Editing Cushing's syndrome (section)

==Causes==
Cushing's syndrome may result from any cause of increased glucocorticoid levels, whether due to medication or internal processes.<ref name=Shar2011/><ref name = "Chaudhry_2019">{{cite book | vauthors = Chaudhry HS, Singh G | chapter =Cushing Syndrome|date=2019|chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK470218/| title = StatPearls|publisher=StatPearls Publishing|pmid=29261900|access-date=2019-04-20 }}</ref> Some sources however do not consider the glucocorticoid medication-induced condition as "Cushing's syndrome" proper, instead using the term "Cushingoid" to describe the medication's side effects which mimic the endogenous condition.<ref name=":0">{{cite journal | vauthors = Baek JH, Kim SK, Jung JH, Hahm JR, Jung J | title = Recovery of Adrenal Function in Patients with Glucocorticoids Induced Secondary Adrenal Insufficiency | journal = Endocrinology and Metabolism | volume = 31 | issue = 1 | pages = 153–160 | date = March 2016 | pmid = 26676337 | pmc = 4803552 | doi = 10.3803/EnM.2016.31.1.153 }}</ref><ref name = "Chaudhry_2019" /><ref>{{cite journal | vauthors = Nieman LK | title = Cushing's syndrome: update on signs, symptoms and biochemical screening | journal = European Journal of Endocrinology | volume = 173 | issue = 4 | pages = M33–M38 | date = October 2015 | pmid = 26156970 | pmc = 4553096 | doi = 10.1530/EJE-15-0464 }}</ref>

[[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. While all Cushing's disease gives Cushing's syndrome, not all Cushing's syndrome is due to Cushing's disease.<ref>Lynnette K. Nieman, Beverly M. K. Biller, James W. Findling, John Newell-Price, Martin O. Savage, Paul M. Stewart, Victor M. Montori,  The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline, ''The Journal of Clinical Endocrinology & Metabolism'', Volume 93, Issue 5, 1 May 2008, Pages 1526–1540,</ref> Several possible causes of Cushing's syndrome are known including the taking of herbal supplements over-the-counter that do not list glucocorticoids in their ingredients.<ref>{{Cite journal |last=Research |first=Center for Drug Evaluation and |date=2022-10-31 |title=Public Notification: Artri King contains hidden drug ingredients |url=https://www.fda.gov/drugs/medication-health-fraud/public-notification-artri-king-contains-hidden-drug-ingredients |journal=FDA |language=en}}</ref><ref>{{Cite journal |last1=Patel |first1=Reema |last2=Sherf |first2=Sahar |last3=Lai |first3=Ngan Betty |last4=Yu |first4=Run |date=2022-11-01 |title=Exogenous Cushing Syndrome Caused by a "Herbal" Supplement |url=https://www.aaceclinicalcasereports.com/article/S2376-0605(22)00051-7/abstract |journal=AACE Clinical Case Reports |language=English |volume=8 |issue=6 |pages=239–242 |doi=10.1016/j.aace.2022.08.001 |pmid=36447831 |pmc=9701910 |issn=2376-0605}}</ref>

===Exogenous===
The most common cause of Cushing's syndrome is the use of prescribed [[glucocorticoid]]s to treat other diseases ([[iatrogenesis|iatrogenic]] Cushing's syndrome). Glucocorticoids are used in treatment of a variety of disorders, including [[asthma]] and [[rheumatoid arthritis]], and also used for [[immunosuppression]] after organ transplants. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility. Rarely, Cushing's syndrome can also be due to the use of [[medroxyprogesterone acetate]].<ref name="pmid2552887">{{cite journal | vauthors = Siminoski K, Goss P, Drucker DJ | title = The Cushing syndrome induced by medroxyprogesterone acetate | journal = Annals of Internal Medicine | volume = 111 | issue = 9 | pages = 758–760 | date = November 1989 | pmid = 2552887 | doi = 10.7326/0003-4819-111-9-758 }}</ref><ref>{{cite journal | vauthors = Merrin PK, Alexander WD | title = Cushing's syndrome induced by medroxyprogesterone | journal = BMJ | volume = 301 | issue = 6747 | pages = 345 | date = August 1990 | pmid = 2144198 | pmc = 1663616 | doi = 10.1136/bmj.301.6747.345-a }}</ref> In exogenous Cushing's, the adrenal glands may often gradually atrophy due to lack of stimulation by ACTH, the production of which is suppressed by glucocorticoid medication. Abruptly stopping the medication can thus result in acute and potentially life-threatening [[adrenal insufficiency]] and the dose must hence be slowly and carefully tapered off to allow internal cortisol production to pick up. In some cases, patients never recover sufficient levels of internal production and must continue taking glucocorticoids at physiological doses for life.<ref name=":0" /><ref>{{cite journal | vauthors = Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM | title = Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 100 | issue = 6 | pages = 2171–2180 | date = June 2015 | pmid = 25844620 | doi = 10.1210/jc.2015-1218 | doi-access = free }}</ref>

