Cushing's disease

Last updated

Cushing's disease
Other namesCushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease [1] [2]
Specialty Endocrinology

Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome, [3] when excluding Cushing's syndrome from exogenously administered corticosteroids.


This should not be confused with ectopic Cushing syndrome or exogenous steroid use. [4]

Signs and symptoms

The symptoms of Cushing's disease are similar to those seen in other causes of Cushing's syndrome. [5] Patients with Cushing's disease usually present with one or more signs and symptoms secondary to the presence of excess cortisol or ACTH. [6] Although uncommon, some patients with Cushing's disease have large pituitary tumors (macroadenomas). In addition to the severe hormonal effects related to increased blood cortisol levels, the large tumor can compress adjacent structures. [ citation needed ] These tumors can compress the nerves that carry information from the eyes, causing a decrease in peripheral vision.[ citation needed ] Glaucoma and cataracts also may occur in Cushing's syndrome. In children, the two main symptoms are obesity and decreased linear growth. [7]

The clinical diagnosis must be based on the presence of one or more of the symptoms listed below, because the syndrome itself has no true pathognomonic signs or symptoms.[ citation needed ] The most common symptoms seen in male patients are purple striae, muscle atrophy, osteoporosis, and kidney stones. [7]


Common signs and symptoms of Cushing's disease include the following:

  • weight gain
  • high blood pressure [8]
  • poor short-term memory
  • irritability
  • excess hair growth (women) [3]
  • Impaired immunological function [8]
  • red, ruddy face
  • extra fat around neck, "Buffalo Hump"
  • moon face
  • fatigue
  • red stretch marks
  • poor concentration
  • irregular menstruation [7]

Less common

The less-common signs and symptoms of Cushing's disease include the following:

  • insomnia
  • recurrent infection
  • thin skin and stretch marks [8]
  • easy bruising
  • weak bones
  • acne
  • balding (women)
  • depression
  • hip and shoulder weakness
  • swelling of feet/legs
  • diabetes mellitus [8]
  • erectile dysfunction


Diagnosis is made first by diagnosing Cushing's syndrome, which can be difficult to do clinically since the most characteristic symptoms only occur in a minority of patients. [9] Some of the biochemical diagnostic tests used include salivary and blood serum cortisol testing, 24-hour urinary free cortisol (UFC) testing, the dexamethasone suppression test (DST), and bilateral inferior petrosal sinus sampling (IPSS or BIPSS for bilateral IPSS). No single test is perfect and multiple tests should always be used to achieve a proper diagnosis. [7] Diagnosing Cushing's disease is a multidisciplinary process involving doctors, endocrinologists, radiologists, surgeons, and chemical pathologists. [7]

ACTH blood test

Once Cushing's syndrome has been diagnosed, the first step towards finding the cause is measuring plasma adrenocorticotropic hormone (ACTH) concentration. A concentration consistently below 1.1 pmol/L is classified as corticotropin-independent and does not lead to a diagnosis of Cushing's disease. In such cases, the next step is adrenal imaging with CT. If plasma corticotropin concentrations are consistently above 3.3 pmol/L, then corticotropin-dependent Cushing's syndrome is most likely. Any intermediate values need to be cautiously interpreted and a corticotropin-releasing hormone (CRH) test is advised in order to confirm corticotropin dependency. If corticotropin-dependent Cushing's syndrome is determined then the next step is to distinguish between Cushing's disease and ectopic corticotropin syndrome. This is done via a combination of techniques including CRH, high-dose DST, BIPSS, and pituitary MRI.

