INTRODUCTION — The diagnosis of Cushing 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 syndrome; these will be reviewed here (figure 1). The clinical manifestations, diagnosis, and treatment of Cushing syndrome are discussed separately. (See "Epidemiology and clinical manifestations of Cushing syndrome" and "Establishing the diagnosis of Cushing syndrome" and "Establishing the cause of Cushing syndrome" and "Overview of the treatment of Cushing syndrome".)
EPIDEMIOLOGY — Cushing syndrome may be either corticotropin (ACTH) dependent or independent (table 1). Approximately 80 percent of endogenous Cushing syndrome cases are ACTH dependent, and approximately 20 percent are ACTH independent (figure 1) [1].
Chronic hypercortisolism inhibits both hypothalamic corticotropin-releasing hormone (CRH) and vasopressin secretion as well as ACTH secretion by normal pituitary corticotrophs [2]. Among all patients presenting with Cushing syndrome, the most common cause is iatrogenic Cushing due to exogenous administration of glucocorticoids. The second most common form overall is Cushing disease (pituitary hypersecretion of ACTH) [3]. (See 'Iatrogenic or factitious' below and 'Cushing disease' below.)
PSEUDO-CUSHING SYNDROME — Hypercortisolism can occur in several disorders other than Cushing syndrome [1,4]. When such patients present with clinical features consistent with Cushing syndrome, they may also be referred to as having physiologic hypercortisolism or pseudo-Cushing syndrome [5]. 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 syndrome [6]. However, these conditions/disorders should be excluded when evaluating patients for Cushing syndrome. (See "Establishing the diagnosis of Cushing syndrome", section on 'Exclude physiologic hypercortisolism'.)
ACTH-DEPENDENT CUSHING SYNDROME — The causes of ACTH-dependent Cushing syndrome are associated with bilateral adrenocortical hyperplasia; their relative frequency is as follows:
●Cushing disease (pituitary hypersecretion of ACTH) – 65 to 70 percent of all Cushing syndrome (see 'Cushing 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 syndrome due to administration of exogenous ACTH (not glucocorticoids) – Less than 1 percent
The hallmark biochemical feature of ACTH-dependent Cushing syndrome is a normal or elevated ACTH level, which reflects tumoral secretion. The tumor secretion of ACTH causes bilateral adrenocortical hyperplasia and hyperfunction [7].
Cushing disease — Almost all patients with Cushing 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 [8,9]. 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 [9]. (See "Establishing the cause of Cushing syndrome".)
The amplitude and duration, but not the frequency, of ACTH secretory episodes are increased in Cushing disease [10-15], and the normal ACTH circadian rhythm is usually lost (figure 2). 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 [16]. The increased plasma ACTH concentrations, acting alone or in concert with other growth factors [17-20], cause bilateral adrenocortical hyperplasia and hypersecretion of cortisol (figure 1). 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 syndrome.
The increased cortisol secretion is reflected by increased urinary excretion of cortisol. ACTH secretion is increased more than that of cortisol, suggesting that the adrenal cortex is relatively unresponsive to excess ACTH [15]. ACTH receptor (MC2R) levels are relatively decreased in the adrenocortical hyperplasia tissues of patients with Cushing disease [21,22]. 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 [23]. 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 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 [24]. In another study, the tumors of 6 of 22 patients with Cushing disease showed loss of heterozygosity for one of five polymorphisms at the glucocorticoid receptor type 1 gene [25]. 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 [26].
●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 1). 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 disease [27].
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 [28,29].
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 Cushing disease-induced severe bilateral macronodular adrenal hyperplasia [30-34], 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 syndrome, but their ACTH levels can increase following administration of CRH [35]. However, no case of Cushing disease has been documented to progress to fully ACTH-independent Cushing syndrome.
Ectopic ACTH syndrome — Except in some patients with benign neuroendocrine ("carcinoid") tumors, usually bronchial in origin [36-38], 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 [39]. 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 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 [40]. Most cases are caused by neuroendocrine tumors of the lung, pancreas, or thymus [7,41,42]. 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 [43].
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 1) [44].
Disease-specific use of two other POMC promoter regions due to enhanced e2F-1 transcription, or demethylation of a region of the gene, account for POMC expression in some ectopic ACTH tumors [45,46].
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 [47]. In some of these patients, pituitary ACTH secretion can be inhibited by dexamethasone [47]. However, many of these tumors also secrete ACTH, which is not inhibited by dexamethasone [48-52].
