Cushing’s Syndrome

The causes of Cushing’s syndrome can be divided into those that are ACTH dependent and those that are ACTH independent (Table 16-1). The ACTH-dependent forms are characterized by excessive ACTH production from a corticotroph adenoma (known as pituitary-dependent Cushing’s syndrome or Cushing’s disease), from an ectopic tumoral source (ectopic ACTH syndrome), or (rarely) from normal corticotrophs under the influence of excessive CRH production (ectopic CRH secretion). ACTH stimulates all three layers of the adrenal cortex to grow and secrete steroids. When excessive, this results in histologic hyperplasia and increased adrenal weight. Micronodules and macronodules (>1 cm) may be seen. Circulating glucocorticoids are increased, often in association with some increase in adrenal androgens.

ACTH-independent forms, apart from exogenous administration of glucocorticoids, represent adrenal activation by mechanisms other than trophic ACTH support. This enlarging group includes unilateral disease (adenoma and carcinoma), bilateral disease (primary pigmented nodular adrenal disease, McCune-Albright syndrome, and macronodular adrenal disease related to aberrations of the cyclic AMP signaling pathway, or caused by ectopic expression of G protein–coupled receptors), and hyperfunction of adrenal rest tissue.

Adrenal adenomas, composed of zona fasciculata cells, generally produce only glucocorticoids, in contrast to activation of the entire adrenal cortex as seen in other causes of Cushing’s syndrome. ACTH levels are suppressed by hypercortisolism and the nonadenomatous tissue atrophies because of lack of this trophic factor. As a result, androgenic signs, such as pustular acne and hirsutism, are relatively uncommon, and dehydroepiandrosterone sulfate levels are typically low. By contrast, case reports have described patients with macronodular adrenal disease with secretion of mineralocorticoids, estrones, or androgens, in addition to cortisol.

Cushing’s Disease

Cushing’s disease is almost always caused by a solitary (probably monoclonal) corticotroph adenoma.¹⁰ Although nodular corticotroph hyperplasia without evidence of a CRH-producing neoplasm does occur, it represents 2% or less of large surgical series,^11,12 and some doubt its existence. Most tumors are intrasellar microadenomas (<1 cm in diameter), although macroadenomas account for approximately 5% to 10% of tumors, and extrasellar extension or invasion may occur. The cause of Cushing’s disease remains unknown, despite much work on the molecular characterization of these tumors. Traditionally, whether the development of pituitary adenomas is due to abnormal hypothalamic hormonal stimulation or feedback regulation or an intrinsic pituitary defect has been the subject of debate, although most data support a primary pituitary abnormality or a series of abnormalities. More recently, a model has been proposed that encompasses both theories. Here, tumors can arise either as a clonal expansion from a primary intrinsic pituitary defect or as excessive hormonal stimulation/abnormal feedback leading to hyperplasia, which in turn predisposes the cells to mutate, with subsequent clonal expansion.¹³ Analysis of the primary corticotroph stimulatory and negative feedback pathways has not revealed a common defect.^14,15 Similarly, the common oncogenes and tumor suppressor genes implicated in other cancers do not seem to be commonly involved in the pathogenesis of corticotropinomas. Studies of knockout mice and analysis of human pituitary tumor samples have implicated the cyclin-dependent kinase inhibitor p27 (Kip1) in corticotroph tumorigenesis. Overall, reduced p27 protein levels in corticotropinomas and a high phosphorylated p27/p27 ratio suggest increased inactivation of this negative cell-cycle regulator, although the cause of this change remains to be elucidated.¹⁶ Cytogenetic studies have revealed a surprising number of gross chromosomal changes in benign pituitary adenomas, and although the number of corticotroph tumors studied has been small, gain of chromosome 6p and loss of chromosomes 2, 15q, and 22 seem to be the most common abnormalities.^17–19 Perhaps improvement in molecular biologic techniques, particularly microarray analysis, will lead to the implication of new genes in the pathogenesis of these tumors that then will require further study.²⁰

Ectopic Adrenocorticotropic Hormone Syndrome

The syndrome of ectopic hormone secretion was first codified by Liddle and colleagues, who defined it as “any hormone produced by a neoplasm which is derived from tissue not normally engaged in the production of the hormone in question.”⁴ ACTH and other pro-opiomelanocortin (POMC) products were subsequently identified in many noncorticotroph tumors, although not all were associated with increased circulating levels or the development of Cushing’s syndrome.^4,21

Although small cell lung cancer is probably the most common cause of ectopic ACTH syndrome, it is not the most common seen in larger series of generally less obvious tumors investigated at endocrine centers, as discussed later (Table 16-2). An intrathoracic neoplasm (carcinoma of the lung or carcinoid of the bronchus or thymus) accounts for approximately 60% of ectopic ACTH secretion, followed by pancreatic tumors (islet cell or carcinoid), pheochromocytoma (≈5% to 10%), and medullary carcinoma of the thyroid (<5%).