Dexamethasone suppression test

Two dexamethasone suppression tests (DSTs) are generally used, the overnight test and the 48 hour test. [7] For both tests, a plasma cortisol level above 50 nmol/L is indicative of Cushing's disease. [7] However, 3–8% of patients with Cushing's disease will test negative due to a retention of dexamethasone suppression abilities. [7] For non-Cushing or healthy patients, the false-positive rate is 30%. [7] The 48-h DST is advantageous since it is more specific and can be done by outpatients upon proper instruction. [7] In the high-dose 48-h DST, 2 mg of dexamethasone is given every 6 hours for 48 hours or a single dose of 8 mg is given. [7] This test is not needed if the 48-h low-dose DST has shown suppression of cortisol by over 30%. [7] These tests are based on the glucocorticoid sensitivity of pituitary adenomas compared to non-pituitary tumors. [7]

ACTH stimulation test

An ACTH stimulation test involving administration of corticotropin-releasing hormone (CRH) or another agent can differentiate this condition from ectopic ACTH secretion. In a patient with Cushing's disease, the tumor cells will be stimulated to release corticotropin and elevated plasma corticotropin levels will be detected. [7] This rarely occurs with ectopic corticotropin syndrome and thus is quite useful for distinguishing between the two conditions. [7] If ectopic, the plasma ACTH and cortisol levels should remain unchanged; if this is pituitary related, levels of both would rise. The CRH test uses recombinant human or bovine-sequence CRH, which is administered via a 100μg intravenous bolus dose. The sensitivity of the CRH test for detecting Cushing's disease is 93% when plasma levels are measured after fifteen and thirty minutes. [7] However, this test is used only as a last resort due to its high cost and complexity. [9]


A CT or MRI of the pituitary may also show the ACTH-secreting tumor if present. However, in 40% of Cushing's disease patients MRI is unable to detect a tumor. [7] In one study of 261 patients with confirmed pituitary Cushing's disease, only 48% of pituitary lesions were identified using MRI prior to surgery. The average size of tumor, both those that were identified on MRI and those that were only discovered during surgery, was 6 mm. [10]

Inferior petrosal sinus sampling

IPSS (inferior petrosal sinus sampling) or BIPSS (bilateral IPSS) is a more accurate but invasive test used to differentiate pituitary from ectopic or adrenal Cushing's syndrome. [11] A corticotropin gradient sample via BIPSS is required to confirm diagnosis when pituitary MRI imaging and biochemical diagnostic tests have been inconclusive. [7] A basal central:peripheral ratio of over 2:1, or a ratio over 3:1 when CRH is administered, is indicative of Cushing’s disease. [7] This test has been the gold standard for distinguishing between Cushing's disease and ectopic corticotropin syndrome. [7] The BIPSS has a sensitivity and specificity of 94% for Cushing's disease but it is usually used as a last resort due to its invasiveness, rare but serious complications, and the expertise required to perform it. [9]

Urinary free cortisol test

Another diagnostic test used is the urinary free cortisol (UFC) test, which measures the excess cortisol excreted by the kidneys into the urine. Results of 4x higher cortisol levels than normal are likely to be Cushing's disease. [7] [9] This test should be repeated three times in order to exclude any normally occurring periods of hypercortisolism. [9] The UFC test has a specificity of 81% and thus has a high rate of false-positives that are due to pseudo-Cushing states, sleep apnea, polycystic ovary syndrome, familial glucocorticoid resistance, and hyperthyroidism. [9]

Late night (midnight) salivary cortisol test

The late night or midnight salivary cortisol test has been gaining support due to its ease of collection and stability at room temperature, therefore it can be assigned to outpatients. [7] The test measures free circulating cortisol and has both a sensitivity and specificity of 95–98%. [7] [9] This test is especially useful for diagnosing children. [7]


The first-line treatment of Cushing's disease is surgical resection of ACTH-secreting pituitary adenoma; this surgery involves removal of the tumor via transsphenoidal surgery (TSS). [12] There are two possible options for access to the sphenoidal sinus, including of endonasal approach (through the nostril) or sublabial approach (through an incision under the upper lip); many factors such as the size of nostril, the size of the lesion, and the preferences of the surgeon cause the selection of one access route over the other. [13] Some tumors do not contain a discrete border between the tumor and pituitary gland; therefore, careful sectioning through the pituitary gland may be required to identify the location of the tumor. [14] The probability of successful resection is higher in patients where the tumor was identified at initial surgery in comparison to patients where no tumor was found initially; the overall remission rates in patients with microadenomas undergoing TSS are in range of 65%–90%, and the remission rate in patients with macroadenomas are lower than 65%. [14] Patients with persistent disease after initial surgery are treated with repeated pituitary surgery as soon as the active persistent disease is evident; however, reoperation has a lower success rate and increases the risk of pituitary insufficiency. [14]

