Cushing Disease

Article Author:
Norah Kairys
Article Editor:
Ari Schwell
5/5/2019 9:57:39 PM
PubMed Link:
Cushing Disease


Cushing disease is a rare disorder characterized by increased adrenocorticotropic hormone (ACTH) production from the anterior pituitary, leading to excess cortisol release from the adrenal glands.[1] Most often, this caused by a pituitary adenoma or as the result of excess production of corticotropin-releasing hormone (CRH) from the hypothalamus.[2] Symptoms include generalized weakness, high blood pressure, diabetes mellitus, menstrual disorders or psychiatric changes.[1] Physical manifestations of excess cortisol levels include moon facies, buffalo hump, bruising, abdominal striae, obesity, facial plethora, and hirsutism.[2]


Pituitary adenomas are responsible for nearly 80% of the cases of Cushing disease.[2] Of note, Cushing syndrome refers to the general state of hypercortisolemia which can be caused by a variety of mechanisms including exogenous steroid use, adrenal tumors, ectopic-ACTH production, or high estrogen levels.[2] Cushing disease is specific to the endogenous production of ACTH that leads to secondary hypercortisolism.[2]

This disease was first described by Harvey Cushing in 1912 after he was presented with a unique case in 1910.[2] Cushing hypothesized that excess basophil pituitary cells were responsible for his patients presenting symptoms of obesity, amenorrhea, abnormal hair growth, underdevelopment of sexual characteristics, hydrocephalus, and cerebral tension.[2]


Cushing disease is a relatively rare disease. The average incidence of new cases is about 2.4 cases per million people per year.[2] This disease often is diagnosed 3 to 6 years after the onset of the illness.[2] The peak incidence of Cushing disease is in women between the ages of 50 and 60 years.[2] The prevalence of hypertension and abnormalities of glucose metabolism are major predictors of morbidity and mortality in untreated cases of the disease.[2] The mortality rate of Cushing disease is estimated to be about 10% to 11%.[2]


The hormone ACTH normally is secreted by the anterior pituitary gland in response to secretion of CRH by the hypothalamus, secondary to increased biological stressors (Figure 1).[1] ACTH then functions within the hypothalamic-pituitary-adrenal (HPA) axis to increase the production and release of the cortisol from the adrenal gland.[1] Cortisol functions primarily as a glucocorticoid; however, in high concentrations, cortisol also can exhibit mineralcorticoid activity, leading to hypertension and hypokalemia through the renin-angiotensin-aldosterone system (RAAS).[1] The RAAS hormone system is involved in the regulation of plasma-sodium concentration and arterial blood pressure, which can indirectly lead to hypokalemia.[1]

History and Physical

Patients with hypercortisolism present with weight gain (50%), hypertension, easy bruising, striae, acne, flushing, poor wound healing, lower limb edema, fatigue, impaired glucose tolerance, osteoporosis, hyperpigmentation of the skin, mood and memory changes, amenorrhea, hirsutism, decreased sexual drive, or frequent infections.[3] Clinical manifestations vary widely among patients thus a high index of clinical suspicion must be maintained in order to correctly make this diagnosis.[3]

Although uncommon, large pituitary tumors (macroadenomas) also can present with mass effects on surrounding structures.[3] These cases may present with decreased peripheral vision or headaches.[3]


On presentation, more than half of the patients with Cushing disease have a microadenoma with a diameter of less than 5 mm.[4] Of these, only 10% are large enough to cause a mass effect on the cerebral tissue to affect the structure of the sellar region.[4] Therefore, most cases of ACTH-secreting pituitary adenomas are found after suspicion of excess cortisol and androgen production.[5]

Biochemical diagnostic tests to confirm hypercortisolism include salivary and blood serum cortisol testing, 24-hour urinary-free cortisol testing, and low-dose overnight dexamethasone suppression testing.[6] The late-night or midnight salivary cortisol test recently has been gaining support due to its ease of administration.[7] This test measures free-circulating cortisol and has both a sensitivity and specificity of 95% to 98%.[7] The urinary-free cortisol test measures the excess cortisol excreted by the kidneys into the urine.[8] Results that are four times higher than normal cortisol levels are considered to be attributable to Cushing syndrome.[8] This test needs to be repeated three times to exclude any normal periods of hypercortisolism.[6] The specificity of this test is 81%.[6] The high false-positive rate can be caused by pseudo-Cushingoid states, sleep apnea, polycystic ovary syndrome, familial glucocorticoid resistance, and hyperthyroidism.[6] In low-dose dexamethasone suppression testing, dexamethasone 0.5 mg is administered by mouth at six-hour intervals for 48 hours.[8] The serum cortisol level is measured 6 hours after the last dose of dexamethasone is given.[8] A cortisol level of less than 50 nmol/L is considered a normal response and rules out Cushing syndrome.[8] The sensitivity and specificity of this test are 100% and 88%, respectively, with a positive predictive value of 92% and a negative predictive value of 89%.[8]