The mechanism whereby the POMC gene becomes derepressed in noncorticotroph tumors is not understood. One hypothesis is that these cells are derived from a common multipotential progenitor cell capable of producing peptide hormones, such that ACTH production is a reversion to a less differentiated state.²² The speculation that many ACTH-producing tumors are derived from neural crest amine precursor uptake and decarboxylation (APUD) cells may support this view,²³ although this embryological hypothesis is not supported by the most recent data. However, because endodermally derived tumors also produce ACTH, the acquisition of APUD characteristics may be but one manifestation of dedifferentiation and may not represent the cause of ectopic ACTH production.

Although the mechanism of gene derepression is not understood, the regulation of POMC production and processing has been investigated. POMC, corticotropin-like intermediate lobe protein, and larger forms of ACTH (“big” or pro-ACTH) that are not usually secreted may circulate, and the intracellular ratio of the POMC products may be abnormal.24,25 Investigation of cell lines of small cell carcinoma of the lung that synthesize POMC and pro-ACTH showed that only ACTH precursors were secreted, suggesting that processing to ACTH is defective.²⁶ The pattern of POMC mRNA species in ACTH-producing tumors has been characterized. A 1200 bp transcript similar to that of a corticotroph adenoma,²⁷ a shorter than normal 800 bp mRNA lacking a signal sequence for secretion,^27,28 and a larger 1400 to 1500 bp POMC transcript have been identified. The larger species appears to originate upstream of the usual pituitary promoter, with preservation of the normal translation start site.^29,30 It is possible that the promoters that initiate this transcription are not regulated by glucocorticoids, and this may explain in part the lack of responsiveness to glucocorticoid suppression noted clinically in these patients. In vitro investigation of human small cell cancer cell lines and pancreatic islet cell tumors with normal glucocorticoid receptor binding has found, for the most part, no regulation of POMC, tyrosine aminotransferase, or the glucocorticoid receptor mRNA at doses of hydrocortisone that would normally suppress pituitary production.^31–33 However, clinical observation of suppression of ACTH production by some bronchial carcinoids during glucocorticoid administration suggests retention of a functional glucocorticoid response element that regulates POMC production, at least in some ectopic tumors.³⁴

Ectopic Corticotropin-Releasing Hormone Secretion

Tumor secretion of CRH with or without ACTH secretion is a rare cause of Cushing’s syndrome. Although many tumors immunostain for CRH, its secretion is less common, and most patients do not develop cushingoid features.³⁵ Thus, the diagnosis primarily rests on the demonstration of elevated plasma CRH levels (requiring an assay that is not readily available). The literature includes fewer than 20 patients who fit this criterion. Tumors may have negative immunostaining for ACTH, but this may be related to reduced storage and rapid secretion. In cases such as these, a CRH and ACTH gradient across the tumor bed can be suggestive that, in fact, the tumor secretes both peptides.³⁶ Tumors include bronchial and thymic carcinoids, small cell lung cancer, medullary thyroid carcinoma, pheochromocytoma, gangliocytoma, prostate carcinoma, and ganglioneuroblastoma.^37,38 The biochemical responses to diagnostic tests can be similar to those seen in ectopic ACTH secretion or in pituitary ACTH-dependent disease.³⁸ It is important to note that many, if not all, ectopic secretors of CRH causing Cushing’s syndrome are also ectopic ACTH secretors.

Primary Adrenal Disease

The primary adrenal forms of Cushing’s syndrome do not share a common cause. Although the cause of adrenocortical neoplasia is not known, some events important in the development of adrenal cancer have been identified. Paternal isodisomy at 11p15.5 with overexpression of insulin-like growth factor-2 (IGF-2) and reduced expression of CDKN1C (a G1 cyclin-dependent kinase inhibitor) and H19 (a putative growth suppressor) seems to be a key event. Mutations of p53 may be involved in a small subset of carcinomas, and mutations of β-catenin may be an early event. Other genes important in pathogenesis remain to be elucidated, although potential loci have been identified at chromosomes 17p, 1p, 2p16, and 11q13 for tumor suppressor genes, and at chromosomes 4, 5, and 12 for oncogenes.³⁹ Adenomas and carcinomas tend to be monoclonal, although the nodular hyperplasias are often polyclonal.⁴⁰ Adrenal adenomas are encapsulated benign tumors, usually less than 40 g in weight. Adrenal carcinomas usually are encapsulated, generally weigh more than 100 g, and may lack classic histologic features of malignancy, although nuclear pleomorphism, necrosis, mitotic figures, and vascular or lymphatic invasion suggest the diagnosis.⁴¹ The adjacent adrenal tissue is atrophic in both conditions.

