|Classification and external resources|
|Patient UK||Cushing's syndrome|
Cushing's syndrome, also known as hypercortisolism, Itsenko-Cushing syndrome, and hyperadrenocorticism, is a collection of signs and symptoms due to prolonged exposure to cortisol. Signs and symptoms may include: high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a round red face, a fat lump between the shoulders, weak muscles, weak bones, acne, and fragile skin that heals poorly. Women may have more hair and irregular menstruation. Occasionally there may be changes in mood, headaches, and a chronic feeling of tiredness.
Cushing's syndrome is caused by either excessive cortisol-like medication such as prednisone or a tumor that either produces, or results in the production of excessive cortisol by the adrenal glands. Cases due to a pituitary adenoma are known as Cushing's disease. It is the second most common cause of Cushing's syndrome after medication. A number of other tumors may also cause Cushing's. Some of these are associated with inherited disorders such as multiple endocrine neoplasia type 1 and Carney complex. Diagnosis requires a number of steps. First step is checking the medications a person takes. The second step is measure levels of cortisol in the urine, saliva or in the blood after taking dexamethasone. If this test is abnormal the cortisol may be measured late at night. If the cortisol remains high testing the blood for ACTH to determine if the pituitary is involved may be done.
Most cases can be treated and cured. If due to medications, these can often be slowly stopped. If caused by a tumor, it may be treated by a combination of surgery, chemotherapy, or radiation. If the pituitary was affected, other medications may be required to replace its lost function. With treatment, life expectancy is usually normal. Some in whom surgery is unable to remove the entire tumor have an increased risk of death.
About two to three people per million are affected each year. It most commonly affects people who are 20 to 50 years of age. Women are affected three times more often than men. A mild degree of over production of cortisol without obvious symptoms, however, is more common. Cushing's syndrome was first described by Harvey Cushing in 1932. Cushing's syndrome may also occur in other animals including cats, dogs, and horses.
Signs and symptoms
Symptoms include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity). Common signs include the growth of fat pads along the collarbone, on the back of the neck or "buffalo hump", and on the face - "moon face". Other symptoms include excess sweating, dilation of capillaries, thinning of the skin (which causes easy bruising and dryness, particularly the hands) and mucous membranes, purple or red striae (the weight gain in Cushing's syndrome stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs, or breasts, proximal muscle weakness (hips, shoulders), and hirsutism (facial male-pattern hair growth), baldness and/or extremely dry and brittle hair. In rare cases, Cushing's can cause hypocalcemia. The excess cortisol may also affect other endocrine systems and cause, for example, insomnia, inhibited aromatase, reduced libido, impotence in men, and amenorrhoea/oligomenorrhea and infertility in women due to elevations in androgens. Studies have also shown that the resultant amenorrhea is due to hypercortisolism, which feeds back onto the hypothalamus resulting in decreased levels of GnRH release.
Cognitive conditions, including memory and attention dysfunctions, as well as depression, are commonly associated with elevated cortisol, and may be early indicators of exogenous or endogenous Cushing's. Depression and anxiety are also common.
Other striking and distressing skin changes that may appear in Cushing's syndrome include facial acne, susceptibility to superficial fungus (dermatophyte and malassezia) infections, and the characteristic purplish, atrophic striae on the abdomen.:500
Other signs include polyuria (and accompanying polydipsia), persistent hypertension (due to cortisol's enhancement of epinephrine's vasoconstrictive effect) and insulin resistance (especially common in ectopic ACTH production), leading to high blood sugar and insulin resistance which can lead to diabetes mellitus. Insulin resistance is accompanied by skin changes such as acanthosis nigricans in the axilla and around the neck, as well as skin tags in the axilla. Untreated Cushing's syndrome can lead to heart disease and increased mortality. Cortisol can also exhibit mineralocorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia (common in ectopic ACTH secretion). Furthermore, excessive cortisol may lead to gastrointestinal disturbances, opportunistic infections, and impaired wound healing related to cortisol's suppression of the immune and inflammatory responses. Osteoporosis is also an issue in Cushing's syndrome since osteoblast activity is inhibited. Additionally, Cushing's syndrome may cause sore and aching joints, particularly in the hip, shoulders, and lower back. Cushing’s syndrome includes all the causes of increased cortisol leading to the diseased state. Cushing’s disease is a specific type of Cushing’s syndrome caused by a pituitary tumor leading to excessive production of ACTH (Adrenocorticotropic hormone). Excessive ACTH stimulates the adrenal cortex to produce high levels of cortisol, producing the disease state. Cushing's disease due to excess ACTH may also result in hyperpigmentation. This is due to Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis from Pro-opiomelanocortin (POMC). A variant of Cushing's disease can be caused by ectopic, i.e. extrapituitary, ACTH production from, for example, a small-cell lung cancer. When Cushing's syndrome is caused by an increase of cortisol at the level of the adrenal glands (via an adenoma or hyperplasia), negative feedback ultimately reduces ACTH production in the pituitary. In these cases, ACTH levels remain low and no hyperpigmentation develops. While all Cushing’s disease is Cushing’s syndrome, not all Cushing’s syndrome is Cushing’s disease.
