Not to be confused with Cushing's triad, due to increased intracranial pressure.
|Synonyms||Hypercortisolism, Itsenko-Cushing syndrome, hyperadrenocorticism|
|Person's facial appearance 3 months after treatment with inhaled fluticasone|
|Symptoms||High blood pressure, abdominal obesity with thin arms and legs, reddish stretch marks, round red face, fat lump between the shoulders, weak muscles, acne, fragile skin|
|Usual onset||20–50 years|
|Causes||Prolonged exposure to cortisol|
|Diagnostic method||Requires a number of steps|
|Treatment||Based on underlying cause|
|Prognosis||Generally good with treatment|
|Frequency||2–3 per million people per year|
[edit on Wikidata]
Cushing's syndrome 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. The first step is to check the medications a person takes. The second step is to 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, a blood test for ACTH may be done to determine if the pituitary is involved.
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, and/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 overproduction 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 ("buffalo hump" or lipodystrophy), 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 disorders 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 increased urination (and accompanying increased thirst), persistent high blood pressure (due to cortisol's enhancement of epinephrine's vasoconstrictive effect) and insulin resistance (especially common with ACTH production outside the pituitary), 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). Alternatively, it is proposed that the high levels of ACTH, β-lipotropin, and γ-lipotropin, which contain weak MSH function, can act on the melanocortin 1 receptor. 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 gives Cushing’s syndrome, not all Cushing’s syndrome is due to Cushing’s disease.
Brain changes such as cerebral atrophy may occur. This atrophy is associated with areas of high glucocorticoid receptor concentrations such as the hippocampus and correlates highly with psychopathological personality changes.
Several possible causes of Cushing's syndrome are known.
External versus internal
The most common cause of Cushing's syndrome is the taking 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 celllung 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 CRH in the hypothalamus, which decreases the amount of ACTH released from the anterior 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 due to extra ACTH it is known as ectopic Cushing syndrome. This may be seen in a paraneoplastic syndrome.
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.
Plasma CRH levels are inadequate at diagnosis (with the possible exception of tumors secreting CRH) because of peripheral dilution and binding to CRHBP.
Most cases of Cushingoid symptoms are caused by corticosteroid medications, such as those used for asthma, arthritis, eczema 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.
People with Cushing's syndrome have increased morbidity and mortality as compared to the general population. The most common cause of mortality in Cushing's syndrome is cardiovascular events. People with Cushing's syndrome have nearly 4 times increased cardiovascular mortality as compared to the general population.
For more information on the form in horses, see pituitary pars intermedia dysfunction.
- ^ abCelik, O; Niyazoglu, M; Soylu, H; Kadioglu, P (29 August 2012). "Iatrogenic Cushing's syndrome with inhaled steroid plus antidepressant drugs". Multidisciplinary respiratory medicine. 7 (1): 26. doi:10.1186/2049-6958-7-26. PMC 3436715. PMID 22958272.
- ^ abcd"What are the symptoms of Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
- ^ abcdefg"Cushing's Syndrome". National Endocrine and Metabolic Diseases Information Service (NEMDIS). July 2008. Archived from the original on 10 February 2015. Retrieved 16 March 2015.
- ^ abcdef"How do health care providers diagnose Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
- ^ abcd"What are the treatments for Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
- ^ abc"Is there a cure for Cushing's syndrome?". 2012-11-30. Archived from the original on 27 March 2015. Retrieved 16 March 2015.
- ^ abcd"How many people are affected by or at risk for Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
- ^Forbis, Pat (2005). Stedman's medical eponyms (2nd ed.). Baltimore, Md.: Lippincott Williams & Wilkins. p. 167. ISBN 9780781754439. Archived from the original on 2017-09-08.
- ^"What causes Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. 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.
- ^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. doi:10.1016/j.ejim.2011.10.013. PMID 22385888.