Primary pigmented nodular adrenal disease (PPNAD), also known as micronodular adrenal disease, is a rare form of Cushing’s syndrome characterized histologically by small to normal-size glands (combined weight <12 g) with cortical micronodules (average 2 to 3 mm) that may be dark or black in color. The intervening cortex is usually atrophic.⁴² Most cases of PPNAD occur as part of the Carney complex in association with a variety of other abnormalities, including myxomatous masses of the heart, skin, or breast; blue nevi or lentigines; and other endocrine disorders (sexual precocity; Sertoli cell, Leydig cell, or adrenal rest tumors; acromegaly). The Carney complex is inherited as an autosomal dominant condition, and Cushing’s syndrome occurs in approximately 30% of cases. The tumor suppressor gene PRKAR1A, coding for the type 1A regulatory subunit of protein kinase A, has been shown to be mutated in approximately one half of patients with Carney complex. Mutations in this gene and also the phosphodiesterase 11A (PDE11A) gene have been shown to be associated with an isolated distinct form of PPNAD.⁴³

Cushing’s syndrome resulting from bilateral nodular adrenal disease is an uncommon feature of the McCune-Albright syndrome,⁴⁴ which is characterized by fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine dysfunction (usually precocious puberty). In this disease, an activating mutation at codon 201 of the α subunit of the G protein that stimulates cyclic adenosine monophosphate formation occurs in a mosaic pattern in early embryogenesis.⁴⁵ If this affects some adrenal cells, constitutive activation of adenylate cyclase and the steroidogenic cascade leads to nodule formation and glucocorticoid excess. The internodular adrenal cortex, where the mutation is not present, becomes atrophic.⁴⁶

A missense mutation of the ACTH receptor, resulting in its constitutive activation and ACTH-independent Cushing’s syndrome, also has been reported.⁴⁷

ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH) is a rare form (<1%) of Cushing’s syndrome that involves large or even huge adrenal glands, usually with definite nodules on imaging. Most cases are sporadic, but a few familial cases have been reported.⁴⁸ Although the cause remains unclear in most cases, some nodules express increased numbers of receptors normally found on the adrenal gland, or ectopic receptors for circulating ligands that then can stimulate cortisol production. Perhaps the best known example of this phenomenon is food-dependent Cushing’s syndrome. The normal postprandial increase in gastric inhibitory peptide (GIP) appeared to cause Cushing’s syndrome in two middle-aged women with bilateral multinodular adrenal enlargement, mildly elevated urinary free cortisol (UFC) values, and undetectable plasma ACTH values. Fasting morning serum cortisol values were low or normal. Cortisol values increased dramatically after meals and after in vivo or in vitro exposure to GIP.^7,8 In one patient, curative bilateral adrenalectomy revealed multinodular adrenal glands weighing 20 and 35 g.⁸ In the other, treatment with octreotide ameliorated the syndrome.⁷ Ectopic expression of GIP receptors was found in these patients. Aberrant expression of vasopressin, β-adrenergic luteinizing hormone/human chorionic gonadotropin, serotonin, angiotensin, leptin, glucagon, interleukin (IL)-1, and thyroid-stimulating hormone (TSH) has been described as functionally linked to cortisol production.⁴⁹ However, it is possible that this apparent ectopic induction of receptors on the adrenal is a response to the adrenal hyperplasia rather than its cause.

Adrenal rest tissue in the liver, in the adrenal beds, or in association with the gonads may rarely cause Cushing’s syndrome, usually in the setting of ACTH-dependent disease after adrenalectomy.50–53 Ectopic cortisol production by an ovarian carcinoma has been reported.⁵⁴

Initial Screening Tests

Hypercortisolemia, demonstrated by loss of the normal circadian rhythm of cortisol secretion, and disturbed feedback of the hypothalamic-pituitary-adrenal (HPA) axis are the cardinal biochemical features of Cushing’s syndrome. Tests to confirm the diagnosis are based on these principles. To screen for Cushing’s syndrome, tests of high sensitivity should be used initially to avoid missing milder cases. All of these screening tests may miss identification of mild cases of hypercortisolemia, and multiple samples or a combination of tests may be needed. A recent guideline suggests that two abnormal first-line test results should be required for the diagnosis of Cushing’s syndrome.¹³⁴

Urinary Free Cortisol

Under normal conditions, 10% of plasma cortisol is free or unbound and physiologically active. Unbound cortisol is filtered by the kidney, with most being reabsorbed in the tubules and the remainder excreted unchanged. Thus, 24-hour UFC collection produces an integrated measure of serum cortisol, smoothing out variations in cortisol during the day. UFC determinations first became clinically available in 1968¹³⁵ and have superseded the historical measurement of urinary metabolites of glucocorticoids and androgens (17-hydroxycorticosteroids [17-OHCS], 17-ketosteroids, and 17-ketogenic steroids).