Cushing's syndrome in childhood is especially rare; it usually results from use of glucocorticoid medication.<ref name="pmid23099271">{{cite journal | vauthors = Stratakis CA | title = Cushing syndrome in pediatrics | journal = Endocrinology and Metabolism Clinics of North America | volume = 41 | issue = 4 | pages = 793–803 | date = December 2012 | pmid = 23099271 | pmc = 3594781 | doi = 10.1016/j.ecl.2012.08.002 }}</ref>

=== Endogenous ===
[[Endogeny|Endogenous]] Cushing's syndrome results from some derangement of the body's own system of cortisol secretion. Normally, [[ACTH]] is released from the [[pituitary gland]] when necessary to stimulate the release of cortisol from the [[adrenal gland]]s.{{cn|date=October 2021}}

* 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.<ref name="endocrine.niddk">[http://endocrine.niddk.nih.gov/pubs/cushings/cushings.htm#1 Cushing's Syndrome] {{webarchive|url=https://web.archive.org/web/20110410084418/http://endocrine.niddk.nih.gov/pubs/cushings/cushings.htm |date=2011-04-10 }} at The National Endocrine and Metabolic Diseases Information Service. July 2008. Citing: * {{cite journal | vauthors = Nieman LK, Ilias I | title = Evaluation and treatment of Cushing's syndrome | journal = The American Journal of Medicine | volume = 118 | issue = 12 | pages = 1340–1346 | date = December 2005 | pmid = 16378774 | doi = 10.1016/j.amjmed.2005.01.059 | url = https://zenodo.org/record/1258724 }}</ref>
* 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 [[paraneoplasia|paraneoplastic]] Cushing's disease and is seen in diseases such as [[small cell carcinoma|small cell]] [[lung cancer]].<ref name="pmid3525603">{{cite journal | vauthors = Schteingart DE, Lloyd RV, Akil H, Chandler WF, Ibarra-Perez G, Rosen SG, Ogletree R | title = Cushing's syndrome secondary to ectopic corticotropin-releasing hormone-adrenocorticotropin secretion | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 63 | issue = 3 | pages = 770–775 | date = September 1986 | pmid = 3525603 | doi = 10.1210/jcem-63-3-770 }}</ref>
* Finally, rare cases of CRH-secreting tumors (without ACTH secretion) have been reported, which stimulates pituitary ACTH production.<ref name="Voyadzis JM, Guttman-Bauman I, Santi M, Cogen P. 2004 212–6">{{cite journal | vauthors = Voyadzis JM, Guttman-Bauman I, Santi M, Cogen P | title = Hypothalamic hamartoma secreting corticotropin-releasing hormone. Case report | journal = Journal of Neurosurgery | volume = 100 | issue = 2 Suppl Pediatrics | pages = 212–216 | date = February 2004 | pmid = 14758953 | doi = 10.3171/ped.2004.100.2.0212 }}</ref>

===Pseudo-Cushing's syndrome===
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 [[transcortin|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.<ref>{{cite journal | vauthors = Katz J | title = Motive to sin | journal = Nature | volume = 359 | issue = 6398 | pages = 769 | date = October 1992 | pmid = 1436049 | pmc = 1436049 | doi = 10.1136/jcp.s1-3.1.11 | bibcode = 1992Natur.359..769K }}</ref>