Causes and Pathophysiology of Cushing's Syndrome

07/12/2018 Causes and pathophysiology of Cushing's syndrome - UpToDate
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Causes and pathophysiology of Cushing's syndrome
Author: Lynnette K Nieman, MD

Section Editor: André Lacroix, MD
Deputy Editor: Kathryn A Martin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2018. | This topic last updated: Feb 15, 2017.
INTRODUCTION — The diagnosis of Cushing's syndrome involves three steps: suspecting it on the basis of the patient's
symptoms and signs, documenting the presence of hypercortisolism, and determining its cause. The last step requires an
understanding of the causes and pathophysiology of the different types of Cushing's syndrome; these will be reviewed here.
The clinical manifestations, diagnosis, and treatment of Cushing's syndrome are discussed separately. (See "Epidemiology and
clinical manifestations of Cushing's syndrome" and "Establishing the diagnosis of Cushing's syndrome" and "Establishing the
cause of Cushing's syndrome" and "Overview of the treatment of Cushing's syndrome".)
PSEUDO-CUSHING'S SYNDROME — Hypercortisolism can occur in several disorders other than Cushing's syndrome [1,2].
When such patients present with clinical features consistent with Cushing's syndrome, they may also be referred to as having
physiologic hypercortisolism or pseudo-Cushing's syndrome. Clinically, patients with these physiologic forms of
hypercortisolism seldom have the cutaneous (ie, easy bruising, thinning, and friability) or muscle (ie, proximal muscle atrophy
and weakness) signs of Cushing's syndrome [3]. However, these conditions/disorders should be excluded when evaluating
patients for Cushing's syndrome. (See "Establishing the diagnosis of Cushing's syndrome", section on 'Exclude physiologic
hypercortisolism'.)
Examples of conditions associated with physiologic hypercortisolism that may have some clinical features of Cushing's
syndrome include:
● Pregnancy
● Patients with severe obesity, especially those with visceral obesity or polycystic ovary syndrome (PCOS)
● Patients with psychological stress, especially patients with a severe major depressive disorder
● Poorly controlled diabetes mellitus
● Rarely, chronic alcoholism [4,5]
Examples of conditions associated with physiologic hypercortisolism that are unlikely to have clinical features of Cushing's
syndrome include:
● Physical stress (illness, hospitalization/surgery, pain)
● Malnutrition, anorexia nervosa
● Intense chronic exercise
● Hypothalamic amenorrhea
● High corticosteroid-binding globulin (CBG) (increased serum cortisol but not urinary free cortisol [UFC])
● Glucocorticoid resistance
We suggest against routine testing for Cushing's syndrome in these patients unless they develop features predictive of
Cushing's syndrome, such as wide purplish stria, proximal myopathy, or easy bruising.
The distinction between physiologic hypercortisolism and Cushing's syndrome is not always simple because patients with
Cushing's syndrome can have serious infections, are frequently depressed (although it is often an atypical, agitated depression)
[6,7], and presumably have a prevalence of chronic alcoholism similar to that of the general population.
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The psychiatric literature suggests that as many as 80 percent of patients with major depressive disorders have increased
cortisol secretion [8-10]. However, cortisol hypersecretion, when present, is usually minimal. Furthermore, even severely
depressed patients with substantial cortisol hypersecretion rarely develop clinical Cushing's syndrome. However, some
depressed patients may be difficult to distinguish clinically or biochemically from those with Cushing's disease. Their abnormal
cortisol secretion presumably results from hypothalamic-pituitary-adrenal axis hyperactivity [9] and disappears after remission
of depression [11].
Approximately seventy patients with chronic alcoholism and clinical or biochemical manifestations of Cushing's syndrome have
been reported [4,5]. Most had liver dysfunction, although the hormonal changes did not correlate closely with the degree of
abnormality in liver function. In addition to liver dysfunction, these patients probably have transiently increased secretion of
corticotropin-releasing hormone (CRH) or vasopressin or impaired hypothalamic or pituitary responsiveness to cortisol.
However, their peripheral and petrosal sinus plasma CRH concentrations are normal [12]. The hormonal abnormalities
disappear rapidly during abstinence from alcohol.
CAUSES OF CUSHING'S SYNDROME — Cushing's syndrome may be either corticotropin (ACTH) dependent or independent
(table 1). Approximately 80 percent of endogenous Cushing's syndrome cases are ACTH dependent, and approximately 20
percent are ACTH independent [1].
This distinction is possible because chronic hypercortisolism inhibits both hypothalamic corticotropin-releasing hormone (CRH)
and vasopressin secretion as well as ACTH secretion by normal pituitary corticotrophs [13]. Among all patients presenting with
Cushing's syndrome, the most common cause is iatrogenic Cushing's due to exogenous administration of glucocorticoids. The
second most common form overall is Cushing's disease (pituitary hypersecretion of ACTH). (See 'Iatrogenic or factitious' below
and 'Cushing's disease' below.)
ACTH dependent — The causes of ACTH-dependent Cushing's syndrome are associated with bilateral adrenocortical
hyperplasia; their relative frequency is as follows:
● Cushing's disease (pituitary hypersecretion of ACTH) – 65 to 70 percent of all Cushing's syndrome (see 'Cushing's
disease' below)
● Ectopic secretion of ACTH by nonpituitary tumors – 10 to 15 percent (see 'Ectopic ACTH syndrome' below)
● Ectopic secretion of CRH by nonhypothalamic tumors causing pituitary hypersecretion of ACTH – Less than 1 percent (see
'Ectopic CRH syndrome' below)
● Iatrogenic or factitious Cushing's syndrome due to administration of exogenous ACTH (not glucocorticoids) – Less than 1
percent
ACTH independent — The causes of ACTH-independent Cushing's syndrome are:
● Iatrogenic or factitious Cushing's syndrome, which is by far the most common cause, as noted above (see 'Iatrogenic or
factitious' below)
● Adrenocortical adenomas and carcinomas – 18 to 20 percent (see 'Primary adrenocortical hyperfunction' below)
● Primary pigmented nodular adrenocortical disease (PPNAD), also called bilateral adrenal micronodular hyperplasia – Less
than 1 percent (see 'Primary pigmented nodular adrenocortical disease' below)
● Bilateral macronodular adrenal hyperplasia (BMAH) – Less than 1 percent; this disorder must be distinguished from
macronodular hyperplasia in Cushing's disease in which plasma ACTH concentrations are not suppressed [14] (see
'Bilateral macronodular adrenal hyperplasia' below)
Iatrogenic or factitious — Iatrogenic or factitious Cushing's syndrome is usually caused by administration of excessive
amounts of a synthetic glucocorticoid and only rarely by ACTH administration [15]. The most common cause of
hypercortisolism is ingestion of prescribed prednisone, usually for treatment of a nonendocrine disease. However, Cushing's
syndrome also can be caused by other oral, injected, topical, and inhaled glucocorticoids [16-18] and by megestrol acetate or
high-dose medroxyprogesterone, progestins with some intrinsic glucocorticoid activity [19]. The clearance of some inhaled
steroids may be delayed by ritonavir, leading to Cushing's syndrome [20]. Cushing's syndrome may also be caused by the use
of glucocorticoid-containing creams or herbal preparations [21,22].
Factitious Cushing's syndrome is a rare disorder (responsible for less than 1 percent of patients with Cushing's syndrome) that
refers to surreptitious intake of a glucocorticoid, often by patients who are close to the health professions [15,23].
ACTH-DEPENDENT CUSHING'S SYNDROME — The hallmark biochemical feature of ACTH-dependent Cushing's syndrome
is a normal or elevated ACTH level, which reflects tumoral secretion. The tumor secretion of ACTH causes bilateral
adrenocortical hyperplasia and hyperfunction [24].
Cushing's disease — Almost all patients with Cushing's disease have a pituitary adenoma, although the tumor is often not
demonstrable by imaging; rare patients have diffuse corticotroph hyperplasia even in the absence of ectopic corticotropin-
releasing hormone (CRH) secretion. The tumors are usually microadenomas; only approximately 5 to 10 percent are
macroadenomas. Patients with macroadenomas are more likely to have supranormal plasma ACTH concentrations than are
those with microadenomas (83 versus 45 percent), and the concentrations are less likely to fall with high doses of
dexamethasone [25,26]. A smaller proportion of those with macroadenomas respond to CRH stimulation (65 versus 84
percent); however, in all of those features, there is considerable overlap between patients with microadenomas and
macroadenomas [26]. (See "Establishing the cause of Cushing's syndrome".)
The amplitude and duration, but not the frequency, of ACTH secretory episodes are increased in Cushing's disease [27-32],
and the normal ACTH circadian rhythm is usually lost (figure 1). There is loss of tight synchrony between ACTH and cortisol
secretory dynamics, perhaps reflecting the fact that ACTH secretion by the adenoma is not subject to hypothalamic regulation,
because of suppressed CRH, and is relatively resistant to direct glucocorticoid inhibition [33]. The increased plasma ACTH
concentrations, acting alone or in concert with other growth factors [34-37], cause bilateral adrenocortical hyperplasia and
hypersecretion of cortisol (figure 2). Consequently, the normal circadian rhythm in cortisol secretion is also lost (figure 3).
Awakening plasma ACTH and serum cortisol concentrations may be normal, but pre-bedtime concentrations are high. Salivary
cortisol concentrations reflect those of serum free cortisol (see "Measurement of cortisol in serum and saliva"). The loss of the
nocturnal nadir in serum and salivary cortisol is used to document the presence of Cushing's syndrome.
The increased cortisol secretion is reflected by increased urinary excretion of cortisol and 17-hydroxycorticosteroid (17-OHCS).
ACTH secretion is increased more than that of cortisol, suggesting that the adrenal cortex is relatively unresponsive to excess
ACTH [32]. ACTH receptor (MC2R) levels are relatively decreased in the adrenocortical hyperplasia tissues of Cushing's
disease patients [38,39]. The relative activity of the enzymes involved in cortisol biosynthesis does not change, and therefore,
the production and excretion of cortisol precursors are increased proportionately.
The corticotroph adenoma cells respond to decreases in serum cortisol concentrations by increasing ACTH secretion and to
increases in serum cortisol concentrations (or other glucocorticoids such as dexamethasone) by decreasing ACTH secretion.
However, quantitatively, the cells are relatively resistant to negative feedback inhibition by glucocorticoids. In effect, the tumor
cells function at a higher than normal set point for cortisol feedback inhibition [6]. This characteristic is clinically important
because it permits the use of dexamethasone suppression to distinguish between pituitary and ectopic ACTH secretion; the
latter is usually more resistant to glucocorticoid negative feedback. (See "Establishing the cause of Cushing's syndrome" and
"Dexamethasone suppression tests".)
The mechanism for the resistance of corticotroph adenoma cells to glucocorticoid negative feedback inhibition is unclear.
● The resistance to glucocorticoids may, in some cases, reflect abnormalities in the glucocorticoid receptor. In one report, a
somatic frame-shift mutation of the glucocorticoid type 2 receptor was found in the tumor in one of four patients with
Nelson syndrome [40]. In another study, the tumors of 6 of 22 patients with Cushing's disease showed loss of
heterozygosity for one of five polymorphisms at the glucocorticoid receptor type 1 gene [41]. Loss of heterozygosity was
not detected in other types of pituitary adenomas.
● Abnormal expression of 11-beta-hydroxysteroid dehydrogenase isoenzyme 2 (11-beta-HSD-2), which converts cortisol to