The major drawback of the test is the potential for overcollection or undercollection of the 24-hour specimen, and written instructions must be given to the patient. In addition, creatinine excretion in the collection can be measured to assess completeness and should equal approximately 1 g per 24 hours in a 70 kg patient (variations depend on muscle mass). This value should not vary by more than 10% between collections in the same individual.¹³⁶ It cannot be used to correct for incomplete collection, however, because rates of cortisol and creatinine excretion are not parallel over the 24-hour period. Various groups have tried to overcome the collection issue by proposing shorter collection periods, usually at night, when the loss of circadian rhythm differs most from normal controls,^137,138 but this approach has not been widely accepted. High-performance liquid chromatography and tandem mass spectrometry are now used to measure UFC, which overcomes the previous problem of cross-reactivity of some exogenous glucocorticoids and other structurally similar steroids with conventional radioimmunoassay.¹³⁹ Occasionally, substances such as carbamazepine, digoxin, and fenofibrate can coelute with cortisol during high-performance liquid chromatography, causing falsely elevated results.^140,141

If the previous caveats have been satisfied, the UFC measurement can be interpreted. In large series, measurement of an elevated UFC above the normal range has a high sensitivity for the diagnosis of Cushing’s syndrome (≈95% to 100%).100,142 However, it should be noted that in the latter study, 11% of 146 patients with proven Cushing’s syndrome had at least one of four UFC collections within the normal range, which confirms the need for multiple collections. Values greater than fourfold normal are rare except in Cushing’s syndrome. Values between this and down to the upper limit of normal are compatible with Cushing’s syndrome or pseudo-Cushing’s states, so that one must exclude the latter diagnosis. In summary, UFC measurements have a high sensitivity if collected correctly, and several completely normal collections make the diagnosis of Cushing’s syndrome very unlikely. However, when biochemical evidence of Cushing’s syndrome is not obtained in the setting of clinical features that suggest the diagnosis, repeated measurement of urine cortisol may demonstrate cyclicity or progression. The specificity is somewhat lower, thus patients with marginally elevated levels require further investigation.⁵⁵

Late-Night Salivary Cortisol

Salivary cortisol measurement offers an excellent reflection of the plasma free cortisol concentration in health and disease because it circumvents the changes in total cortisol due to corticosteroid-binding globulin alterations.143,144 Salivary cortisol is stable for some days at room temperature, and the simple noninvasive collection procedure means that it can be performed conveniently at home and delivered via mail. Thus, it offers a number of attractive advantages over blood collection, particularly in children. Analysis is performed using a modification of the plasma cortisol radioimmunoassay, enzyme-linked immunosorbent assay, or liquid chromatography/tandem mass spectrometry, and commercial kits are internationally available for this.¹⁴⁵ The diagnostic value cutoff varies between studies (0.13 µg/dL [3.6 nmol/L] to 0.55 µg/dL [15.2 nmol/L]) because of different assays and comparison groups studied.^146–153 Normal values also differ between adult and pediatric populations, and this may be affected by other comorbidities such as diabetes and hypertension.¹⁵⁴ However, from these studies, the sensitivity and specificity of this test appear to be relatively consistent at different centers, ranging from 92% to 100%, and from 93% to 100% respectively. It does not appear to make a difference if sampling is done at bedtime (≈23.00 hr) or at midnight, although it should be determined that the patient has a normal sleep pattern. Positive or negative results should be confirmed by repeat sampling. In summary, therefore, although late-night salivary cortisol appears to be a useful and convenient additional screening test for Cushing’s syndrome, particularly in the outpatient setting, local normal ranges should be validated based on the assay used and the population studied.