Two or more positive initial screening tests in a patient with a high pretest probability of Cushing disease confirms the biochemical diagnosis of Cushing syndrome.[6][9] Once Cushing syndrome has been diagnosed, the first step toward finding the cause is by measuring a baseline plasma ACTH level.[8] A level consistently greater than 3.3 pmol/L is classified as corticotropin-dependent.[8] To differentiate Cushing disease from ectopic corticotropin syndrome, a corticotropin-releasing hormone (CRH) test is needed.[8] In a patient with Cushing disease, the administered CRH stimulates the release of additional corticotropin, resulting in an elevated plasma corticotropin level.[8] The sensitivity of the CRH test for detecting Cushing disease is 93% when plasma levels are measured at fifteen and thirty minutes.[8] Alternatively, a high-dose 48-hour dexamethasone suppression test or pituitary magnetic resonance imaging (MRI) can be used.[8]

For high-dose 48-hour dexamethasone suppression testing, a plasma cortisol level above 50 nmol/L (measured 48-hours after either administration of dexamethasone 2 mg by mouth every 6 hours for 48 hours, or 48-hours after one dose of 8 mg is given) is indicative of Cushing disease.[2] This test has an 8% false-negative rate.[2] Pituitary MRI may show the ACTH secreting tumor if present.[4] However, MRI fails to detect a tumor in 40% of patients with Cushing disease.[4] The average size of the tumor that was detected on MRI was about 6 mm.[4]

The most accurate test used to differentiate a pituitary adenoma from ectopic or adrenal Cushing syndrome is inferior petrosal sinus sampling.[6][10] This invasive method measures the difference in the level of ACTH found in the inferior petrosal sinus (where the pituitary gland drains) as compared to the periphery.[6][10] A basal central to peripheral ratio of over 3:1 when CRH is administered confirms the diagnosis of Cushing disease.[10] This test is considered the gold standard in diagnosing Cushing disease because it has a sensitivity and specificity of nearly 94%, but it is rarely used in clinical practice due to its high cost, invasiveness, rare but serious complications, and required expertise to administer.[10]

Treatment / Management

If a primary ACTH secreting tumor is found, first-line treatment is surgical resection of the adenoma via trans-sphenoidal surgery (TSS).[8] This can either be conducted via an endonasal or sublabial approach, depending on surgeon preferences.[11] The probability of successful resection is higher in patients when the tumor can be identified during the initial surgery.[11] Overall, remission rates after TSS are in the range of 65% to 90% for microadenomas and less than 65% for macroadenomas.[8] Patients with persistent disease after initial surgery frequently undergo repeat pituitary surgery despite a lower success rate and increased risk for pituitary insufficiency.[11] The most common complications of this procedure include diabetes insipidus (15%), fluid and electrolyte abnormalities (12.5%), and neurological deficits (5.6%).[11] Patients over age 64 have a higher incidence of adverse outcomes.[11][12]

Alternatively, pituitary radiation therapy can be used after an unsuccessful TSS.[8][13][8] External-beam pituitary radiotherapy is most effective in pediatric patients, with cure rates in this population as high as 80% to 88%.[14] The most common complication from this treatment is hypopituitarism, causing growth hormone deficiency.[14] This complication has been reported in 36% to 68% of patients.[14]

Lastly, bilateral adrenalectomy can be used to provide an immediate reduction of cortisol levels in patients with Cushing disease.[2] However, these patients will then require lifelong administration of glucocorticoid and mineralocorticoid replacement therapy.[2] A major complication of this treatment is Nelson syndrome, which is the development of ACTH secreting macroadenomas post-bilateral adrenalectomy.[2] The incidence is between 8% to 29% and is diagnosed an average of 15 years post-bilateral adrenalectomy.[2]