cortisone in ACTH-secreting adenoma cells, is a second possible mechanism for insensitivity to glucocorticoid feedback
[42].
● Another study found deficient nuclear expression of one or two proteins, Brg1 and histone deacetylase 2 (HDAC2), in 17 of
36 human corticotroph adenomas (figure 2). Decreased nuclear localization of these proteins, which are involved in
repression of the proopiomelanocortin (POMC) gene, may account for resistance to glucocorticoid feedback in a subset of
patients with Cushing's disease [43].
The corticotroph adenomas that occur in approximately 2 percent of patients with multiple endocrine neoplasia type 1 (MEN 1)
syndrome occur at the same age but tend to be larger and more resistant to glucocorticoid negative feedback than sporadic
corticotroph adenomas [44,45].
As the adrenal glands become increasingly hyperplastic, they secrete proportionately more cortisol in response to a given
increment in plasma ACTH. This response serves to restrain ACTH secretion, even to the point of "autosuppression." This
phenomenon is especially pronounced in patients with severe bilateral macronodular adrenal hyperplasia (BMAH) [46-50], in
whom plasma ACTH concentrations may not exceed 15 pg/mL (3 pmol/L). Such patients may be thought erroneously to have
ACTH-independent Cushing's syndrome, but their ACTH levels can increase following administration of CRH [51]. However, no
case of Cushing's disease has been documented to progress to fully ACTH-independent Cushing's syndrome.
Ectopic ACTH syndrome — Except in some patients with benign neuroendocrine ("carcinoid") tumors, usually bronchial in
origin [52-54], ACTH secretion from malignant ectopic sources (such as from oat-cell carcinoma) is not inhibited by cortisol,
dexamethasone, or other glucocorticoids. In rare patients, glucocorticoids increase tumor secretion of ACTH [55]. In general,
tumors causing the ectopic ACTH syndrome tend to secrete a disproportionately greater proportion of POMC precursors, and
these may be their major product. As in Cushing's disease, salivary cortisol concentrations reflect those of serum free cortisol
and urinary excretion of cortisol and its precursors is increased proportionately.
Tumors of a wide variety of tissues, usually carcinomas rather than sarcomas or lymphomas, have been associated with the
ectopic ACTH syndrome; however, Ewing sarcoma has been reported in children [56]. Most cases are caused by
neuroendocrine tumors of the lung, pancreas, or thymus [24,57,58]. Small-cell carcinomas of the lung are probably the most
common cause of biochemical hypercortisolism; often, this is not apparent clinically. Intrathoracic tumors (pulmonary and
thymic carcinoids and rare multiple pulmonary tumorlets) represent the majority of patients presenting with Cushingoid features
[59].
Inappropriate repression or expression of certain genes, presumably similar to those in normal pituitary corticotropes, causes
these tumors to secrete ACTH and other POMC-derived peptides (figure 2) [60].
Ectopic CRH syndrome — In the ectopic corticotropin-releasing hormone (CRH) syndrome, CRH secretion by the tumor
causes hyperplasia and hypersecretion of the pituitary corticotrophs, resulting sequentially in ACTH hypersecretion, cortisol
hypersecretion, and bilateral adrenal hyperplasia [61]. In some of these patients, pituitary ACTH secretion can be inhibited by
dexamethasone [61]. However, many of these tumors also secrete ACTH, which is not inhibited by dexamethasone [62-66].
ACTH-INDEPENDENT CUSHING'S SYNDROME
Primary adrenocortical hyperfunction — In Cushing's syndrome due to primary adrenocortical disease (eg, adrenocortical
tumor, micronodular dysplasia, or ACTH-independent macronodular hyperplasia), increased cortisol secretion suppresses both
corticotropin-releasing hormone (CRH) and ACTH secretion, as it does in normal subjects and those with ACTH-dependent
Cushing's syndrome. The normal pituitary corticotrophs atrophy, as do the normal zonae fasciculata and reticularis of the
adrenal glands.
● Adrenal adenomas that cause Cushing's syndrome produce cortisol very efficiently. As ACTH is suppressed, serum
dehydroepiandrosterone sulfate (DHEAS) concentrations and urinary excretion of DHEAS are usually low relative to
urinary cortisol excretion or may be normal. However, occasional adrenal adenomas produce relatively large amounts of
androgen due to an increase in the 17,20-lyase activity of CYP17 (P450c17, 17-alpha-hydroxylase) [67]. Levels of
CYP21A2 (P450c21, 21-hydroxylase), CYP17, and CYP11A1 (P450scc, cholesterol side-chain cleavage enzyme,
cholesterol desmolase) mRNA are normal in cortisol-producing adenomas and 60 to 80 percent of normal in carcinomas,
roughly proportional to their steroidogenic activities [68].
● By contrast, adrenal carcinomas are frequently inefficient in terms of steroidogenesis. Since the efficiency per cell in
converting cholesterol to cortisol is low but cell mass is very large, their production of cortisol precursors (eg, urinary 17-KS
and serum and urinary DHEAS) is disproportionately higher. Even in patients with adrenal carcinomas who presumably do
not produce excess steroids, more sensitive methods such as gas chromatography-mass spectrometry (GC-MS) identify
increased urinary metabolites of several steroids and precursors of androgens (pregnanediol, pregnanetriol, androsterone,
etiocholanolone) or glucocorticoids (17-hydroxyproesterone, tetrahydro-11-deoxycortisol, cortisol, 6-hydroxy cortisol,
tetrahydrocortisol, and alpha-cortol) [69].
● Low serum aldosterone concentrations but normal or high serum or urinary concentrations of aldosterone precursors (ie,
deoxycorticosterone, 18-hydroxydeoxycorticosterone, corticosterone, and 18-hydroxycorticosterone, tetrahydro-11-
deoxycorticosterone [THDOC and 5-alpha THDOC]) are found in most adrenal carcinomas but not in adrenal adenomas
[69,70].
Most adrenocortical tumors are monoclonal, suggesting that they result from accumulated genetic abnormalities, such as
activation of proto-oncogenes and inactivation of tumor suppressor genes. The association of adrenal cancer with familial
syndromes suggests specific gene abnormalities (see "Clinical presentation and evaluation of adrenocortical tumors"):
● The Li-Fraumeni syndrome is caused by abnormalities in TP53, a tumor suppressor gene. An inherited mutation of the
gene was found in cases of pediatric adrenal cancer in Brazil [71]. In another study, the gene was abnormal in 5 of 20
adults with adrenal cancer [72]. (See "Li-Fraumeni syndrome".)
● The association of Beckwith-Wiedemann syndrome with adrenal cancer implicates insulin-like growth factor-2 (IGF-2) in
the disorder. In one study, loss of heterozygosity in 11p15, which includes the IGF2 gene, or overexpression of the gene,
was demonstrated in 27 of 29 of sporadic malignant tumors and 3 of 35 benign tumors [73].
● A high proportion of adrenal tumors, mostly adenomas, causing Cushing's syndrome have receptors for and are
responsive to agonists such as gastric inhibitory polypeptide (GIP), vasopressin, beta-adrenergic agents, serotonin,
luteinizing hormone/chorionic gonadotropin, and perhaps leptin or interleukin-1 [14]. In addition, rare pure androgen-