- ^Steffensen, C; Bak, AM; Rubeck, KZ; Jørgensen, JO (2010). "Epidemiology of Cushing's syndrome". Neuroendocrinology. 92 Suppl 1: 1–5. doi:10.1159/000314297. PMID 20829610.
- ^"Cushing Syndrome: Condition Information". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
- ^Etienne Cote (2014). Clinical Veterinary Advisor: Dogs and Cats (3 ed.). Elsevier Health Sciences. p. 502. ISBN 9780323240741. Archived from the original on 2017-09-08.
- ^McCue, PM (December 2002). "Equine Cushing's disease". The Veterinary Clinics of North America. Equine Practice. 18 (3): 533–43, viii. doi:10.1016/s0749-0739(02)00038-x. PMID 12516933.
- ^"Cushing syndrome". Mayo Clinic. March 28, 2013. Archived from the original on May 25, 2015. Retrieved 2015-05-25.
- ^Fudge, EB; von Allmen, D; Volmar, KE; Calikoglu, AS (2009). "Cushing Syndrome in a 6-Month-Old Infant due to Adrenocortical Tumor". International journal of pediatric endocrinology. 2009: 168749. doi:10.1155/2009/168749. PMC 2798106. PMID 20049152.
- ^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/JCEM.83.9.5084. 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.
- ^Andela, CD; van Haalen, FM; Ragnarsson, O; Papakokkinou, E; Johannsson, G; Santos, A; Webb, SM; Biermasz, NR; van der Wee, NJ; Pereira, AM (July 2015). "MECHANISMS IN ENDOCRINOLOGY: Cushing's syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies". European Journal of Endocrinology. 173 (1): R1–14. doi:10.1530/EJE-14-1101. PMID 25650405.
- ^Dorn, Lorah D.; Burgess, Ellen S.; Friedman, Theodore C.; Dubbert, Billinda; Gold, Philip W.; Chrousos, George P. (1997). "The Longitudinal Course of Psychopathology in Cushing's Syndrome after Correction of Hypercortisolism". The Journal of Clinical Endocrinology & Metabolism. 82 (3): 912–919. doi:10.1210/jcem.82.3.3834. ISSN 0021-972X.
- ^Cope, Lora M.; Shane, Matthew S.; Segall, Judith M.; Nyalakanti, Prashanth K.; Stevens, Michael C.; Pearlson, Godfrey D.; Calhoun, Vince D.; Kiehl, Kent A. (2012). "Examining the effect of psychopathic traits on gray matter volume in a community substance abuse sample". Psychiatry Research: Neuroimaging. 204 (2–3): 91–100. doi:10.1016/j.pscychresns.2012.10.004. ISSN 0925-4927. PMC 3536442. PMID 23217577.
- ^Wolkowitz, Owen M.; Lupien, Sonia J.; Bigler, Erin D. (2007). "The "Steroid Dementia Syndrome": A Possible Model of Human Glucocorticoid Neurotoxicity". Neurocase. 13 (3): 189–200. doi:10.1080/13554790701475468. ISSN 1355-4794. PMID 17786779.
- ^Weber, Sabrina; Habel, Ute; Amunts, Katrin; Schneider, Frank (2008). "Structural brain abnormalities in psychopaths—a review". Behavioral Sciences & the Law. 26 (1): 7–28. doi:10.1002/bsl.802. ISSN 0735-3936. PMID 18327824.