Low-Dose Dexamethasone Suppression Tests

In normal individuals, administration of the potent synthetic glucocorticoid dexamethasone results in suppression of the HPA axis, whereas patients with Cushing’s syndrome are resistant, at least partially, to this negative feedback. The original low-dose dexamethasone test (LDDST), as described by Liddle in 1960, measured urinary 17-OHCS before and during 48 hours of 0.5 mg dexamethasone every 6 hours, and an excretion of greater than 4 mg/day on the second day of dexamethasone treatment was considered to indicate Cushing’s syndrome.¹⁵⁵ Dexamethasone does not cross-react with modern cortisol immunoassays, and the simpler measurement of a single plasma cortisol post dexamethasone has been validated in various series and gives the test a sensitivity of between 97% and 100% for the diagnosis of Cushing’s syndrome.^156–159 The simpler overnight LDDST was proposed by Nugent and colleagues in 1965; this measured a 9:00 a.m. plasma cortisol after a single dose of 1 mg dexamethasone taken at midnight.¹⁶⁰ Since then, various other doses, between 0.5 and 2 mg, have been proposed for the overnight test, and various diagnostic cutoffs have been applied.^161–163 There appears to be no difference in discrimination between single doses of 1, 1.5, and 2 mg.¹⁶⁴ Higher doses significantly decrease the sensitivity of the test.¹⁶⁵ In a comprehensive review of the LDDST, both the original 2 day test and the 1 mg overnight protocol appear to have comparably high sensitivities (98% to 100%), provided a conservative postdexamethasone serum cortisol cutoff of 1.8 µg/dL (50 nmol/L) is applied. However, the specificity of the overnight test (88%) is lower compared with the 2 day test, particularly if serum cortisol is measured at both 24 and 48 hours (97% to 100%), with potential misclassification of patients with pseudo-Cushing’s states and acute or chronic illnesses. Many endocrinologists use the overnight test because of its greater simplicity and lower cost, although some centers still advocate the 48-hour test because of its high sensitivity and specificity, and the information it can provide in the differential diagnosis of ACTH-dependent Cushing’s syndrome (see later).¹⁵⁹ Written instructions should be given to the patient if the latter is to be performed on an outpatient basis. Salivary rather than serum cortisol has been evaluated as the end point for the LDDST. This offers potential benefit in terms of convenience but requires further evaluation.^149,166

Factors such as variable absorption and increased or decreased dexamethasone metabolism due to other compounds (Table 16-5) can influence any oral dexamethasone test.¹⁶⁷ Therefore, a history of symptoms of malabsorption and a careful drug history should be taken before the test is used in a patient. Measurement of plasma dexamethasone is available in some centers and can be useful in patients of concern. One solution to overcome demonstrated malabsorption is to use one of the published intravenous dexamethasone suppression tests, recognizing that criteria for response have not been standardized.^168,169 Pregnancy and other causes of increased or decreased corticosteroid-binding globulin (such as exogenous estrogens and the nephrotic syndrome) also should be excluded because these are likely to result in false-positive and false-negative tests.¹⁷⁰

Second-Line Tests

Other Second-Line Tests

The insulin tolerance test has been used to distinguish Cushing’s syndrome from pseudo-Cushing’s states. Serum cortisol values increase in normal people after acute hypoglycemia, presumably because of central stimulation of CRH and vasopressin. The sustained hypercortisolism of Cushing’s syndrome suppresses CRH and vasopressin secretion and so blunts this response. The CRH/vasopressin neurons are presumed to be overactive in pseudo-Cushing’s states, particularly those that are depression associated, so a normal response to hypoglycemia (<40 mg/dL; <2.2 nmol/L) usually is maintained. Unfortunately, approximately 18% of patients with Cushing’s syndrome, especially those with minimal hypercortisolism, show a normal response to adequate hypoglycemia.¹⁶⁴ Additionally, criteria for interpretation of results have not been established. If used, a dose of insulin of 0.3 U/kg should be used to overcome insulin resistance in these patients.¹³⁰

The opiate agonist loperamide (16 mg orally) has been shown to inhibit CRH and thus ACTH and cortisol levels in most normal individuals, but not in patients with Cushing’s syndrome. This test has not been used widely but has been evaluated in one center, revealing a sensitivity of 100% and a specificity of 95%.179,180 However, it is unclear as to how well this test may exclude pseudo-Cushing’s states because a significant proportion of patients with depression also fail to suppress the HPA axis.¹⁸¹ It does not appear to be affected by drugs that affect the metabolism of dexamethasone and could potentially be useful in assessing patients on such treatment.¹⁸⁰

