Cushing's disease

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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. The equine version of this disease is Pituitary pars intermedia dysfunction.

Contents

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. [7] 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. [8]

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. [7] The most common symptoms seen in male patients are purple striae, muscle atrophy, osteoporosis, and kidney stones. [8]

Common

Common signs and symptoms of Cushing's disease include the following:[ citation needed ]

  • weight gain
  • high blood pressure [9]
  • poor short-term memory
  • irritability
  • excess hair growth (women) [3]
  • Impaired immunological function [9]
  • red, ruddy face
  • extra fat around neck, "Buffalo Hump"
  • moon face
  • fatigue
  • red stretch marks
  • poor concentration
  • irregular menstruation [8]

Less common

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

  • insomnia
  • recurrent infection
  • thin skin and stretch marks [9]
  • easy bruising
  • weak bones
  • acne
  • balding (women)
  • depression
  • hip and shoulder weakness
  • swelling of feet/legs
  • diabetes mellitus [9]
  • erectile dysfunction

Diagnosis

Diagnostic algorithm of suspected Cushing's syndrome: ACTH=adrenocorticotropic hormone. CBG=corticosteroid-binding globulin CRH=corticotropin-releasing hormone DST=dexamethasone suppression test. IPSS=inferior petrosal sinus sampling UFC=urinary free cortisol. *There is consensus that all patients with lesions smaller than 6 mm in diameter should have IPSS and those with lesions of >=10 mm do not need IPSS, but expert opinions differed for lesions 6-9 mm in diameter +This alternative option does not have clear consensus and needs further research, and this is indicated by darker boxes. Green boxes indicate points to consider Darker colors indicate less validated testing pathways. Diagnostic algorithm of suspected Cushing's syndrome.png
Diagnostic algorithm of suspected Cushing's syndrome:
ACTH=adrenocorticotropic hormone.
CBG=corticosteroid-binding globulin
CRH=corticotropin-releasing hormone
DST=dexamethasone suppression test.
IPSS=inferior petrosal sinus sampling
UFC=urinary free cortisol.
*There is consensus that all patients with lesions smaller than 6 mm in diameter should have IPSS and those with lesions of ≥10 mm do not need IPSS, but expert opinions differed for lesions 6–9 mm in diameter
†This alternative option does not have clear consensus and needs further research, and this is indicated by darker boxes.
Green boxes indicate points to consider
Darker colors indicate less validated testing pathways.

Diagnosis is made first by diagnosing Cushing's syndrome (hypercortisolism), which can be difficult to do clinically since the most characteristic symptoms only occur in a minority of patients. [11] 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). No single test is perfect and multiple tests should always be used to achieve a proper diagnosis. [8] Diagnosing Cushing's disease is a multidisciplinary process involving doctors, endocrinologists, radiologists, surgeons, and chemical pathologists. [8] Often, it is hard to differentiate true Cushing's from pseudo-Cushing's (non-neoplastic hypercortisolism). [12]

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. [13] 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, pituitary MRI and bilateral inferior petrosal sinus sampling (IPSS).[ citation needed ]

Dexamethasone suppression test

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

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. [8] This rarely occurs with ectopic corticotropin syndrome and thus is quite useful for distinguishing between the two conditions. [8] 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. [8] However, this test is used only as a last resort due to its high cost and complexity. [11]

Imaging

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. [8] 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. [14]

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. [15] A corticotropin gradient sample via BIPSS is required to confirm diagnosis when pituitary MRI imaging and biochemical diagnostic tests have been inconclusive. [8] 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. [8] This test has been the gold standard for distinguishing between Cushing's disease and ectopic corticotropin syndrome, [8] with a sensitivity and specificity of 94% for Cushing's disease, [11] and a very low rate of complications. [16]

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. [8] [11] This test should be repeated three times in order to exclude any normally occurring periods of hypercortisolism. [11] 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. [11]

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. [8] The test measures free circulating cortisol and have both a sensitivity and specificity of 95–98%. [8] [11] This test is especially useful for diagnosing children. [8]

Treatment

Management algorithm of Cushing's disease: DST=dexamethasone suppression test. IPSS=inferior petrosal sinus sampling. ACTH=adrenocorticotropic hormone. *Pituitary surgery should be performed by an experienced surgeon. +Absence of ACTH-staining adenoma. ++See table 2 and panel 3 for considerations regarding selection of medical therapy. SSLifelong monitoring for hypopituitarism and secondary neoplasia in the radiation field required. POn maximum tolerated dose of the drug. Management algorithm of Cushing's disease.png
Management algorithm of Cushing's disease:
DST=dexamethasone suppression test.
IPSS=inferior petrosal sinus sampling.
ACTH=adrenocorticotropic hormone.
*Pituitary surgery should be performed by an experienced surgeon.
†Absence of ACTH-staining adenoma.
‡See table 2 and panel 3 for considerations regarding selection of medical therapy.
§Lifelong monitoring for hypopituitarism and secondary neoplasia in the radiation field required.
¶On maximum tolerated dose of the drug.

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). [17] 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. [18] 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. [19] 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%. [19] 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. [19]

Pituitary radiation therapy is another option for treatment of postoperative persisting hypercortisolemia following unsuccessful transsphenoidal surgery. [20] 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. [20]

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. [21]

During post-surgical recovery, patients collect a 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 [22]

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. [23]

Epidemiology

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. [24] 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. [24] Several studies have shown that Cushing's disease is more prevalent in women than men at a ratio of 3–6:1, respectively. [25] [26] 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. [24] The mortality rate of Cushing's disease was reported to be 10–11%, [24] [27] with the majority of deaths due to vascular disease. [9] [24] Women aged 45–70 years have a significantly higher mortality rate than men. [24] 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. [24]

History

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 [28] [29] 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. [30] [31] 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 had 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

<span class="mw-page-title-main">Adrenocorticotropic hormone</span> Pituitary hormone

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 and androgens by the zona fasiculata and zona reticularis, respectively. ACTH is also related to the circadian rhythm in many organisms.