- Rapid weight gain
- Moodiness, irritability, or depression
- Muscle and bone weakness
- Memory and attention dysfunction
- Diabetes mellitus
- Immune suppression
- Sleep disturbances
- Menstrual disorders such as amenorrhea in women
- Decreased fertility in men
Several possible causes of Cushing's syndrome are known.
Exogenous vs. endogenous
The most common cause of Cushing's syndrome is exogenous administration of glucocorticoids prescribed by a health care practitioner to treat other diseases (called iatrogenic Cushing's syndrome). This can be an effect of corticosteroid treatment of a variety of disorders such as asthma and rheumatoid arthritis, or in immunosuppression after an organ transplant. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility. Although rare, Cushing's syndrome can also be due to the use of medroxyprogesterone acetate. In this form of Cushing's, the adrenal glands atrophy due to lack of stimulation by ACTH, since glucocorticoids downregulate production of ACTH. Cushing's syndrome in childhood usually results from use of glucocorticoid medication.
Endogenous Cushing's syndrome results from some derangement of the body's own system of secreting cortisol. Normally, ACTH is released from the pituitary gland when necessary to stimulate the release of cortisol from the adrenal glands.
- In pituitary Cushing's, a benign pituitary adenoma secretes ACTH. This is also known as Cushing's disease and is responsible for 70% of endogenous Cushing's syndrome.
- In adrenal Cushing's, excess cortisol is produced by adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia.
- Tumors outside the normal pituitary-adrenal system can produce ACTH (occasionally with CRH) that affects the adrenal glands. This etiology is called ectopic or paraneoplastic Cushing's disease and is seen in diseases such as small cell lung cancer.
- Finally, rare cases of CRH-secreting tumors (without ACTH secretion) have been reported, which stimulates pituitary ACTH production.
Elevated levels of total cortisol can also be due to estrogen found in oral contraceptive pills that contain a mixture of estrogen and progesterone, leading to Pseudo-Cushing's syndrome. Estrogen can cause an increase of cortisol-binding globulin and thereby cause the total cortisol level to be elevated. However, the total free cortisol, which is the active hormone in the body, as measured by a 24-hour urine collection for urinary free cortisol, is normal.
The hypothalamus is in the brain and the pituitary gland sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland.
Strictly, Cushing's syndrome refers to excess cortisol of any etiology (as syndrome means a group of symptoms). One of the causes of Cushing's syndrome is a cortisol-secreting adenoma in the cortex of the adrenal gland (primary hypercortisolism/hypercorticism). The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low.
Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotroph pituitary adenoma (secondary hypercortisolism/hypercorticism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism). This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because the tumor is unresponsive to negative feedback from high cortisol levels.
When Cushing's syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offers equal detection rates. Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, cortisol levels >50 nmol/l (1.81 µg/dl) would be indicative of Cushing's syndrome because an ectopic source of cortisol or ACTH (such as adrenal adenoma) exists which is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late-night levels of salivary cortisol are high in cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm, causing typical bitemporal hemianopia.
When any of these tests is positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Occasionally, determining the ACTH levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary. In many cases, the tumors causing Cushing's disease are less than 2 mm in size and difficult to detect using MRI or CT imaging. In one study of 261 patients with confirmed pituitary Cushing's disease, only 48% of pituitary lesions were identified using MRI prior to surgery.
Most Cushing's syndrome cases are caused by corticosteroid medications (iatrogenic), such as those used for asthma, arthritis, and other inflammatory conditions. Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms.
If an adrenal adenoma is identified, it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma should be removed after diagnosis. Regardless of the adenoma's location, most patients require steroid replacement postoperatively at least in the interim, as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative.