Post-treatment testing with 24-hour urine and blood samples are used to detect the level of cortisol.[8] The disappearance of the response to the desmopressin test after surgery may suggest complete removal of the tumor and, therefore, a lower possibility of recurrence.[15] Recurrence of hypercortisolemia occurs in about a third of patients after initial treatment of Cushing disease.[14][16] Therefore, lifelong monitoring is required.[16] Late-night salivary cortisol appears to be the best predictor of recurrence.[17][18]

Pearls and Other Issues

Recently, medical therapy has been gaining popularity in the treatment of pituitary tumors.[5] Although surgery is still considered the first-line treatment, pharmacological therapy can be used to control the associated hormonal imbalances.[19] These medical therapies either target the central inhibition of ACTH secretion, adrenal inhibition of steroidogenesis, or glucocorticoid-receptor blockade.[5] Centrally acting agents include pasireotide and cabergoline.[5][20] Adrenal steroidogenesis inhibitors include ketoconazole, metyrapone, etomidate, mitotane, and osilodrostat.[5] Lastly, mifepristone can be used as a glucocorticoid-receptor blocker.[5] Currently, although regulatory authorities have approved several pharmaceutical treatments, their use remains limited due to high cost and associated side effects.[5]

Enhancing Healthcare Team Outcomes

Cushing disease is a rare pituitary gland disorder that is best managed by a multidisciplinary team that includes a neurosurgeon, radiation consultant, endocrinologist, radiologist, primary care provider, nurse practitioner, and an internist. Large pituitary lesions usually require resection but small lesions may be treated with medications. These patients need life long follow up with regular monitoring of cortisol levels.  Recurrence of disease is not uncommon and too much or too little cortisol can be life-threatening.[21] The prognosis for most patients is somewhat reduced.[22] (Level V)

  • (Move Mouse on Image to Enlarge)
    • Image 5726 Not availableImage 5726 Not available
      Contributed by Hine J, Schwell A, Kairys N. (