- ^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 SyndromeArchived 2011-04-10 at the Wayback Machine. 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 syndromeArchived 2013-10-02 at the Wayback Machine. 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. (2010). "Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease". Journal of Neurosurgery. 111: 531–9. doi:10.3171/2008.8.JNS08339. PMC 2945523. PMID
Bartholin T. Bartholinus anatomy in four books and four manuals. N Culpepper, ed. London, 1668Google Scholar
Winslow JB. An anatomical exposition of the structure of the human body. London, 1733.Google Scholar
Coxe JR.On the function of the capsuleÿ renales. Am J Med Sci 18276:40–49.Google Scholar
v. Sömmering ST. Lehre von der Eingeweiden und Sinnesorganen des menschlichen Körpers. E Huschke, ed. Leipzig, 1845.Google Scholar
Addison T. On the constitution and local effects of disease of the suprarenal capsules. London, 1855.Google Scholar
Brown-Séquard ME. Recherches experimentales sur la physiologie et la pathologie des capsules surrénales. Acad Sci Paris 1856;43:422–425.Google Scholar
Shumacker HB. The early history of the adrenal glands. Bull Instit Hist Med 1936;4:39–46.Google Scholar
Ingall JRF. Glandulae renibus imcumbentes. Surgery 1965; 57:331–333.Google Scholar
Schneider CV. Dissertatio de osse cribriformi. Wittenberg, 1655.Google Scholar
Ascher B. Ñber die Funktion der Hypophyse. Pflüger's Arch gesamm Physiol 1912:146:1–46.Google Scholar
Schaefer EA, Hering PT. The action of pituitary extracts upon the kidney. Philos Trans R Soc London, Series B. 1908;199:1–29.Google Scholar
Fritsche CF, Klebs E. Ein Beitrag zur Pathologie des Riesenwuchses. Vogel, Leipzig, 1884.Google Scholar
Cunningham ED. A large sub-arachnoid cyst involving the greater part of the parietal lobe of the brain. J Anat Physiol 1879;13:508–517.Google Scholar
Landolt AM, Zachmann M. The Irish giant: new observations concerning the nature of his ailment. Lancet 1980;1: 1311–1312.Google Scholar
Harris GW. Humours and hormones. J Endocrinol 1972; 53:2–23.Google Scholar
Bulloch W, Sequeira JH. On the relation of the suprarenal capsules to the sexual organs. Transact Path Soc London 1905;56:189–208.Google Scholar
Guthrie L, Emery WE. Precocious obesity, premature sexual and physical development, and hirsuties in relation to hypernephroma and other morbid conditions. Transact Clin Soc Lond 1907;40:175–202.Google Scholar
Cushing H. The pituitary body and its disorders. Philadelphia & London: Lippincott Comp., 1912.Google Scholar
Cushing H. Surgical experiences with pituitary disorders. J Am Med Assn 1914;63:1515–1525.Google Scholar
Cushing H. The basophilic adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;50:137–195.Google Scholar
Carney JA. The search for Harvey Cushing's patient, Minnie G., and the cause of her hypercortisolism. Am J Surg Pathol 1995;19:100–108.Google Scholar
Young WF Jr, Carney JA, Musa BU, Wulffstraat NM, Lens JW, Drexhage HA. Familial Cushing's syndrome due to primary pigmented nodular adrenocortical disease. Reinvestigation 50 years later. N Engl J Med 1989;321:1659–1664.Google Scholar
Turney HG. Discussion on disease of the pituitary body. Proc Roy Soc Med 1913;6:69–78.Google Scholar
Anderson J. A case of polyglandular syndrome with adrenal hypernephroma. Glasgow Med J 1915;83:178–192.Google Scholar
Reichman V. Ñber ein ungewöhlisches Krankheitsbild bei Hypophysenadenom. Dtsch Arch klin Med 1919;130:133–150.Google Scholar