Pituitary radiation therapy is another option for treatment of postoperative persisting hypercortisolemia following unsuccessful transsphenoidal surgery. [15] External-beam pituitary RT is more effective treatment for pediatric CD in children with cure rates of 80–88%. Hypopituitarism specifically growth hormone deficiency has been reported as the only most common late morbidity of this treatment; GHD has been reported in 36% and 68% of the patients undergoing post-pituitary RT for Cushing's disease. [15]

Bilateral adrenalectomy is another treatment that provides immediate reduction of cortisol level and control of hypercortisolism. However, it requires education of patients, because lifelong glucocorticoid and mineralocorticoid replacement therapy is needed for these patients. One of the major complications of this treatment is progression of Nelson's syndrome which is caused by enhance level of tumor growth and ACTH secretion post adrenalectomy in 8–29% of patients with CD. [16]

During post surgical recovery, patients collect 24-hour urine sample and blood sample for detecting the level of cortisol with the purpose of cure test; level of cortisol near the detection limit assay, corresponds to cure. Hormonal replacement such as steroid is given to patients because of steroid withdrawal. After the completion of collecting urine and blood samples, patients are asked to switch to glucocorticoid such as prednisone to decrease symptoms associated with adrenal withdrawal. Mitotane is also used [17]

A study of 3,525 cases of TSS for Cushing's disease in the nationally representative sample of US hospitals between 1993 and 2002 was conducted and revealed the following results: the in-hospital mortality rate was 0.7%; the complication rate was 42.1%. Diabetes insipidus (15%), fluid and electrolyte abnormalities (12.5%), and neurological deficits (5.6%) were the most common complications reported. The analyses of the study show that complications were more likely in patients with pre-operative comorbidities. Patients older than 64 years were more likely to have an adverse outcome and prolonged hospital stay. Women were 0.3 times less likely to have adverse outcomes in comparison to men. [18]


Cases of Cushing's disease are rare, and little epidemiological data is available on the disease. An 18-year study conducted on the population of Vizcaya, Spain reported a 0.004% prevalence of Cushing's disease. [19] The average incidence of newly diagnosed cases was 2.4 cases per million inhabitants per year. The disease is often diagnosed 3–6 years after the onset of illness. [19] Several studies have shown that Cushing's disease is more prevalent in women than men at a ratio of 3–6:1, respectively. [20] [21] Moreover, most women affected were between the ages of 50 and 60 years. The prevalence of hypertension, and abnormalities in glucose metabolism are major predictors of mortality and morbidity in untreated cases of the disease. [19] The mortality rate of Cushing's disease was reported to be 10–11%, [19] [22] with the majority of deaths due to vascular disease [8] [19] Women aged 45–70 years have a significantly higher mortality rate than men. [19] Moreover, the disease shows a progressive increase with time. Reasons for the trend are unknown, but better diagnostic tools, and a higher incidence rate are two possible explanations. [19]


