Editing Cushing's syndrome (section)

==Pathophysiology==
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.{{citation needed|date=August 2020}}

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.{{citation needed|date=August 2020}}

[[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.{{cn|date=October 2021}}

When Cushing's syndrome is due to extra [[ACTH]] it is known as ectopic Cushing syndrome.<ref>[https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001443/ Ectopic Cushing syndrome] {{webarchive|url=https://web.archive.org/web/20131002064759/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001443/ |date=2013-10-02 }} at A.D.A.M. Medical Encyclopedia, PubMedHealth, National Institute of Health</ref> 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.<ref name="pmid12809455">{{cite journal | vauthors = Raff H, Findling JW | title = A physiologic approach to diagnosis of the Cushing syndrome | journal = Annals of Internal Medicine | volume = 138 | issue = 12 | pages = 980–991 | date = June 2003 | pmid = 12809455 | doi = 10.7326/0003-4819-138-12-200306170-00010 | s2cid = 14930007 }}</ref> 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&nbsp;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]].{{citation needed|date=August 2020}}

When any of these tests is positive, [[CT scan]]ning of the adrenal gland and [[MRI]] of the [[pituitary gland]] are performed to detect the presence of any adrenal or pituitary adenomas or [[incidentaloma]]s (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 ([[Inferior petrosal sinus|petrosal sinus]] sampling) is necessary. In many cases, the tumors causing Cushing's disease are less than 2&nbsp;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.<ref>{{cite journal | vauthors = Jagannathan J, Smith R, DeVroom HL, Vortmeyer AO, Stratakis CA, Nieman LK, Oldfield EH | title = Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease | journal = Journal of Neurosurgery | volume = 111 | issue = 3 | pages = 531–539 | date = September 2009 | pmid = 19267526 | pmc = 2945523 | doi = 10.3171/2008.8.JNS08339 }}</ref>

Plasma CRH levels are inadequate at diagnosis (with the possible exception of tumors secreting CRH) because of peripheral dilution and binding to [[CRHBP]].<ref>{{cite book| veditors = Blevins LS |title=Cushing's syndrome|year=2002|publisher=Kluwer Academic|location=Boston|isbn=978-1-4020-7131-7|page=115}}</ref>