secreting tumors respond to luteinizing hormone [14,74]. Approximately 50 percent of the adenomas also respond to
ACTH by increasing cortisol production, presumably because they have normal ACTH (melanocortin-2) receptors.
Primary pigmented nodular adrenocortical disease — There are both sporadic and familial forms of primary pigmented
nodular adrenocortical disease (PPNAD), also called bilateral adrenal micronodular hyperplasia [75]. The familial form, Carney
syndrome or complex, is an autosomal dominant disorder characterized by two major types of findings: pigmented lentigines
and blue nevi on the face, neck, and trunk, including the lips, conjunctivae, and sclerae; and multiple neoplasms, both
endocrine (testicular Sertoli cells and occasionally adrenal, pituitary, or thyroid) and nonendocrine (cutaneous, mammary, atrial
myxomas, and psammomatous melanotic schwannomas) (figure 2) [76]. (See "Cushing's syndrome due to primary pigmented
nodular adrenocortical disease" and "Anatomy and pathology of testicular tumors", section on 'Sex cord-stromal tumors'.)
Bilateral macronodular adrenal hyperplasia — This syndrome is associated with adrenal glands that weigh from 24 to 500 g
or more and contain multiple nonpigmented nodules greater than 5 mm in diameter. The nodules appear to be typical benign
adrenal nodules, but the internodular cortex may be hypertrophic, rather than atrophic [14].
The pathogenesis of bilateral macronodular adrenal hyperplasia (BMAH) appears to involve overexpression of eutopic
receptors, inappropriate expression of ectopic receptors, or coupling of eutopic receptors to steroidogenic signaling pathways;
in the majority of patients, increases in cortisol secretion are mediated by overexpression of receptors for either vasopressin,
serotonin, beta-adrenergic agonists, luteinizing hormone/chorionic gonadotropin, GIP, or perhaps glucagon or leptin [14]. (See
"Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia".)
Most initial cases of BMAH appeared to be sporadic. There are now several reports of familial cases of BMAH whose
presentation suggests autosomal dominant transmission. In familial cases, a number of aberrant hormone receptors have been
identified in individual families, including V1-V2- and V3-vasopressin, beta-adrenergic, combined V1-vasopressin and beta-
adrenergic, and combined 5-hydroxytryptamine 4 (5HT4) and V1-V2 vasopressin. Another study has identified a germline
mutation of ARMC5 in patients with apparently sporadic BMAH (figure 2). This is discussed in detail separately. (See
"Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia".)
There are occasional reports that are difficult to reconcile with current understanding of the pathophysiology of ACTH-
independent primary adrenal disease. As an example, adrenal adenomas have been described in association with bilateral
nodular hyperplasia [77], as has nonpigmented bilateral micronodular hyperplasia thought to have resulted from longstanding
Cushing's disease [78]. A woman with virilization but no stigmata of Cushing's syndrome was found to have BMAH with
overexpression of luteinizing hormone/chorionic gonadotropin receptors and excessive adrenal testosterone production [79].
Her serum testosterone levels were increased, but her serum cortisol concentrations were normal.
Iatrogenic or factitious Cushing's syndrome — Iatrogenic or factitious Cushing's syndrome is usually caused by
administration of excessive amounts of a synthetic glucocorticoid or compounds such as megestrol acetate, which have some
intrinsic glucocorticoid activity [19]. Exogenous glucocorticoids inhibit CRH and ACTH secretion, causing bilateral
adrenocortical atrophy. Plasma ACTH, serum and salivary cortisol concentrations, and urinary cortisol excretion (unless cortisol
is the steroid administered) are all low [15]. (See "Establishing the diagnosis of Cushing's syndrome", section on 'Who should
be tested?'.)
Rare disorders
● Ectopic cortisol secretion – Rare cases of ectopic cortisol production from ovarian tumors that led to ACTH-independent
Cushing's syndrome have been described [80].
● Normocortisolemic Cushing's syndrome – Two patients have been described who had signs of Cushing's syndrome but
had normal or low cortisol secretion. One was a 54-year-old man with centripetal obesity, moon facies, and type 2 diabetes
but no other clinical abnormalities [81]. He had low serum cortisol and undetectable plasma ACTH concentrations and
failed to respond normally to the short ACTH, insulin-induced hypoglycemia, CRH-plus-vasopressin, and metyrapone
stimulation tests. Cortisol secretion increased markedly in response to a two-day ACTH stimulation test. These findings are
typical of administration of exogenous synthetic glucocorticoid, which was excluded by prolonged observation. The
investigators concluded that there was increased tissue sensitivity to cortisol and demonstrated increased induction of a
glucocorticoid-responsive gene in the patient's fibroblasts by dexamethasone [82].
The other patient was a 10-year-old girl with centripetal obesity, moon facies, purple striae, osteopenia, vertebral
compression fractures, and amenorrhea but normal linear growth [83]. Her plasma ACTH concentrations were normal and,
although she appeared on occasion to have an abnormal diurnal rhythm in serum cortisol, urinary cortisol excretion was
always normal, excluding hypercortisolism. She had a variable increase in type 2 corticosteroid (glucocorticoid) receptor
numbers in her peripheral lymphocytes, but these did not correlate with her clinical course. The receptor gene and its
promoter usage were normal. Her condition improved when she took mifepristone but did not worsen when it was
discontinued after 21 months at age 15.5 years. The pathogenesis of this forme fruste of Cushing's syndrome is unknown.
● Biochemical hypercortisolism without Cushingoid features – Two patients with clear-cut, moderate to severe
hypercortisolism but absent clinical features have been described [84,85]. Each had impaired cortisone-to-cortisol
conversion in vivo and decreased cortisol:cortisone metabolites, consistent with impaired 11-beta hydroxysteroid
dehydrogenase type 1 activity. Increased cortisol clearance was postulated as the mechanism by which the patients were
protected from tissue actions of cortisol.
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Cushing's syndrome treatment (Beyond the Basics)")
SUMMARY
● Cushing's syndrome may be either corticotropin (ACTH) dependent or independent (table 1). Among all patients presenting
with Cushing's syndrome, the most common cause is iatrogenic Cushing's due to exogenous administration of
glucocorticoids. The second most common form overall is Cushing's disease (pituitary tumoral hypersecretion of ACTH).
● The causes of ACTH-dependent Cushing's syndrome are associated with bilateral adrenocortical hyperplasia. Their
relative frequency is as follows:
• Cushing's disease (pituitary hypersecretion of ACTH) – 65 to 70 percent (see 'Cushing's disease' above)
• Ectopic secretion of ACTH by nonpituitary tumors – 10 to 15 percent (see 'Ectopic ACTH syndrome' above)
• Ectopic secretion of corticotropin-releasing hormone (CRH) by nonhypothalamic tumors causing pituitary