Investigating Adrenocorticotropic Hormone–Independent Cushing’s Syndrome

Radiologic tests are the mainstay in differentiating between the various types of ACTH-independent Cushing’s syndrome. High-resolution CT scanning of the adrenal glands has excellent diagnostic accuracy for masses greater than 1 cm and allows evaluation of the contralateral gland.¹⁸³ MRI may be useful for the differential diagnosis of adrenal masses; the T₂-weighted signal is progressively brighter in normal tissue, adenoma, carcinoma, and finally pheochromocytoma.¹⁸⁴ With this approach, adrenal tumors appear as a unilateral mass with an atrophic or less commonly a normal-size contralateral gland.¹⁸⁵ If the lesion is greater than 5 cm in diameter, it should be considered to be malignant until proven otherwise, and imaging characteristics should not be relied upon. Very rarely, bilateral adenomas may be present.¹⁸⁶ The adrenal glands in PPNAD appear normal or slightly lumpy from multiple small nodules but generally are not enlarged.¹⁸⁷ AIMAH is characterized by bilaterally huge (>5 cm) nodular or hyperplastic glands.¹⁸⁸ Exogenous administration of glucocorticoids results in adrenal atrophy; very small glands may provide a clue as to this entity.

The CT appearance of the adrenals in AIMAH may be similar to that of ACTH-dependent forms of Cushing’s syndrome, in which adrenal enlargement is present in 70% of cases.¹⁸⁹ However, in our experience, the adrenal glands in Cushing’s disease are smaller and usually are symmetrically enlarged with an occasional nodule, as opposed to large or huge glands with definite nodules in AIMAH. In addition, the two can usually be differentiated by the ACTH level, although some patients with the macronodular subset of Cushing’s disease can develop a degree of adrenal autonomy that can cause biochemical confusion.¹⁹⁰ Occasionally, confusion also may arise with apparent unilateral adrenal lesions, when the biochemistry is consistent with an ACTH-dependent cause; we generally would rely on the biochemistry in this situation and would examine the contralateral gland to see whether it is hyperplastic.

Differentiating Between Adrenocorticotropic Hormone–Dependent Causes of Cushing’s Syndrome

Although some patients with ectopic ACTH secretion, usually those with overt tumors, have extremely elevated values of plasma ACTH (>100 ng/L [>20 pmol/L]), complete overlap is seen between values in occult ectopic ACTH secretion and in Cushing’s disease.¹⁹¹ Therefore, ACTH values alone cannot differentiate reliably the ACTH-dependent forms of Cushing’s syndrome.

The ACTH-dependent forms of Cushing’s syndrome present the greatest diagnostic challenge. Cushing’s disease accounts for by far the majority of cases of ACTH-dependent Cushing’s syndrome—overall approximately 80% to 90% in most series. This percentage is gender dependent and is higher in women than in men,¹⁹² although in prepubertal childhood, an anomalous 80% male preponderance is noted. Therefore, even before one starts further investigation, the pretest probability that the patient has Cushing’s disease is very high, and any investigation must improve on this. The specificity of any test should be as close to 100% as possible for the diagnosis of Cushing’s disease, to avoid inappropriate pituitary surgery in patients with ectopic ACTH production. A variety of functional tests of the HPA axis have been developed to take advantage of the differences in pathophysiology between ACTH-dependent causes of Cushing’s syndrome. Some of these investigations have evolved, and others have fallen by the wayside.

Combined Test Strategies

Because none of the noninvasive tests have 100% diagnostic accuracy, a number of investigators have evaluated the utility of combined test strategies. The CRH and the HDDST have been paired in this way, and combined, they have a diagnostic accuracy greater than that of either test alone, yielding 98% to 100% sensitivity and 88% to 100% specificity.229–231 Similar high accuracy has been obtained by combining the results of the LDDST and the CRH test.¹⁵⁹

Strategy for Diagnosis and Differential Diagnosis of Cushing’s Syndrome

After an international workshop in 2002, a consensus statement was published for the diagnosis and differential diagnosis of Cushing’s syndrome.¹²⁹ Most of its recommendations are still valid. We would advocate that three 24-hour UFC, late-night salivary cortisols and/or the LDDST should be used as first-line screening tests. (This approach also was advocated in a recent guidelines statement issued by the Endocrine Society.¹³⁴) False-positive results will be common, and second-line tests should be used as necessary for confirmation. Once the diagnosis of Cushing’s syndrome is unequivocal, ACTH levels, the CRH test, and a dexamethasone suppression test, together with appropriate imaging, are the most useful noninvasive investigations to determine the cause. Bilateral inferior petrosal sinus sampling is recommended in cases of ACTH-dependent Cushing’s syndrome in which the clinical, biochemical, or radiologic results are discordant or equivocal, although others would recommend its use in almost all cases of ACTH-dependent Cushing’s syndrome.