<span class="mw-page-title-main">Cushing's syndrome</span> Symptoms from excessive exposure to glucocorticoids such as cortisol

Cushing's syndrome is a 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 due to facial plethora, 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.

<span class="mw-page-title-main">Anterior pituitary</span> 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) which, in humans, is located at the base of the brain, protruding off the bottom of the hypothalamus.

<span class="mw-page-title-main">Adrenal insufficiency</span> Insufficient production of steroid hormones by the adrenal glands

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids, mineralocorticoids, and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue, low blood pressure, depression, mood and personality changes to organ failure and shock. Adrenal crisis may occur if a person having adrenal insufficiency experiences stresses, such as an accident, injury, surgery, or severe infection; this is a life-threatening medical condition resulting from severe deficiency of cortisol in the body. Death may quickly follow.

Corticotropic cells, 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.

<span class="mw-page-title-main">Hypopituitarism</span> Medical condition

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.

<span class="mw-page-title-main">Metyrapone</span> 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). It is part of the steroidogenesis inhibitor class of drugs.

<span class="mw-page-title-main">Pituitary adenoma</span> Tumor of the pituitary gland

Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors 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, with an estimated prevalence rate in the general population of approximately 17%.

Nelson's syndrome is a disorder that occurs in about one in four patients who have had both adrenal glands removed to treat Cushing's disease. In patients with pre-existing adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, loss of adrenal feedback following bilateral adrenalectomy can trigger the rapid growth of the tumor, leading to visual symptoms and hyperpigmentation. The severity of the disease is dependent upon the effect of ACTH release on the skin, pituitary hormone loss from mass compression, as well as invasion into surrounding structures around the pituitary gland.

<span class="mw-page-title-main">Adrenocorticotropic hormone deficiency</span> Medical condition

Adrenocorticotropic hormone deficiency is a rare disorder characterized by secondary adrenal insufficiency with minimal or no cortisol production and normal pituitary hormone secretion apart from ACTH. ACTH deficiency may be congenital or acquired, and its symptoms are clinically similar to those of glucocorticoid deficiency. Symptoms consist of weight loss, diminished appetite, muscle weakness, nausea, vomiting, and hypotension. Low blood sugar and hyponatremia are possible; however, blood potassium levels typically remain normal because affected patients are deficient in glucocorticoids rather than mineralocorticoids because of their intact renin-angiotensin-aldosterone system. ACTH may be undetectable in blood tests, and cortisol is abnormally low. Glucocorticoid replacement therapy is required. With the exception of stressful situations, some patients with mild or nearly asymptomatic disease may not require glucocorticoid replacement therapy. As of 2008 about two hundred cases have been described in the literature.

<span class="mw-page-title-main">Dexamethasone suppression test</span> Medical test

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

<span class="mw-page-title-main">Hyperpituitarism</span> Medical condition

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.

Pseudo-Cushing's syndrome or non-neoplastic hypercortisolism is a medical condition in which patients display the signs, symptoms, and abnormal cortisol 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.

<span class="mw-page-title-main">Adrenocortical adenoma</span> Benign tumor of the adrenal gland

An adrenocortical adenoma or adrenal 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 adrenocortical adenomas.

The ACTH test is a medical test usually requested 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).

Inferior petrosal sinus sampling, is a diagnostic medical procedure used to determine whether excess adrenocorticotropic hormone (ACTH) is coming from the pituitary gland or from a source outside the pituitary. The procedure is usually reserved for patients with consistent ACTH-dependent Cushing's syndrome without a clear cut lesion on pituitary MRI.

<span class="mw-page-title-main">Primary pigmented nodular adrenocortical disease</span> Medical condition

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.

<span class="mw-page-title-main">Generalized glucocorticoid resistance</span> Medical condition

Generalized glucocorticoid resistance or Chrousos syndrome is a rare genetic disorder that can run in families or be sporadic. It is characterized by partial or generalized target-tissue insensitivity to glucocorticoids.

<span class="mw-page-title-main">Adrenalism</span>

Adrenalism describes the condition of an excessive or substandard secretion of hormones related to the adrenal glands, which are found directly superior to the kidneys. Adrenalism can be further distinguished as hyperadrenalism, referring to the excessive secretion of hormones, and hypoadrenalism, referring to the insufficient secretion of hormones.

References

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  17. ↑ 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.
  18. ↑ Laws, Edward R (2010). Transsphenoidal Surgery. Elsevier Inc. Archived from the original on February 4, 2014.
  19. 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.
  20. 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.
  21. ↑ 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. S2CID   21444684.
  22. ↑ Fairfield, Wesley P. (2003). "Cushing's Disease after Successful Transsphenoidal Surgery – What to Expect and How to Manage" . Retrieved January 31, 2014.
  23. ↑ 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.
  24. 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. S2CID   9409591.
  25. ↑ 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.
  26. ↑ 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. S2CID   2569895.
  27. ↑ 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.
  28. ↑ Cushing H: The Pituitary Body and its Disorders: Clinical States Produced by Disorders of the Hypophysis Cerebra. Philadelphia: JB Lippincott, 1912
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ "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.

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