hypersecretion of ACTH – Less than 1 percent (see 'Ectopic CRH syndrome' above)
● The causes and frequencies of ACTH-independent Cushing's syndrome are:
• Iatrogenic or factitious Cushing's syndrome (see 'Iatrogenic or factitious' above)
• Adrenocortical adenomas and carcinomas – 18 to 20 percent (see 'Primary adrenocortical hyperfunction' above)
• Primary pigmented nodular adrenocortical disease (PPNAD), also called bilateral adrenal micronodular hyperplasia –
Less than 1 percent (see 'Primary pigmented nodular adrenocortical disease' above)
• Bilateral macronodular adrenal hyperplasia (BMAH) – Less than 1 percent (see 'Bilateral macronodular adrenal
hyperplasia' above)
● Pseudo-Cushing's syndrome refers to physiologic hypercortisolism that can occur in several disorders other than Cushing's
syndrome. Examples include severe obesity, depression, chronic strenuous activity, and alcoholism. (See 'Pseudo-
Cushing's syndrome' above.)
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REFERENCES
1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet 2015; 386:913.
2. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab 2008; 93:1526.
3. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J
Clin Endocrinol Metab 2003; 88:5593.
4. Groote Veldman R, Meinders AE. On the mechanism of alcohol-induced pseudo-Cushing's syndrome. Endocr Rev 1996;
17:262.
5. Besemer F, Pereira AM, Smit JW. Alcohol-induced Cushing syndrome. Hypercortisolism caused by alcohol abuse. Neth J
Med 2011; 69:318.
6. LIDDLE GW. Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab
1960; 20:1539.
7. Loosen PT, Chambliss B, DeBold CR, et al. Psychiatric phenomenology in Cushing's disease. Pharmacopsychiatry 1992;
25:192.
8. Pfohl B, Sherman B, Schlechte J, Winokur G. Differences in plasma ACTH and cortisol between depressed patients and
normal controls. Biol Psychiatry 1985; 20:1055.
9. Pfohl B, Sherman B, Schlechte J, Stone R. Pituitary-adrenal axis rhythm disturbances in psychiatric depression. Arch Gen
Psychiatry 1985; 42:897.
10. Gold PW, Loriaux DL, Roy A, et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression
and Cushing's disease. Pathophysiologic and diagnostic implications. N Engl J Med 1986; 314:1329.
11. Amsterdam JD, Maislin G, Winokur A, et al. The oCRH stimulation test before and after clinical recovery from depression.
J Affect Disord 1988; 14:213.
12. Yanovski JA, Nieman LK, Doppman JL, et al. Plasma levels of corticotropin-releasing hormone in the inferior petrosal
sinuses of healthy volunteers, patients with Cushing's syndrome, and patients with pseudo-Cushing states. J Clin
Endocrinol Metab 1998; 83:1485.
13. Kling MA, Roy A, Doran AR, et al. Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and
adrenocorticotropin secretion in Cushing's disease and major depression: potential clinical implications. J Clin Endocrinol
Metab 1991; 72:260.
14. Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome.
Endocr Rev 2001; 22:75.
15. Quddusi S, Browne P, Toivola B, Hirsch IB. Cushing syndrome due to surreptitious glucocorticoid administration. Arch
Intern Med 1998; 158:294.
16. Weber SL. Cushing'S syndrome attributable to topical use of lotrisone. Endocr Pract 1997; 3:140.
17. Nutting CM, Page SR. Iatrogenic Cushing's syndrome due to nasal betamethasone: a problem not to be sniffed at!
Postgrad Med J 1995; 71:231.
18. Hughes JM, Hichens M, Booze GW, Thorner MO. Cushing's syndrome from the therapeutic use of intramuscular
dexamethasone acetate. Arch Intern Med 1986; 146:1848.
19. Mann M, Koller E, Murgo A, et al. Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration
experience and a review of the literature. Arch Intern Med 1997; 157:1651.
20. Samaras K, Pett S, Gowers A, et al. Iatrogenic Cushing's syndrome with osteoporosis and secondary adrenal failure in
human immunodeficiency virus-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease
inhibitors: six cases. J Clin Endocrinol Metab 2005; 90:4394.
21. Olumide YM, Akinkugbe AO, Altraide D, et al. Complications of chronic use of skin lightening cosmetics. Int J Dermatol
2008; 47:344.
22. Oldenburg-Ligtenberg PC, van der Westerlaken MM. A woman with Cushing's syndrome after use of an Indonesian herb:
a case report. Neth J Med 2007; 65:150.
23. Cizza G, Nieman LK, Doppman JL, et al. Factitious Cushing syndrome. J Clin Endocrinol Metab 1996; 81:3573.
24. Orth DN. Ectopic hormone production. In: Endocrinology and metabolism, 2nd, Felig P, Baxter JD, Broadus AE, Frohman
LA (Eds), McGraw-Hill, New York 1987. p.1692.
25. Katznelson L, Bogan JS, Trob JR, et al. Biochemical assessment of Cushing's disease in patients with corticotroph
macroadenomas. J Clin Endocrinol Metab 1998; 83:1619.
26. Woo YS, Isidori AM, Wat WZ, et al. Clinical and biochemical characteristics of adrenocorticotropin-secreting
macroadenomas. J Clin Endocrinol Metab 2005; 90:4963.
27. Hellman L, Weitzman ED, Roffwarg H, et al. Cortisol is secreted episodically in Cushing's syndrome. J Clin Endocrinol
Metab 1970; 30:686.
28. Sederberg-Olsen P, Binder C, Kehlet H, et al. Episodic variation in plasma corticosteroids in subjects with Cushing's
syndrome of differing etiology. J Clin Endocrinol Metab 1973; 36:906.
29. Boyar RM, Witkin M, Carruth A, Ramsey J. Circadian cortisol secretory rhythms in Cushing's disease. J Clin Endocrinol
Metab 1979; 48:760.
30. Liu JH, Kazer RR, Rasmussen DD. Characterization of the twenty-four hour secretion patterns of adrenocorticotropin and
cortisol in normal women and patients with Cushing's disease. J Clin Endocrinol Metab 1987; 64:1027.
31. Stewart PM, Penn R, Gibson R, et al. Hypothalamic abnormalities in patients with pituitary-dependent Cushing's
syndrome. Clin Endocrinol (Oxf) 1992; 36:453.
32. van den Berg G, Frölich M, Veldhuis JD, Roelfsema F. Combined amplification of the pulsatile and basal modes of
adrenocorticotropin and cortisol secretion in patients with Cushing's disease: evidence for decreased responsiveness of
the adrenal glands. J Clin Endocrinol Metab 1995; 80:3750.
33. Roelfsema F, Pincus SM, Veldhuis JD. Patients with Cushing's disease secrete adrenocorticotropin and cortisol jointly