Preoperative Evaluation and Treatment

Some centers use routine preoperative medical adrenal blockade to attain a period of eucortisolemia for 4 to 6 weeks before surgery. The aim is to allow reversal of some of the metabolic and catabolic effects of the hypercortisolemia that may inhibit wound healing and cause other complications in the perioperative period. The disadvantage of this strategy is that the normal corticotrope may be disinhibited by the time of surgery, so that expected hypocortisolism after successful tumor resection does not occur, and this index of remission is not reliable. This rationale is only empirical, and a randomized trial undertaken to see whether this approach improves outcome would be welcomed.²⁴⁹

Because Cushing’s syndrome is a prothrombotic state, anticoagulant prophylaxis should be considered perioperatively.²⁵⁰ The lipid abnormalities, hypertension, and diabetes common in Cushing’s syndrome predispose these patients to atherosclerotic cardiac disease and should be treated by conventional approaches.

Transsphenoidal Resection of Corticotropinoma

Transsphenoidal resection is regarded as the treatment of choice in Cushing’s disease.²⁴⁸ The procedure usually is performed via a gingival approach, as originally devised by Kanavel and Halsted and later popularized by Cushing.²⁵¹ The development of the operating microscope led to the introduction of transsphenoidal resection of pituitary microadenomas by Hardy in 1968. Additional advances have been made over the past decade with the use of rigid endoscopes and more recently flexible endoscopes. The goal of surgery is a selective adenomectomy and thus preservation of as much normal pituitary tissue as possible; the procedure should be performed by a neurosurgeon who is experienced in transsphenoidal surgery. Most large series report immediate remission rates of approximately 70% to 90%,^252–259 with lower rates noted for macroadenomas.^254,260 These reports use variable remission criteria that include normal postoperative cortisol levels, normal UFC levels, and/or a normal response to an LDDST, associated with clinical resolution of the disease. Data are insufficient regarding whether endoscopic surgery offers any benefit.²⁶¹ However, a recent report suggests that resection achieved through a technique that enucleates microadenomas via their pseudocapsule may improve remission rates to 98%.²⁶²

Long-term recurrence rates are as high as 20% by 10 years after surgery. Thus, in reality, transsphenoidal surgery achieves long-term cure even in the best of hands in only approximately 60% to 80% of adult patients, and therefore is somewhat disappointing; the data emphasize the need for long-term endocrinologic follow-up of these patients.²⁶³ Favorable indicators of long-term remission are patients older than 25 years, a microadenoma detected by MRI, lack of invasion of the dura or cavernous sinus, histologic confirmation of an ACTH-secreting tumor, low postoperative cortisol levels, and long-lasting adrenal insufficiency.²⁴⁸ If a tumor cannot be identified at surgery, hemihypophysectomy on the side of the gland with an ACTH gradient on petrosal sinus sampling is usually the best way to proceed, and in some series, this yields better results than those attained by selective microadenomectomy.^256,264

The mortality associated with transsphenoidal surgery is approximately 1% to 2%.11,258 Transient diabetes insipidus is probably the most common complication, being reported in as many as 28% of patients.²⁶⁴ Other perioperative complications, including cerebrospinal fluid leak, meningitis, and profuse bleeding, occur in less than 10% of patients. Permanent complications such as persistent diabetes insipidus and injury to the optic nerve or nerves of the cavernous sinus (causing ptosis or diplopia) occur much less frequently.^11,258 However, hypopituitarism, particularly growth hormone deficiency, is common (53% to 59%), with other anterior hormone deficits occurring in approximately 35% to 45% of patients.^264,265 Such complications are more common after resection of larger tumors or with the presence of larger amounts of normal pituitary tissue (or stalk), or after repeat surgery.

Postoperative Evaluation and Management

Patients typically receive supraphysiologic doses of glucocorticoids to cover transsphenoidal surgery at initial daily doses of as high as 400 mg hydrocortisone (4 mg dexamethasone), tapering off within 1 to 3 days. Morning (9:00 am) serum cortisol measurements then are obtained for 3 days, starting 24 hours after the last glucocorticoid administration, during which time the patient should be observed for development of signs of adrenal insufficiency. This approach allows prompt classification of likely cure, normocortisolemia, or persistent hypercortisolism. Where close perioperative supervision is possible, such glucocorticoid “cover” may be omitted, permitting a very early postoperative assessment of cure. What defines apparent cure or remission after transsphenoidal surgery is still debated. Postoperative hypocortisolemia (<1.8 µg/dL [50 nmol/L] at 9:00 am) is probably the best indicator of the likelihood of long-term remission. However, detectable cortisol levels of <5 µg/dL (140 nmol/L) are also compatible with sustained remission.266,267 Higher postoperative cortisol levels are more likely to be associated with failed surgery; however, cortisol levels sometimes may decline gradually over 4 to 6 weeks, reflecting gradual infarction of remnant tumor or some degree of adrenal semiautonomy. Persistent cortisol levels >5 µg/dL (140 nmol/L) 6 weeks after surgery require further investigation.

