Phone #: 301-496-3583
800 #: --
Home page: http://www2.niddk.nih.gov/
Beers MH, Berkow R, eds. The Merck Manual 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:106-09.
Berkow R, ed. The Merck Manual-Home Edition. Whitehouse Station, NJ: Merck Research Laboratories; 1997:714-15.
Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co;1996:1247-49.
Wilson JD, et al. Textbook of Endocrinology. 8th ed. Philadelphia, PA: W.B. Saunders Co; 1992:536-62.
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 http://www.ncbi.nlm.nih.gov/pubmed/22399509
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. http://www.ncbi.nlm.nih.gov/pubmed/22466348
Lindholm J. Cushing's syndrome: historical aspects. Pituitary. 2000 Oct;3(2):97-104.
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. http://www.ncbi.nlm.nih.gov/pubmed/22399509
Tritos NA, Biller BM. Advances in medical therapies for Cushing's syndrome. Discov Med. 2012;13(69):171-9. http://www.ncbi.nlm.nih.gov/pubmed/22369976
Castinetti F, Morange I, Conte-Devolx B, Brue T. Cushing's disease. Orphanet J Rare Dis. 2012;7(1):41. http://www.ncbi.nlm.nih.gov/pubmed/22710101
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. http://www.ncbi.nlm.nih.gov/pubmed/20089611
Kobayashi T. Long-term results of stereotactic gamma knife radiosurgery for pituitary adenomas. Specific strategies for different types of adenoma. Prog Neurol Surg. 2009;22:77-95. http://www.ncbi.nlm.nih.gov/pubmed/18948721
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. http://www.ncbi.nlm.nih.gov/pubmed/20129193
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. http://www.ncbi.nlm.nih.gov/pubmed/18957500
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. 1.http://www.ncbi.nlm.nih.gov/pubmed/18334580
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. http://www.ncbi.nlm.nih.gov/pubmed/18413427
Stratakis CA, Boikos SA. Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias. Nat Clin Pract Endocrinol Metab. 2007;3(11):748-57. http://www.ncbi.nlm.nih.gov/pubmed/17955016
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. http://www.ncbi.nlm.nih.gov/pubmed/17698579
Findling AW, Raff H. Diagnosis and differential diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am. 2002;30:729-47. Endocrinol Metab Clin North Am. 2001;30(3):729-47. http://www.ncbi.nlm.nih.gov/pubmed/11571938
Boscaro M, Barzon L, Fallo F, Sonino N. Cushing's syndrome. Lancet. 2001;357(9258):783-91. http://www.ncbi.nlm.nih.gov/pubmed/11253984
Chee GH, Mathias DB, James RA, Kendall-Taylor P. Transsphenoidal pituitary surgery in Cushing's disease: can we predict outcome? Clin Endocrinol (Oxf). 2001;54(5):617-26. http://www.ncbi.nlm.nih.gov/pubmed/11380492
Estrada J, Garcia-Uria J, Lamas C, et al. The complete normalization of the adrenocortical function as the criterion of cure after transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab. 2001;86(12):5695-99. http://www.ncbi.nlm.nih.gov/pubmed/11739423
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. http://www.ncbi.nlm.nih.gov/pubmed/11331216
Khiat A, Yared Z, Bard C, Lacroix A, Boulanger Y. Long-term brain metabolic alterations in exogenous Cushing's syndrome as monitored by proton magnetic resonance spectroscopy. Brain Res. 2001;911(2):134-40. http://www.ncbi.nlm.nih.gov/pubmed/11511380
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. http://www.ncbi.nlm.nih.gov/pubmed/10997609
Kumagai M, Suzuki S, Yumita W, et al. An ectopic ACTH-producing carcinoid tumor localized by the measurement of ACTH in the bronchial lavage. Endocr J. 2001;48(3):363-67. http://www.ncbi.nlm.nih.gov/pubmed/11523908
Lienhardt A, Grossman AB, Dacie JE, et al. Relative contributions of the inferior petrosal sinus sampling and pituitary imaging in the investigation of children and adolescents with ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab. 2001;86(12):5711-14. http://www.ncbi.nlm.nih.gov/pubmed/11739426
Newell-Price J, Grossman AB. The differential diagnosis of Cushing's syndrome. Ann Endocrinol (Paris). 2001;62(2):173-79. http://www.ncbi.nlm.nih.gov/pubmed/11353890
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. http://www.ncbi.nlm.nih.gov/pubmed/11408758
Sonino N, Fava GA. Psychiatric disorders associated with Cushing's syndrome. Epidemiology, pathophysiology and treatment. CNS Drugs. 2001;15(5):361-73. http://www.ncbi.nlm.nih.gov/pubmed/11475942
Barbetta L, Dall'Asta C, Tomei G, et al. Assessment of cure and recurrence after pituitary surgery for Cushing's disease. Acta Neurochir (Wien) 2001;143(5):477-81; discussion 481-82. http://www.ncbi.nlm.nih.gov/pubmed/11482698
Lindholm J. Cushing's syndrome: historical aspects. Pituitary. 2000 Oct;3(2):97-104.
Stratakis CA, Sarlis N, Kirschner LS, et al. Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med. 1999;131(8):585-91. http://www.ncbi.nlm.nih.gov/pubmed/10523219
Utiger R. Treatment, and retreatment, of Cushing's disease. N Eng J Med. 1997;336(3):215-17. http://www.ncbi.nlm.nih.gov/pubmed/8988904
Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing's disease. N Eng J Med. 1997;336(3):172-7. http://www.ncbi.nlm.nih.gov/pubmed/8988897
Adler GK. Cushing Syndrome. Emedicine. http://emedicine.medscape.com/article/117365-overview. Updated February 22, 2012. Accessed October 16, 2012.
Cushing syndrome. MedlinePlus. http://www.nlm.nih.gov/medlineplus/ency/article/000410.htm. Last Updated December 11, 2011. Accessed October 16, 2012.
Sabet A. Cushing’s Syndrome. Johns Hopkins Medicine. http://www.hopkinsguides.com/hopkins/ub/view/Johns_Hopkins_Diabetes_Guide/547032/all/Cushing%26apos%3Bs+Syndrome. Last Updated June 14, 2011. Accessed October 16, 2012.
Cushing’s syndrome. Mayo Clinic. http://www.mayoclinic.com/health/cushings-syndrome/DS00470. Updated September 11, 2010. Accessed October 16, 2012.
Cushing syndrome - exogenous. MedlinePlus. http://www.nlm.nih.gov/medlineplus/ency/article/000389.htm. Last Updated November 23, 2009. Accessed October 16, 2012.
Cushing’s Syndrome. National Endocrine and Metabolic Diseases Information Service. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). http://www.endocrine.niddk.nih.gov/pubs/cushings/Cushings_Syndrome_508.pdf. July 2008. Accessed October 16, 2012.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. ACTH-Independent Macronodular Adrenal Hyperplasia; AIMAH. Entry No: 219080. Last Edited September 20, 2007. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed October 16, 2012.
Report last updated: 2012/10/16 00:00:00 GMT+0