more asynchronously than healthy subjects. J Clin Endocrinol Metab 1998; 83:688.
34. LIDDLE GW, ISLAND D, RINFRET AP, FORSHAM PH. Factors enhancing the response of the human adrenal to
corticotropin. Is there an adrenal growth factor? J Clin Endocrinol Metab 1954; 14:839.
35. Segal BM, Drucker WD, Benovitz H, et al. Further studies of adrenal weight-maintaining activity in the plasma of patients
with Cushing's disease. Am J Med 1970; 49:34.
36. Hornsby PJ, Sturek M, Harris SE, Simonian MH. Serum and growth factor requirements for proliferation of human
adrenocortical cells in culture: comparison with bovine adrenocortical cells. In Vitro 1983; 19:863.
37. Estivariz FE, Morano MI, Carino M, et al. Adrenal regeneration in the rat is mediated by mitogenic N-terminal pro-
opiomelanocortin peptides generated by changes in precursor processing in the anterior pituitary. J Endocrinol 1988;
116:207.
38. Reincke M, Beuschlein F, Latronico AC, et al. Expression of adrenocorticotrophic hormone receptor mRNA in human
adrenocortical neoplasms: correlation with P450scc expression. Clin Endocrinol (Oxf) 1997; 46:619.
39. Antonini SR, Baldacchino V, Tremblay J, et al. Expression of ACTH receptor pathway genes in glucose-dependent
insulinotrophic peptide (GIP)-dependent Cushing's syndrome. Clin Endocrinol (Oxf) 2006; 64:29.
40. Karl M, Von Wichert G, Kempter E, et al. Nelson's syndrome associated with a somatic frame shift mutation in the
glucocorticoid receptor gene. J Clin Endocrinol Metab 1996; 81:124.
41. Huizenga NA, de Lange P, Koper JW, et al. Human adrenocorticotropin-secreting pituitary adenomas show frequent loss
of heterozygosity at the glucocorticoid receptor gene locus. J Clin Endocrinol Metab 1998; 83:917.
42. Korbonits M, Bujalska I, Shimojo M, et al. Expression of 11 beta-hydroxysteroid dehydrogenase isoenzymes in the human
pituitary: induction of the type 2 enzyme in corticotropinomas and other pituitary tumors. J Clin Endocrinol Metab 2001;
86:2728.
43. Bilodeau S, Vallette-Kasic S, Gauthier Y, et al. Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC
gene and misexpression in Cushing disease. Genes Dev 2006; 20:2871.
44. Vergès B, Boureille F, Goudet P, et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1
multicenter study. J Clin Endocrinol Metab 2002; 87:457.
45. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol
Metab 2001; 86:5658.
46. Choi Y, Werk EE Jr, Sholiton LJ. Cushing's syndrome with dual pituitary-adrenal control. Arch Intern Med 1970; 125:1045.
47. Burke CW. Disorders of cortisol production: diagnostic and therapeutic progress. Recent Adv Endocrinol Metab 1978;
1:61.
48. Aron DC, Findling JW, Fitzgerald PA, et al. Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing's
syndrome. Report of two cases and review of the literature. Am J Med 1981; 71:302.
49. Smals AG, Pieters GF, van Haelst UJ, Kloppenborg PW. Macronodular adrenocortical hyperplasia in long-standing
Cushing's disease. J Clin Endocrinol Metab 1984; 58:25.
50. Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab 1985; 14:947.
51. Hermus AR, Pieters GF, Smals AG, et al. Transition from pituitary-dependent to adrenal-dependent Cushing's syndrome.
N Engl J Med 1988; 318:966.
52. Strott CA, Nugent CA, Tyler FH. Cushing's syndrome caused by bronchial adenomas. Am J Med 1968; 44:97.
53. Malchoff CD, Orth DN, Abboud C, et al. Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to
dexamethasone, metyrapone, and corticotropin-releasing factor. Am J Med 1988; 84:760.
54. de Keyzer Y, Lenne F, Auzan C, et al. The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic
ACTH syndrome. J Clin Invest 1996; 97:1311.
55. White A, Ray DW, Talbot A, et al. Cushing's syndrome due to phaeochromocytoma secreting the precursors of
adrenocorticotropin. J Clin Endocrinol Metab 2000; 85:4771.
56. More J, Young J, Reznik Y, et al. Ectopic ACTH syndrome in children and adolescents. J Clin Endocrinol Metab 2011;
96:1213.
57. Ilias I, Torpy DJ, Pacak K, et al. Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at
the National Institutes of Health. J Clin Endocrinol Metab 2005; 90:4955.
58. Neary NM, Lopez-Chavez A, Abel BS, et al. Neuroendocrine ACTH-producing tumor of the thymus--experience with 12
patients over 25 years. J Clin Endocrinol Metab 2012; 97:2223.
59. Arioglu E, Doppman J, Gomes M, et al. Cushing's syndrome caused by corticotropin secretion by pulmonary tumorlets. N
Engl J Med 1998; 339:883.
60. Pascual-Le Tallec L, Dulmet E, Bertagna X, de Keyzer Y. Identification of genes associated with the corticotroph
phenotype in bronchial carcinoid tumors. J Clin Endocrinol Metab 2002; 87:5015.
61. Carey RM, Varma SK, Drake CR Jr, et al. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's
syndrome. A clinical, morphologic, and biochemical study. N Engl J Med 1984; 311:13.
62. Schteingart DE, Lloyd RV, Akil H, et al. Cushing's syndrome secondary to ectopic corticotropin-releasing hormone-
adrenocorticotropin secretion. J Clin Endocrinol Metab 1986; 63:770.
63. Zorate A, Kovacs K, Flores M, et al. ACTH and CRF-producing bronchial carcinoid associated with Cushing's syndrome.
Clin Endocrinol 1986; 24:523.
64. Jessop DS, Cunnah D, Millar JG, et al. A phaeochromocytoma presenting with Cushing's syndrome associated with
increased concentrations of circulating corticotrophin-releasing factor. J Endocrinol 1987; 113:133.
65. O'Brien T, Young WF Jr, Davila DG, et al. Cushing's syndrome associated with ectopic production of corticotrophin-
releasing hormone, corticotrophin and vasopressin by a phaeochromocytoma. Clin Endocrinol (Oxf) 1992; 37:460.
66. Orth DN. Corticotropin-releasing hormone in humans. Endocr Rev 1992; 13:164.
67. Sakai Y, Yanase T, Takayanagi R, et al. High expression of cytochrome b5 in adrenocortical adenomas from patients with
Cushing's syndrome associated with high secretion of adrenal androgens. J Clin Endocrinol Metab 1993; 76:1286.
68. Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid
expression in human adrenocortical tumors. J Clin Endocrinol Metab 1998; 83:2585.