The disease associated with this increased secretion of cortisol was described by the American neurosurgeon Harvey Cushing in 1912, after he was presented with a unique case of the disease in 1910 [23] [24] a 23-year-old woman called Minnie G. whose symptoms included painful obesity, amenorrhea, hypertrichosis (abnormal hair growth), underdevelopment of secondary sexual characteristics, hydrocephalus and cerebral tension. [3] This combination of symptoms was not yet described by any medical disorder at the time. [3] However, Cushing was confident that Minnie's symptoms were due to dysfunction of the pituitary gland and resembled those associated with an adrenal tumor. Given this conviction, and his knowledge of the three anterior pituitary cell types, Cushing hypothesized that if acidophil hyperpituitarism (excess secretion from the acidophil cells) caused acromegaly, then an excess of basophil cells must be involved in another pituitary disorder that involves sexual dysfunction (amenorrhea in females and erectile dysfunction in males) and could explain Minnie's symptoms. [3] Experimental evidence and case reports by Cushing led to his publication in 1932 on pituitary basophilism as the cause of Cushing's disease. In this publication, the clinical symptoms of the disease, named after Cushing, were described. [25] [26] Out of the 12 cases with hypercortisolism described in Cushing's monograph on the pituitary body, 67% died within a few years after symptom presentation, whereas Minnie G. survived for more than 40 years after symptom presentation, despite the fact that she did not receive any treatments for a pituitary tumor. [3] The prolonged survival made Minnie's case unique at the time. The reason behind this survival remains a mystery, since an autopsy of Minnie was refused after her death. [3] However, the most likely explanation, proposed by J. Aidan Carney and based on statistical evidence, was that the basophil adenoma Minnie might have harbored underwent partial infarction, leading to symptom regression. [3] The other hypothesis was that Minnie might have suffered from Primary Pigmented Nodular Adrenocortical Disease (PPNAD), which when associated with Cushing's syndrome (Carney complex) can infrequently cause spontaneous symptom regression of the latter. [3]

In 1924, the Soviet neurologist Nikolai Itsenko reported two patients with pituitary adenoma. The resulting excessive adrenocorticotropic hormone secretion led to the production of large amounts of cortisol by the adrenal glands. Considering this impact, the name of Itsenko was added to the title in some East European and Asian countries, and the disease is called Itsenko-Kushing disease.[ citation needed ]

Related Research Articles

Adrenocorticotropic hormone is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production and release of cortisol by the cortex of the adrenal gland. ACTH is also related to the circadian rhythm in many organisms.

Cushings syndrome Symptoms from excessive exposure to glucocorticoids such as cortisol

Cushing's syndrome is the collection of signs and symptoms due to prolonged exposure to glucocorticoids such as 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.

Anterior pituitary Anterior lobe of the pituitary gland

A major organ of the endocrine system, the anterior pituitary is the glandular, anterior lobe that together with the posterior lobe makes up the pituitary gland (hypophysis). The anterior pituitary regulates several physiological processes, including stress, growth, reproduction, and lactation. Proper functioning of the anterior pituitary and of the organs it regulates can often be ascertained via blood tests that measure hormone levels.

Adrenal insufficiency human disease

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones, primarily cortisol; but may also include impaired production of aldosterone, which regulates sodium conservation, potassium secretion, and water retention. Craving for salt or salty foods due to the urinary losses of sodium is common.

Corticotropes are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

Hypopituitarism pituitary gland disease characterized by the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland

Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism is used.

Metyrapone chemical compound

Metyrapone, sold under the brand name Metopirone, is a medication which is used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism).

Pituitary adenoma Human disease

Pituitary adenomas are tumors that occur in the pituitary gland. Pituitary adenomas are generally divided into three categories dependent upon their biological functioning: benign adenoma, invasive adenoma, and carcinomas. Most adenomas are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. Pituitary adenomas represent from 10% to 25% of all intracranial neoplasms and the estimated prevalence rate in the general population is approximately 17%.

Hyperandrogenism medical condition characterized by excessive levels of androgens in the body

Hyperandrogenism is a medical condition characterized by high levels of androgens in females. Symptoms may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation. Complications may include high blood cholesterol.

Nelson's syndrome is a rare disorder and occurs in patients who have had both adrenal glands removed owing to Cushing's syndrome. During the disorder the patient develops macroadenomas that secrete adrenocorticotropic hormone (ACTH). The severity of the disease is dependent upon the effect of ACTH release on the skin, pituitary hormone loss, and the effect the tumor has on the surrounding structures within the body.

Dexamethasone suppression test diagnostic test

The dexamethasone suppression test (DST) is used to assess adrenal gland function by measuring how cortisol levels change in response to an injection of dexamethasone. It is typically used to diagnose Cushing's syndrome.