ACTH-INDEPENDENT CUSHING SYNDROME — The causes of ACTH-independent Cushing syndrome are:
●Iatrogenic or factitious Cushing 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 disease in which plasma ACTH concentrations are not suppressed [53]. (See 'Bilateral macronodular adrenal hyperplasia' below.)
Primary adrenocortical hyperfunction — In Cushing 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 syndrome. The normal pituitary corticotrophs atrophy, as do the normal zonae fasciculata and reticularis of the adrenal glands.
●Adrenal adenomas that cause Cushing 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) [54]. 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 [55].
●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-hydroxyprogesterone, tetrahydro-11-deoxycortisol, cortisol, 6-hydroxy cortisol, tetrahydrocortisol, and alpha-cortol) [56]. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Clinical presentation'.)
●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 [56,57].
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. In addition, a high proportion of adrenal tumors, mostly adenomas, causing Cushing 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. These disorders are reviewed separately. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Adrenocortical carcinoma' and "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia", section on 'Aberrant hormone 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 [58]. 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 1) [59]. (See "Cushing 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 [53].
Bilateral macronodular adrenal hyperplasia (BMAH) is associated with three potential pathogenetic pathways involving ligand receptors, ARMC5 mutations, and intra-adrenal production of ACTH [60]. 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 [53]. (See "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia".)
Most initial cases of BMAH appeared to be sporadic, but there are now several reports of familial cases of BMAH whose presentation suggests autosomal dominant transmission of an ARMC5 mutation. The relationship between inappropriate receptor expression and the ARMC5 mutation is not clear. This is discussed in detail separately. (See "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia", section on 'Pathogenesis'.)
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 [61], as has nonpigmented bilateral micronodular hyperplasia thought to have resulted from longstanding Cushing disease [62].
Iatrogenic or factitious — Iatrogenic or factitious Cushing syndrome is usually caused by administration of excessive amounts of a synthetic glucocorticoid [63]. It is only rarely caused by ACTH administration. (See 'ACTH-dependent Cushing syndrome' above.)
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 [63].
The most common cause of iatrogenic Cushing syndrome is ingestion of prescribed prednisone, usually for treatment of a nonendocrine disease (see "Major adverse effects of systemic glucocorticoids", section on 'Metabolic and endocrine effects'). However, Cushing syndrome also can be caused by other oral, injected, topical, and inhaled glucocorticoids [64-66] and by megestrol acetate or high-dose medroxyprogesterone, progestins with some intrinsic glucocorticoid activity [67]. The clearance of some inhaled steroids may be delayed by ritonavir, leading to Cushing syndrome [68]. Cushing syndrome may also be caused by the use of glucocorticoid-containing creams or herbal preparations [69,70]. (See "Major side effects of inhaled glucocorticoids", section on 'Adrenal suppression' and "Causes of secondary and tertiary adrenal insufficiency in adults", section on 'Chronic high-dose glucocorticoid therapy'.)
Factitious Cushing syndrome is a rare disorder (responsible for less than 1 percent of patients with Cushing syndrome) that refers to surreptitious intake of a glucocorticoid, often by patients who are close to the health professions [63,71].
Rare disorders
●Ectopic cortisol secretion – Rare cases of ectopic cortisol production from ovarian tumors that led to ACTH-independent Cushing syndrome have been described [72].
●Normocortisolemic Cushing syndrome – Two patients have been described who had signs of Cushing 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 [73]. 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 [74].
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 [75]. 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 syndrome is unknown.
●Biochemical hypercortisolism without Cushingoid features – Two patients with clear-cut, moderate to severe hypercortisolism but absent clinical features have been described [76,77]. Each had impaired cortisone-to-cortisol conversion in vivo and decreased cortisol-to-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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SUMMARY
●Cushing syndrome may be either corticotropin (ACTH) dependent or independent (table 1). Among all patients presenting with Cushing syndrome, the most common cause is iatrogenic Cushing due to exogenous administration of glucocorticoids. The second most common form overall is Cushing disease (pituitary tumoral hypersecretion of ACTH). (See 'Iatrogenic or factitious' above and 'Cushing disease' above.)
●Pseudo-Cushing syndrome refers to physiologic hypercortisolism that can occur in several disorders other than Cushing syndrome. Examples include severe obesity, depression, chronic strenuous activity, and alcoholism. (See 'Pseudo-Cushing syndrome' above.)
●The causes of ACTH-dependent Cushing syndrome are associated with bilateral adrenocortical hyperplasia. Their relative frequency is as follows:
•Cushing disease (pituitary hypersecretion of ACTH) – 65 to 70 percent. (See 'Cushing 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 syndrome are:
•Iatrogenic or factitious Cushing 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.)
ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
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