69. Arlt W, Biehl M, Taylor AE, et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal
tumors. J Clin Endocrinol Metab 2011; 96:3775.
70. Aupetit-Faisant B, Battaglia C, Zenatti M, et al. Hypoaldosteronism accompanied by normal or elevated
mineralocorticosteroid pathway steroid: a marker of adrenal carcinoma. J Clin Endocrinol Metab 1993; 76:38.
71. Figueiredo BC, Sandrini R, Zambetti GP, et al. Penetrance of adrenocortical tumours associated with the germline TP53
R337H mutation. J Med Genet 2006; 43:91.
72. Sidhu S, Martin E, Gicquel C, et al. Mutation and methylation analysis of TP53 in adrenal carcinogenesis. Eur J Surg
Oncol 2005; 31:549.
73. Gicquel C, Raffin-Sanson ML, Gaston V, et al. Structural and functional abnormalities at 11p15 are associated with the
malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J Clin Endocrinol Metab 1997;
82:2559.
74. Lacroix A, Bourdeau I, Lampron A, et al. Aberrant G-protein coupled receptor expression in relation to adrenocortical
overfunction. Clin Endocrinol (Oxf) 2010; 73:1.
75. Larsen JL, Cathey WJ, Odell WD. Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing's syndrome.
Case report and review of the literature. Am J Med 1986; 80:976.
76. Carney JA, Young WF Jr. Primary pigmented nodular adrenocortical disease and its associated conditions.
Endocrinologist 1992; 2:6.
77. Hocher B, Bähr V, Dorfmüller S, Oelkers W. Hypercortisolism with non-pigmented micronodular adrenal hyperplasia:
transition from pituitary-dependent to adrenal-dependent Cushing's syndrome. Acta Endocrinol (Copenh) 1993; 128:120.
78. Iino K, Sasano H, Nagura H, et al. Adrenal adenoma with bilateral adrenocortical nodular change in a patient with
Cushing's syndrome. Clin Endocrinol (Oxf) 1997; 47:371.
79. Goodarzi MO, Dawson DW, Li X, et al. Virilization in bilateral macronodular adrenal hyperplasia controlled by luteinizing
hormone. J Clin Endocrinol Metab 2003; 88:73.
80. Marieb NJ, Spangler S, Kashgarian M, et al. Cushing's syndrome secondary to ectopic cortisol production by an ovarian
carcinoma. J Clin Endocrinol Metab 1983; 57:737.
81. Iida S, Nakamura Y, Fujii H, et al. A patient with hypocortisolism and Cushing's syndrome-like manifestations: cortisol
hyperreactive syndrome. J Clin Endocrinol Metab 1990; 70:729.
82. Fujii H, Iida S, Gomi M, et al. Augmented induction by dexamethasone of metallothionein IIa messenger ribonucleic acid
in fibroblasts from a patient with cortisol hyperreactive syndrome. J Clin Endocrinol Metab 1993; 76:445.
83. Newfield RS, Kalaitzoglou G, Licholai T, et al. Normocortisolemic Cushing's syndrome initially presenting with increased
glucocorticoid receptor numbers. J Clin Endocrinol Metab 2000; 85:14.
84. Tomlinson JW, Draper N, Mackie J, et al. Absence of Cushingoid phenotype in a patient with Cushing's disease due to
defective cortisone to cortisol conversion. J Clin Endocrinol Metab 2002; 87:57.
85. Arai H, Kobayashi N, Nakatsuru Y, et al. A case of cortisol producing adrenal adenoma without phenotype of Cushing's
syndrome due to impaired 11beta-hydroxysteroid dehydrogenase 1 activity. Endocr J 2008; 55:709.
Topic 125 Version 15.0
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GRAPHICS
Frequency of causes of Cushing's syndrome
Diagnosis Percent of patients
ACTH-dependent Cushing's syndrome
Cushing's disease 68
Ectopic ACTH syndrome 12
Ectopic CRH syndrome <<1
ACTH-independent Cushing's syndrome
Adrenal adenoma 10
Adrenal carcinoma 8
Micronodular hyperplasia <1
Macronodular hyperplasia <1
Pseudo-Cushing's syndrome
Major depressive disorder 1
Alcoholism <<1
Relative prevalence of various causes of Cushing's syndrome in 630 patients (146 consecutive patients seen at Vanderbilt University
Medical Center before 1993 and published reports describing 484 patients). The prevalence of pseudo-Cushing's syndrome depends
upon the individual clinician's threshold of clinical suspicion; in our experience, it is very rare. The relative prevalence of various
causes of Cushing's syndrome among children and adolescents may differ somewhat from that of adults. The ectopic ACTH syndrome,
for example, is less common in children.
ACTH: corticotropin; CRH: corticotropin-releasing hormone.
Graphic 50582 Version 6.0
Pulse analysis of plasma ACTH in Cushing's disease
Analysis of specimens sampled at 10-minute intervals for 24 hours in normal subjects (left four
panels) and patients with Cushing's disease (right four panels) reveals that in Cushing's disease,
the amplitude and duration, but not the frequency of ACTH secretory episodes are increased.
ACTH: corticotropin.
Data from: van den Berg G, Frölich M, Veldhuis JD, Roelfsema F. Combined amplification of the
pulsatile and basal modes of adrenocorticotropin and cortisol secretion in patients with Cushing's
disease: evidence for decreased responsiveness of the adrenal glands. J Clin Endocrinol Metab 1995;
80:3750.
Summary of genetic and molecular mechanisms implicated in Cushing's syndrome
For each cause, the various genetic mutations or abnormal protein expression believed to play a part in the pathophysiology are shown.
The most frequent mechanisms are highlighted in blue characters; the well-characterized mechanisms are highlighted in bold characters,
and other potential mechanisms are in normal characters; a question marks shows an unconfirmed association or genetic predisposition.
ACTH: corticotropin; AC: adenylate cyclase; GPCR: G-protein-coupled receptor; Gs-alpha: alpha subunit of Gs; ATP: adenosine triphosphate; cAMP:
cyclic adenosine monophosphate; PDEs: phosphodiesterases; GEP-NETs: gastroenteropancreatic neuroendocrine tumors; PKA: protein kinase; R1-
alpha: type 1-alpha regulatory subunit of PKA; C-alpha: catalytic subunit of PKA; BMAH: bilateral macronodular adrenal hyperplasia; PPNAD:
primary pigmented nodular adrenocortical disease.
From: Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet 2015; 386:913. Illustration used with the permission of
Elsevier Inc. All rights reserved.
Episodic cortisol secretion in Cushing's syndrome
Serum cortisol concentrations throughout the day in patients with different