[1] An Unlikely Cause of Hypokalemia., Hine J,Schwell A,Kairys N,, The Journal of emergency medicine, 2017 May     [PubMed PMID: 28139270]
[2] Cushing's disease: a multidisciplinary overview of the clinical features, diagnosis, and treatment., Buliman A,Tataranu LG,Paun DL,Mirica A,Dumitrache C,, Journal of medicine and life, 2016 Jan-Mar     [PubMed PMID: 27974908]
[3] Cushing's syndrome: a practical approach to diagnosis and differential diagnoses., Pappachan JM,Hariman C,Edavalath M,Waldron J,Hanna FW,, Journal of clinical pathology, 2017 Apr     [PubMed PMID: 28069628]
[4] Magnetic resonance imaging and histology correlation in Cushing's disease., Masopust V,Netuka D,Beneš V,Májovský M,Belšán T,Bradáč O,Hořínek D,Kosák M,Hána V,Kršek M,, Neurologia i neurochirurgia polska, 2017 Jan - Feb     [PubMed PMID: 27988033]
[5] Recent Progress in the Medical Therapy of Pituitary Tumors., Langlois F,McCartney S,Fleseriu M,, Endocrinology and metabolism (Seoul, Korea), 2017 Jun     [PubMed PMID: 28685507]
[6] Cushing Syndrome: Diagnostic Workup and Imaging Features, With Clinical and Pathologic Correlation., Wagner-Bartak NA,Baiomy A,Habra MA,Mukhi SV,Morani AC,Korivi BR,Waguespack SG,Elsayes KM,, AJR. American journal of roentgenology, 2017 Jul     [PubMed PMID: 28639924]
[7] [Comparison of efficacy between the serum cortisol and 24 hour urine free cortisol in combined dexamethasone suppression test in the diagnosis of Cushing syndrome]., Lu L,Chen JH,Zhu HJ,Song AL,Li M,Chen S,Pan H,Gong FY,Wang RZ,Xing B,Yao Y,Feng M,Lu ZL,, Zhonghua yi xue za zhi, 2016 Jul 19     [PubMed PMID: 27464539]
[8] Diagnosis and Treatment of Pituitary Adenomas: A Review., Molitch ME,, JAMA, 2017 Feb 7     [PubMed PMID: 28170483]
[9] The Desmopressin Test Predicts Better Than Basal Cortisol the Long-Term Surgical Outcome of Cushing's Disease., Vassiliadi DA,Balomenaki M,Asimakopoulou A,Botoula E,Tzanela M,Tsagarakis S,, The Journal of clinical endocrinology and metabolism, 2016 Dec     [PubMed PMID: 27662440]
[10] The role of inferior petrosal sinus sampling in the diagnostic localization of Cushing's disease., Lad SP,Patil CG,Laws ER Jr,Katznelson L,, Neurosurgical focus, 2007     [PubMed PMID: 17961020]
[11] Perioperative Quality of Life in Cushing's Disease., Ye VC,Akagami R,, The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 2017 Jan     [PubMed PMID: 27645104]
[12] Currently used and investigational drugs for Cushing´s disease., Ciato D,Mumbach AG,Paez-Pereda M,Stalla GK,, Expert opinion on investigational drugs, 2017 Jan     [PubMed PMID: 27894193]
[13] Target delineation and optimal radiosurgical dose for pituitary tumors., Minniti G,Osti MF,Niyazi M,, Radiation oncology (London, England), 2016 Oct 11     [PubMed PMID: 27729088]
[14] Long-term outcomes of children treated for Cushing's disease: a single center experience., Yordanova G,Martin L,Afshar F,Sabin I,Alusi G,Plowman NP,Riddoch F,Evanson J,Matson M,Grossman AB,Akker SA,Monson JP,Drake WM,Savage MO,Storr HL,, Pituitary, 2016 Dec     [PubMed PMID: 27678103]
[15] Abellán Galiana P,Fajardo Montañana C,Riesgo Suárez PA,Gómez Vela J,Escrivá CM,Lillo VR, [Predictors of long-term remission after transsphenoidal surgery in Cushing's disease]. Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion. 2013 Oct;     [PubMed PMID: 23266144]
[16] Adrenocorticotropic hormone levels before treatment predict recurrence of Cushing's disease., Kuo CH,Shih SR,Li HY,Chen SC,Hung PJ,Tseng FY,Chang TC,, Journal of the Formosan Medical Association = Taiwan yi zhi, 2017 Jun     [PubMed PMID: 28029519]
[17] THE CHALLENGE OF EARLY DIAGNOSIS OF CUSHING DISEASE RECURRENCE!, Bertherat J,, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 2016 Nov     [PubMed PMID: 27749130]
[18] AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: DIAGNOSIS OF RECURRENCE IN CUSHING DISEASE., Fleseriu M,Hamrahian AH,Hoffman AR,Kelly DF,Katznelson L,, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 2016 Dec     [PubMed PMID: 27643842]
[19] Long-term results of treatment of Cushing's disease by adrenalectomy., Grabner P,Hauer-Jensen M,Jervell J,Flatmark A,, The European journal of surgery = Acta chirurgica, 1991 Aug     [PubMed PMID: 1681932]
[20] Cabergoline for Cushing's disease: a large retrospective multicenter study., Ferriere A,Cortet C,Chanson P,Delemer B,Caron P,Chabre O,Reznik Y,Bertherat J,Rohmer V,Briet C,Raingeard I,Castinetti F,Beckers A,Vroonen L,Maiter D,Cephise-Velayoudom FL,Nunes ML,Haissaguerre M,Tabarin A,, European journal of endocrinology, 2017 Mar     [PubMed PMID: 28007845]
[21] Vega-Beyhart A,Enriquez-Estrada VM,Bello-Chavolla OY,Torres-Victoria TR,Martínez-Sánchez FD,López-Navarro JM,Pérez-Guzmán MC,Hinojosa-Amaya JM,León-Suárez A,Espinoza-Salazar HD,Roldán-Sarmiento P,Gómez-Sámano MA,Gómez-Pérez FJ,Cuevas-Ramos D, Quality of life is significantly impaired in both secretory and non-functioning pituitary adenomas. Clinical endocrinology. 2019 Mar;     [PubMed PMID: 30548674]
[22] Rotman LE,Vaughan TB,Hackney JR,Riley KO, Long-Term Survival After Transformation of an Adrenocorticotropic Hormone-Secreting Pituitary Macroadenoma to a Silent Corticotroph Pituitary Carcinoma. World neurosurgery. 2019 Feb;     [PubMed PMID: 30447452]