Hyperpituitarism endocrine disease

Hyperpituitarism is a condition due to the primary hypersecretion of pituitary hormones; it typically results from a pituitary adenoma. In children with hyperpituitarism, disruption of growth regulation is rare, either because of hormone hypersecretion or because of manifestations caused by local compression of the adenoma.

In humans and other animals, the adrenocortical hormones are hormones produced by the adrenal cortex, the outer region of the adrenal gland. These polycyclic steroid hormones have a variety of roles that are crucial for the body’s response to stress, and they also regulate other functions in the body. Threats to homeostasis, such as injury, chemical imbalances, infection, or psychological stress, can initiate a stress response. Examples of adrenocortical hormones that are involved in the stress response are aldosterone and cortisol. These hormones also function in regulating the conservation of water by the kidneys and glucose metabolism, respectively.

Pituitary apoplexy is bleeding into or impaired blood supply of the pituitary gland. This usually occurs in the presence of a tumor of the pituitary, although in 80% of cases this has not been diagnosed previously. The most common initial symptom is a sudden headache, often associated with a rapidly worsening visual field defect or double vision caused by compression of nerves surrounding the gland. This is often followed by acute symptoms caused by lack of secretion of essential hormones, predominantly adrenal insufficiency.

Pseudo-Cushing's syndrome is a medical condition in which patients display the signs, symptoms, and abnormal hormone levels seen in Cushing's syndrome. However, pseudo-Cushing's syndrome is not caused by a problem with the hypothalamic-pituitary-adrenal axis as Cushing's is; it is mainly an idiopathic condition, however a cushingoid appearance is sometimes linked to excessive alcohol consumption. Elevated levels of total cortisol can also be due to estrogen found in oral contraceptive pills that contain a mixture of estrogen and progesterone. Estrogen can cause an increase of cortisol-binding globulin and thereby cause the total cortisol level to be elevated.

Hypophysectomy is the surgical removal of the hypophysis. It is most commonly performed to treat tumors, especially craniopharyngioma tumors. Sometimes it is used to treat Cushing's syndrome due to pituitary adenoma or Simmond's disease It is also applied in neurosciences to understand the functioning of hypophysis. There are various ways a hypophysectomy can be carried out. These methods include transsphenoidal hypophysectomy, open craniotomy, and stereotactic radiosurgery.

Adrenocortical adenoma adrenal adenoma that is a benign tumor of the adrenal cortex

Adrenocortical adenoma is commonly described as a benign neoplasm emerging from the cells that comprise the adrenal cortex. Like most adenomas, the adrenocortical adenoma is considered a benign tumor since the majority of them are non-functioning and asymptomatic. Adrenocortical adenomas are classified as ACTH-independent disorders, and are commonly associated with conditions linked to hyperadrenalism such as Cushing's syndrome (hypercortisolism) or Conn's syndrome (hyperaldosteronism), which is also known as primary aldosteronism. In addition, recent case reports further support the affiliation of adrenocortical adenomas with hyperandrogenism or florid hyperandrogenism which can cause hyperandrogenic hirsutism in females. "Cushing's syndrome" differs from the "Cushing's disease" even though both conditions are induced by hypercortisolism. The term "Cushing's disease" refers specifically to "secondary hypercortisolism" classified as "ACTH-dependent Cushing's syndrome" caused by pituitary adenomas. In contrast, "Cushing's syndrome" refers specifically to "primary hypercortisolism" classified as "ACTH-independent Cushing's syndrome" caused by adrenal adenomas.

The ACTH test is a medical test usually ordered and interpreted by endocrinologists to assess the functioning of the adrenal glands' stress response by measuring the adrenal response to adrenocorticotropic hormone or another corticotropic agent such as tetracosactide or alsactide (Synchrodyn). ACTH is a hormone produced in the anterior pituitary gland that stimulates the adrenal glands to release cortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and aldosterone.

Corticorelin is a diagnostic agent. It is a synthetic form of human corticotropin-releasing hormone (hCRH).