In those patients not suited for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy. Mifepristone is a powerful glucocorticoid type II receptor antagonist and, since it does not interfere with normal cortisol homeostatis type I receptor transmission, may be especially useful for treating the cognitive effects of Cushing's syndrome. However, the medication faces considerable controversy due to its use as an abortifacient. In February 2012, the FDA approved mifepristone to control high blood sugar levels (hyperglycemia) in adult patients who are not candidates for surgery, or who did not respond to prior surgery, with the warning that mifepristone should never be used by pregnant women.
Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome.
Iatrogenic Cushing's syndrome (caused by treatment with corticosteroids) is the most common form of Cushing's syndrome. Cushing's disease is rare, a Danish study found an incidence of less than one case per million people per year. However, asymptomatic microadenomas (less than 10 mm in size) of the pituitary are found in about one in six individuals.
Timely diagnosis and management of Cushing's syndrome is important, because these patients have increased morbidity and mortality as compared to the general population. The most common cause of mortality in Cushing's syndrome is cardiovascular events. Patients with Cushing's syndrome have nearly 4 times increased cardiovascular mortality as compared to the general population. Recently in was demonstrated that serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1) and glutathione peroxidase (a measure of oxidative stress) are good novel predictors of carotid intima media thickness, which in turn is a very strong predictor of cardiovascular events, in patients with Cushing's syndrome.
The word "cushingoid" is a useful way to consider the complications and symptoms of Cushing's.
Cataracts, Ulcers, Skin: striae, thinning, bruising, Hypertension/ hirsutism/ hyperglycemia, Infections,Necrosis, avascular necrosis of the femoral head, Glycosuria, Osteoporosis, obesity, Immunosuppression, and Diabetes
For more information on the form in horses, see pituitary pars intermedia dysfunction.
- "Cushing's Syndrome". National Endocrine and Metabolic Diseases Information Service (NEMDIS). July 2008. Retrieved 16 March 2015.
- Forbis, Pat (2005). Stedman's medical eponyms (2nd ed. ed.). Baltimore, Md.: Lippincott Williams & Wilkins. p. 167. ISBN 9780781754439.
- "What are the symptoms of Cushing’s syndrome?". 2012-11-30. Retrieved 16 March 2015.
- "What causes Cushing’s syndrome?". 2012-11-30. Retrieved 16 March 2015.
- Nieman, LK; Ilias, I (December 2005). "Evaluation and treatment of Cushing's syndrome.". The American Journal of Medicine 118 (12): 1340–6. doi:10.1016/j.amjmed.2005.01.059. PMID 16378774.
- "How many people are affected by or at risk for Cushing’s syndrome?". 2012-11-30. Retrieved 16 March 2015.
- "How do health care providers diagnose Cushing’s syndrome?". 2012-11-30. Retrieved 16 March 2015.
- "Is there a cure for Cushing’s syndrome?". 2012-11-30. Retrieved 16 March 2015.
- "What are the treatments for Cushing’s syndrome?". 2012-11-30. Retrieved 16 March 2015.
- Graversen, D; Vestergaard, P; Stochholm, K; Gravholt, CH; Jørgensen, JO (April 2012). "Mortality in Cushing's syndrome: a systematic review and meta-analysis.". European journal of internal medicine 23 (3): 278–82. PMID 22385888.
- Steffensen, C; Bak, AM; Rubeck, KZ; Jørgensen, JO (2010). "Epidemiology of Cushing's syndrome.". Neuroendocrinology. 92 Suppl 1: 1–5. PMID 20829610.
- "Cushing Syndrome: Condition Information". 2012-11-30. Retrieved 16 March 2015.
- Etienne Cote (2014). Clinical Veterinary Advisor: Dogs and Cats (3 ed.). Elsevier Health Sciences. p. 502. ISBN 9780323240741.
- McCue, PM (December 2002). "Equine Cushing's disease.". The Veterinary clinics of North America. Equine practice 18 (3): 533–43, viii. PMID 12516933.
- Lado-Abeal, J; Rodriguez-Arnao, J; Newell-Price, JD; Perry, LA; Grossman, AB; Besser, GM; Trainer, PJ (September 1998). "Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels." (PDF). The Journal of Clinical Endocrinology and Metabolism 83 (9): 3083–8. doi:10.1210/jc.83.9.3083. PMID 9745407.
- Belanoff et al. (2001). "Corticosteroids and cognition". J Psychiatric Research 35 (3): 127–145. doi:10.1016/s0022-3956(01)00018-8. PMID 11461709.
- Yudofsky, Stuart C.; Robert E. Hales (2007). The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences (5th ed.). American Psychiatric Pub, Inc. ISBN 1-58562-239-7.