forms of Cushing's syndrome. There is episodic hormone release in both ACTH-
dependent and ACTH-independent (adrenal adenoma) forms of the syndrome.
To convert serum cortisol to nmol/L, multiply by 27.6.
ACTH: corticotropin.
Data from: Sederberg-Olsen P, Binder C, Kehlet H, et al. Episodic variation in plasma

corticosteroids in subjects with Cushing's syndrome of differing etiology. J Clin
Endocrinol Metab 1973; 36:906.
Contributor Disclosures
Lynnette K Nieman, MD Grant/Research/Clinical Trial Support: HRA Pharma [Cushing's syndrome (Metyrapone)]. André
Lacroix, MD Grant/Research/Clinical Trial Support: Novartis [Pituitary tumors, Cushing's syndrome (Pasireotide, octreotide,
osilodrostat)]; Cortendo [Cushing's syndrome (Levoketoconazole)]; GLWL Research Inc [Prader-Willi syndrome (GLWL-01)].
Speaker’s Bureau: Novartis [Cushing's syndrome (Pasireotide, octreotide, osilodrostat)]; Pfizer [Aberrant hormone receptors in
adrenocortical function]. Consultant/Advisory Boards: Novartis [Pituitary tumors, Cushing's syndrome (Pasireotide, octreotide,
osilodrostat)]. Other Financial Interest: Encyclopedia of Endocrinology [Adrenal (Editor)]; European Journal of Endocrinology
[Senior editor]. Kathryn A Martin, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for references to be provided to support the content.
Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Causes and Pathophysiology of Cushing's Syndrome - UpToDate