Primary pigmented nodular adrenocortical disease adrenal cortex disease characterized by small to normal sized adrenal glands containing multiple small cortical pigmented nodules

Primary pigmented nodular adrenocortical disease (PPNAD) was first coined in 1984 by Carney et al. it often occurs in association with Carney complex (CNC). CNC is a rare syndrome that involves the formation of abnormal tumours that cause endocrine hyperactivity.


  1. "Whonamedit – Nikolai Mikhailovich Itsenko". "Nikolai Mikhailovich Itsenko investigated neural infections, vegetative nervous system diseases and cerebral tumors. In 1926 he was the first one who described Itsenko-Cushing's disease, six years before Cushing."
  2. A.I. Gozhenko; I.P. Gurkalova; W. Zukow; Z. Kwasnik; B. Mroczkowska (2009). "Trematoda". Pathology: Medical Student's Library. Radomska Szkola Wyžsza uk. Zubrzyckiego. p. 280. ISBN   978-83-61047-18-6.
  3. 1 2 3 4 5 6 7 8 9 Lanzino, Giuseppe; Maartens, Niki F.; Laws, Edward R. (2002). "Cushing's case XLV: Minnie G.". Journal of Neurosurgery. 97 (1): 231–234. doi:10.3171/jns.2002.97.1.0231. PMID   12134925.
  5. "Cushing's Syndrome Information Page". Archived from the original on July 27, 2013. Retrieved August 26, 2013.
  6. Kirk, Lawrence F., Jr; Robert B. Hash; Harold P. Katner; Tom Jones (September 2000). "Cushing's Disease: Clinical Manifestations and Diagnostic Evaluation". American Family Physician. 62 (5): 1119–27, 1133–4. PMID   10997535 . Retrieved August 26, 2013.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Newell-Price, J.; Bertagna, X.; Grossman, A.B.; Nieman, L.K. (2006). "Cushing's syndrome". The Lancet. 367 (9522): 1605–1617. doi:10.1016/S0140-6736(06)68699-6. PMID   16698415. S2CID   36208358 . Retrieved January 30, 2014.
  8. 1 2 3 4 5 Wilson, P.J.; Williams, J.R.; Smee, R.I. (2014). "Cushing's disease: A single centre's experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy". Journal of Clinical Neuroscience. 21 (1): 100–106. doi:10.1016/j.jocn.2013.04.007. PMID   24074805. S2CID   35091145.
  9. 1 2 3 4 5 6 7 Nieman, L.K.; Ilias, I. (2005). "Evaluation and treatment of Cushing's syndrome". The American Journal of Medicine. 118 (12): 1340–1346. doi:10.1016/j.amjmed.2005.01.059. PMID   16378774 . Retrieved January 30, 2014.
  10. Jagannathan J.; et al. (2009). "Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease". Journal of Neurosurgery. 111 (3): 531–9. doi:10.3171/2008.8.JNS08339. PMC   2945523 . PMID   19267526.
  11. Deipolyi, A; Karaosmanoglu, A; Habito, C; Brannan, S; Wicky, S; Hirsch, J; Oklu, R (February 23, 2011). "The role of bilateral inferior petrosal sinus sampling in the diagnostic evaluation of Cushing disease". Diagnostic and Interventional Radiology (Ankara, Turkey). 18 (1): 132–8. doi:10.4261/1305-3825.DIR.4279-11.0. PMID   21348009. S2CID   41885668.
  12. Ding D, Starke RM, Sheehan JP (May 2014). "Treatment paradigms for pituitary adenomas: defining the roles of radiosurgery and radiation therapy". J. Neurooncol. 117 (3): 445–57. doi:10.1007/s11060-013-1262-8. PMID   24122025. S2CID   9927830.
  13. Laws, Edward R (2010). Transsphenoidal Surgery. Elsevier Inc.[ permanent dead link ]