- James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
- Siminoski, K; Goss, P; Drucker, DJ (1989). "The Cushing syndrome induced by medroxyprogesterone acetate". Annals of internal medicine 111 (9): 758–60. doi:10.7326/0003-4819-111-9-758. PMID 2552887.
- Merrin, PK; Alexander, WD (1990). "Cushing's syndrome induced by medroxyprogesterone". BMJ (Clinical research ed.) 301 (6747): 345. doi:10.1136/bmj.301.6747.345-a. PMC 1663616. PMID 2144198.
- Stratakis, CA (2012). "Cushing syndrome in pediatrics". Endocrinology and Metabolism Clinics of North America 41 (4): 793–803. doi:10.1016/j.ecl.2012.08.002. PMC 3594781. PMID 23099271.
- Cushing's Syndrome at The National Endocrine and Metabolic Diseases Information Service. July 2008. Citing: * Nieman, LK; Ilias, I (December 2005). "Evaluation and treatment of Cushing's syndrome.". The American Journal of Medicine 118 (12): 1340–6. doi:10.1016/j.amjmed.2005.01.059. PMID 16378774.
- Schteingart, DE; Lloyd, RV; Akil, H; Chandler, WF; Ibarra-Perez, G; Rosen, SG; Ogletree, R (September 1986). "Cushing's syndrome secondary to ectopic corticotropin-releasing hormone-adrenocorticotropin secretion.". The Journal of Clinical Endocrinology and Metabolism 63 (3): 770–5. doi:10.1210/jcem-63-3-770. PMID 3525603.
- Voyadzis JM, Guttman-Bauman I, Santi M, Cogen P. (2004). "Hypothalamic hamartoma secreting corticotropin-releasing hormone. Case report.". J Neurosurg 100 (2 Suppl Pediatrics): 212–6. doi:10.3171/ped.2004.100.2.0212. PMID 14758953.
- C. W. Burke (1969). "The effect of oral contraceptives on cortisol metabolism". J Clin Pathol 3: 11–18. doi:10.1136/jcp.s1-3.1.11. PMC 1436049.
- Ectopic Cushing syndrome at A.D.A.M. Medical Encyclopedia, PubMedHealth, National Institute of Health
- Raff Hershel, Findling JW (2003). "A physiologic approach to diagnosis of the Cushing syndrome". Annals of Internal Medicine 138 (12): 980–91. doi:10.7326/0003-4819-138-12-200306170-00010. PMID 12809455.
- Jagannathan, J. et al, Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease, Journal of Neurosurgery, 25 September 2010, Retrieved 2014-01-27
- Jr, edited by Lewis S. Blevins (2002). Cushing's syndrome. Boston: Kluwer Academic. p. 115. ISBN 1-4020-7131-0.
- Belanoff et al., 2001, Rapid reversal of psychotic depression using mifepristone, J Clin Psychopharmacol, 21(5) 516-521
- "FDA approves mifepristone (Korlym*) for patients with endogenous Cushing' s syndrome". February 18, 2012.
- Nelson DH, Meakin JW, Thorn GW (1960). "ACTH-producing pituitary tumors following adrenalectomy for Cushing syndrome". Annals of Internal Medicine 52 (3): 560–9. doi:10.7326/0003-4819-52-3-560. PMID 14426442.
- Lindholm J, Juul S et al. (2001). "Incidence and late prognosis of cushing's syndrome: a population-based study.". J Clin Endocrinol Metab 86 (1): 117–23. doi:10.1210/jc.86.1.117. PMID 11231987.
- Ezzat S, Asa SL, Couldwell WT et al. (2004). "The prevalence of pituitary adenomas: a systematic review". Cancer 101 (3): 613–9. doi:10.1002/cncr.20412. PMID 15274075.
- Shivaprasad KS Kumar M, Dutta D, Sinha B, Mondal SA, Maisnam I, Mukhopadhyay S, Chowdhury S. Increased soluble TNF receptor-1 and glutathione peroxidase may predict carotid intima media thickness in females with Cushing’s syndrome. Endocr Pract. 2014 Nov 4:1-22. doi:10.4158/EP14399.OR PMID 25370329
- The European Register on Cushing's Syndrome
- Patient information (PDF)
- Cushing's Support and Research Foundation
- Brochure for Primary Care Physicians, to increase awareness of Cushing's syndrome
- The Pituitary Foundation providing support to patients with Cushing's and other pituitary disorders
- The difference between Cushing’s disease and other forms of Cushing’s syndrome