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Causes and Pathophysiology of Cushing's Syndrome - UpToDate

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Author: Lynnette K Nieman, MD

● Poorly controlled diabetes mellitus

● Rarely, chronic alcoholism [4,5]

● Physical stress (illness, hospitalization/surgery, pain)

● Malnutrition, anorexia nervosa

● Intense chronic exercise

ACTH independent — The causes of ACTH-independent Cushing's syndrome are:

● Abnormal expression of 11-beta-hydroxysteroid dehydrogenase isoenzyme 2 (11-beta-HSD-2), which converts cortisol to

ACTH-INDEPENDENT CUSHING'S SYNDROME

● Basics topics (see "Patient education: Cushing's syndrome (The Basics)")

• Ectopic secretion of corticotropin-releasing hormone (CRH) by nonhypothalamic tumors causing pituitary

● The causes and frequencies of ACTH-independent Cushing's syndrome are:

• Iatrogenic or factitious Cushing's syndrome (see 'Iatrogenic or factitious' above)

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Topic 125 Version 15.0

Frequency of causes of Cushing's syndrome

Diagnosis Percent of patients

ACTH-dependent Cushing's syndrome

Ectopic ACTH syndrome 12

Ectopic CRH syndrome <<1

ACTH-independent Cushing's syndrome

Micronodular hyperplasia <1

Macronodular hyperplasia <1

Major depressive disorder 1

ACTH: corticotropin; CRH: corticotropin-releasing hormone.

Graphic 50582 Version 6.0

Pulse analysis of plasma ACTH in Cushing's disease

Graphic 54316 Version 3.0

Summary of genetic and molecular mechanisms implicated in Cushing's syndrome

Graphic 112079 Version 1.0

Episodic cortisol secretion in Cushing's syndrome

Serum cortisol concentrations throughout the day in patients with different

Data from: Sederberg-Olsen P, Binder C, Kehlet H, et al. Episodic variation in plasma

Graphic 60086 Version 5.0

Conflict of interest policy

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