Parkes Weber F. Cutaneous striae, purpura, high blood pressure, amenorrhoea and obesity, of the type sometimes connected with cortical tumours of the adrenal glands, occurring in the absence of any such tumour-with some remarks on the morphogenetic and hormonic effects of true hypernephromata of the adrenal cortex. Brit J Dermatol 1926;38:1–19.Google Scholar
Christy NP. Cushing's syndrome: the natural disease. In: Christy NP, ed. The Human Adrenal Cortex. New York: Harper & Row, 1971, 360–364.Google Scholar
Cushing H. Further notes on pituitary basophilism. JAMA 1932;99:281–284.Google Scholar
Cushing H. Dyspituitarism: twenty years later; with special consideration of the pituitary adenomas. Arch Intern Med 1933;51:487–557.Google Scholar
Thompson KW, Cushing H. Experimental pituitary basophilism. Proc Roy Soc Lond (Series B) 1932;115:88–100.Google Scholar
Cushing H. Posterior pituitary activity from an anatomical standpoint. Am J Path 1933;9:539–547.Google Scholar
Oppenheimer BS, Fishberg Am. The association of hypertension with suprarenal tumors. Arch Intern Med 1924;34:631–644.Google Scholar
Bishop PMF, Close HG. A case of basophil adenoma of the anterior lobe of the pituitary: “Cushing's syndrome”. Guy's Hosp Rep 1932;82:143–153.Google Scholar
Bauer J. Ñberfunktion des gesamten Nervensystems ohne anatomischen Befund. Wien klin Wschr 1930;43:582–586.Google Scholar
Medvei CV, Wermer P. Zur Differentialdiagnose des basophilen Adenoms der Hypophyse. Medizin Klinik 1934;2: 992–994.Google Scholar
Evans HM, Long JA. Characteristic effects upon growth, oestrus, and ovulation induced by the intraperitoneal administration of fresh anterior hypophyseal substance. Proc Nat Acad Sci 1922;8:38–39.Google Scholar
Collip JB, Anderson E, Thomson DL. The adrenotropic hormone of the anterior pituitary lobe. Lancet 1933;2:347–348.Google Scholar
Li CH, Simpson ME, Evans HM. Adrenocorticotropic hormone. J Biol Chem 1943;149:413–424.Google Scholar
Sayers G, White A, Long CNH. Preparation and properties of pituitary adrenocorticotropic hormone. J Biol Chem 1943; 149:425–436.Google Scholar
Jores A. Ñber Hormonuntersuchungen bei Morbus Cushing. Klin Wochensch 1935;14:1348–1352.Google Scholar
Crooke AC. A change in the basophilic cells of the pituitary gland common to conditions which exhibit the syndrome attributed to the basophilic adenoma. J Pathol Bacteriol 1935;41:339–349.Google Scholar
Albright F. Cushing's syndrome: its pathology and physiology, its relationship to the adreno-genital syndrome, and its connection with the problem of the reaction of the body to injurious agents. Harvey Lectures 1942–43 1943;38:123–186.Google Scholar
Kepler EJ. Cushing's disease: a primary disorder of the adrenal cortices? Ann NY Acad Sci 1948:50:657–678.Google Scholar
Bauer J. The so-called Cushing's syndrome, its history, terminology and differential diagnosis. Acta Med Scand 1950; 137:411–416.Google Scholar
Brown WH. A case of pluriglandular syndrome: “diabetes of bearded women”. Lancet 1928;2:1022–1023.Google Scholar
Achard C, Thiers T. Le virilisme pilaire (diabete des femmes a barbe). Bull Acad Natl Med (Paris) (3 series) 1921;86: 51–56.Google Scholar
Christy NP. Adrenocorticotrophic activity in the plasma of patients with Cushing's syndrome associated with pulmonary neoplasms. Lancet 1961;1:85–86.Google Scholar
Meador CK, Liddle GW, Island DP, et al. Cause of Cushing's syndrome in patients with tumors arising from “nonendocrine” tissue. J Clin Endocrinol Metab 1962;22:693–703.Google Scholar