  14. 1 2 3 Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M (2008). "Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement". J Clin Endocrinol Metab. 93 (7): 2454–2462. doi:10.1210/jc.2007-2734. PMC   3214276 . PMID   18413427.
  15. 1 2 Storr, HL; Plowman PN; Carroll PV; François I; Krassas GE; Afshar F; Besser GM; Grossman AB; Savage MO. (2003). "Clinical and Endocrine Responses to Pituitary Radiotherapy in Pediatric Cushing's Disease: An Effective Second-Line Treatment". J Clin Endocrinol Metab. 88 (1): 34–37. doi: 10.1210/jc.2002-021032 . PMID   12519825.
  16. Gadelha, Mônica R.; Leonardo Vieira Neto (2014). "Efficacy of medical treatment in Cushing's disease: a systematic review". Clinical Endocrinology. 80 (1): 1–12. doi:10.1111/cen.12345. PMID   24118077.
  17. Fairfield, Wesley P. (2003). "Cushing's Disease after Successful Transsphenoidal Surgery – What to Expect and How to Manage" . Retrieved January 31, 2014.
  18. Patil, CG; Lad, SP; Harsh, GR; Laws ER, Jr; Boakye, M (2007). "National trends, complications, and outcomes following transsphenoidal surgery for Cushing's disease from 1993 to 2002". Neurosurgical Focus. 23 (3): E7. doi:10.3171/foc.2007.23.3.9. PMID   17961019. S2CID   24097046.
  19. 1 2 3 4 5 6 7 Etxabe, J.; J. A. Vazquez (1994). "Morbidity and mortality in Cushing's disease: an epidemiological approach". Clinical Endocrinology. 40 (4): 479–484. doi:10.1111/j.1365-2265.1994.tb02486.x. PMID   8187313.
  20. Boggan, J.E; Tyrell, J.B; Wilson C.B (1983). "Transsphenoidal microsurgical management of Cushing's disease: report of 100 cases". Journal of Neurosurgery. 59 (2): 195–200. doi:10.3171/jns.1983.59.2.0195. PMID   6306181. S2CID   23636688.
  21. Howlet, T.A; Perry L.; Doniach I.; Rees LH.; Besser G.M (1986). "Diagnosis and management of ACTHdependent Cushing's syndrome: comparison of the features in ectopic and pituitary ACTH production". Clinical Endocrinology. 24 (6): 699–713. doi:10.1111/j.1365-2265.1986.tb01667.x. PMID   3024870.
  22. Lindholm, J.; Juul, S.; Jørgensen, J.O.L.; Astrup, J.; Bjerre, P.; Feldt-Rasmussen, U.; Hagen, C.; Jørgensen, J.; Kosteljanetz, M.; Kristensen, L.Ø.; Laurberg, P.; Schmidt, K.; Weeke, J (2001). "Incidence and late prognosis of Cushing's syndrome: A population-based study". Journal of Clinical Endocrinology and Metabolism. 86 (1): 117–123. doi: 10.1210/jcem.86.1.7093 . PMID   11231987.
  23. Cushing H: The Pituitary Body and its Disorders: Clinical States Produced by Disorders of the Hypophysis Cerebra. Philadelphia: JB Lippincott, 1912
  24. Laws ER, Ezzat S, Asa SL, Rio LM, Michel L, Knutzen R, eds. (2013). Pituitary Disorders: Diagnosis and Management. United Kingdom: Wiley-blackwell. p. xiv. ISBN   978-0-470-67201-3.
  25. Cushing, Harvey (1932). "The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism)". Bulletin of the Johns Hopkins Hospital . 50: 137–95. Reprinted in Cushing H (April 1969). "The basophil adenomas of the pituitary body". Ann R Coll Surg Engl. 44 (4): 180–1. PMC   2387613 . PMID   19310569.
  26. "Dr. Cushing Dead; Brain Surgeon, 70. A Pioneer Who Won Fame as Founder of New School of Neuro-Surgery. Discovered Malady Affecting Pituitary dre. Was Noted Teacher and author". The New York Times . October 8, 1939. Retrieved March 21, 2010.