Carey RM, Varma SK, Drake CR, Thorner MO, Kovacs K, Rivier J, Vale W. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's syndrome. N Engl J Med 1984;311:13–20.Google Scholar
Belsky JL, Cuello B, Svanson LW, Simmons DM, Jarrett RM, Brasa F. Cushing's syndrome due to ectopic production of corticotropin-releasing factor. J Clin Endocrinol Metab 1985;60:496–500.Google Scholar
Mosier HD, Flynn PJ, Will DW, Turner RD. Cushing's syndrome with multinodular adrenal glands. J Clin Endocrinol Metab 1960;20:632–640.Google Scholar
De Moor P, Roels H, Delaere K, Crabbé J. Unusual case of adrenocortical hyperplasia. J Clin Endocrinol Metab 1965; 25:612–620.Google Scholar
Meador CK, Bowdoin B, Owen WC Jr, Farmer TA Jr. Primary adrenocortical nodular dysplasia: a rare cause of Cushing's syndrome. J Clin Endocrinol Metab 1967;27:1255–1263.Google Scholar
Carney AJ, Gordon H, Carpenter PC, Shenoy BV, Go VLW. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 1985;64:270–283.Google Scholar
Kirschner MA, Powell RD, Lipsett MB. Cushing's syndrome: nodular cortical hyperplasia of adrenal glands with clinical and pathologic features suggesting adrenocortical tumor. J Clin Endocrinol Metab 1964;24:947–955.Google Scholar
Lacroix A, Bolté E, Tremblay J, Dupré J, Poitras P, Foutnier H, et al. Gastric inhibitory polypeptide-dependent cortisol hypersecretion—a new cause of Cushing's syndrome. N Engl J Med 1992;327:974–980.Google Scholar
Reznik Y, Allali-Zerah V, Chayvialle JA, Leroyer R, Leymarie P, Travert G, et al. Food-dependent Cushing's syndrome mediated by aberrant adrenal sensitivy to gastric inhibitory polypeptide. N Engl J Med 1992;327:981–986.Google Scholar
Thornton JK. Abdominal nephrectomy for large sarcoma of the left suprarenal capsule: recovery. Trans Clin Soc Lond 1890;23:150–153.Google Scholar
Priestley JT, Sprague RG, Walters W, Salassa RM. Subtotal adrenalctomy for Cushing's syndrome. Ann Surg 1951;134: 464–472.Google Scholar
Nelson DH, Meakin JW, Thorn GW. ACTH producing pituitary tumours following adrenalectomy for Cushing's syndrome. Ann Intern Med 1960;52:560–569.Google Scholar
Horsley V. On the technique of operation on the central nervous system. Br Med J 1906;2:411–423.Google Scholar
Krause F. Hirnchurgie. I: Die deutsche Klinik am Eingange des zwanzigsten Jahrhunderts, vol. VIII. In: v. Leyden E, Klemperer F, eds Berlin, Wien: Urban & Schwarzenberg, 1905: p. 1004.Google Scholar
Schloffer, H. Erfolgreiche Operation eines Hypophysentumors auf nasalem Wege. Wien klin Wochensch 1907;20:621–624.Google Scholar
Hirsch O. Eine neue Methode der endonasalen Operation von Hypophysentumoren. Wien klin Wochensch 1909;21: 636–637.Google Scholar
Lisser H. Hypophysectomy in Cushing's disease. J Nerv Ment Dis 1944;99:727–733.Google Scholar
Arner B, Luft R, Olivecrona H, Sjögren B. Successful treatment of a case of Cushing's syndrome. J Clin Endocrinol Metab 1953;13:1101–1108.Google Scholar
Landolt A. Development of pituitary adenoma treatment—a critical essay. Pituitary 1999;2:103–112.Google Scholar
Osler W. On six cases of Addison's disease with the report of a case greatly benefited by the use of the suprarenal gland extract. Bull Johns Hopkins Hosp 1896;7:208–209.Google Scholar
Guiot G, Thibaut B. L'extirpation des adéenomes hypophysaires par voie transsphénoidale. Neurochirurgia 1959; 1:133–150.Google Scholar
Hardy J. Transsphenoidal microsurgery of the normal and pathological pituitary. Clin Neurosurg 1969;16:185–217.Google Scholar