Dynamic tests have been used to predict long-term remission. The cortisol and ACTH response to CRH in the early postoperative period may provide a useful index of the risk for recurrence of Cushing’s disease, the rationale being that responsiveness may indicate residual tumor.60,268 A study of postoperative responses to CRH in 221 patients suggested that a cortisol response greater than 5 µg/dL (138 nmol/L) at 60 minutes had a positive predictive value of 42% and a negative predictive value of 94% for recurrence of disease.²⁶⁹ Because patients with partial recovery of the axis would be expected to have a normal response, regardless of the risk for recurrence, the CRH test cannot be interpreted and should not be used in this setting. Some evidence suggests that persistence of the ACTH response to desmopressin postoperatively probably is linked to a higher rate of relapse.^270,271

Patients who are hypocortisolemic should be started on glucocorticoid replacement, and 15 to 30 mg hydrocortisone (12 to 15 mg/m²) in two to three divided doses is the preferred choice. The first dose (usually half to two thirds of the total dose) should be taken before getting out of bed, and the last dose should be taken no later than 6:00 pm, because later administration of glucocorticoids may result in disordered sleep. In this situation, the lowest possible dose of hydrocortisone should be used to avoid long-term suppression of the HPA axis. All patients receiving long-term glucocorticoid replacement therapy should be instructed that they are “dependent” on taking glucocorticoids as prescribed, and that failure to take or absorb the medication will lead to adrenal crisis and possibly death. They should be prescribed a 100 mg hydrocortisone (or other high-dose glucocorticoid) intramuscular injection pack for emergency use. They also should obtain a medical information bracelet or necklace that identifies this requirement (Medic Alert Foundation). Education should stress the effects of glucocorticoid withdrawal²⁷²; the need for compliance with the daily dose of glucocorticoid; the need to double the oral dose for nausea, diarrhea, and fever; and the need for parenteral administration and medical evaluation during emesis, trauma, or severe medical stress.

The patient should be told to expect desquamation of the skin and flu-like symptoms (malaise, joint aching, anorexia, and nausea) during the postoperative months, and that these are signs that indicate remission: some of these symptoms have been related to high levels of circulating interleukin-6.²⁷³ Most patients tolerate these symptoms of glucocorticoid withdrawal much better if they are forewarned and alerted to their positive nature. Physicians should not increase the glucocorticoid dose in the absence of intercurrent illness based on these symptoms alone but should seek signs of adrenal insufficiency, such as vomiting, electrolyte abnormalities, and postural hypotension.²⁷⁴ The affective and cognitive changes associated with Cushing’s syndrome are particularly slow to resolve and may not normalize. Evidence of persisting physical and emotional dysfunction has been found, even after prolonged duration of cure.²⁷⁵ Postoperatively, assessment for deficiencies of other pituitary hormones should be sought, and the appropriate replacement regimen initiated as necessary.

Diuresis is common after transsphenoidal surgery and may result from intraoperative or glucocorticoid-induced fluid overload or may be due to diabetes insipidus. For these reasons, assessment of paired serum and urine osmolality and the serum sodium concentration is essential. It is advisable to withhold specific therapy unless the serum osmolality is greater than 295 mOsm/kg, the serum sodium is greater than 145 mmol/L, and the urine output is greater than 200 mL/hr, with an inappropriately low urine osmolality. Desmopressin (DDAVP, Ferring) 1 µg given subcutaneously, will provide adequate vasopressin replacement for 12 hours or longer. Hyponatremia may occur in as many as 20% of patients within 10 days of surgery. This may be due to injudicious fluid replacement or inappropriate antidiuretic hormone secretion, as is frequently seen after extensive gland exploration, and fluid intake should be restricted.²⁷⁶ A small minority of patients proceed to (apparently) permanent diabetes insipidus, requiring long-term treatment with a vasopressin analogue. A dose and schedule of administration should be chosen to provide unbroken sleep but allowing a period of “breakthrough” urination each day. This goal is often achieved when 10 to 20 µg desmopressin is given intranasally (or an equivalent oral dose) in the evening.

Some glucocorticoid-induced abnormalities, including hypokalemia, hypertension, and glucose intolerance, may be normalized during the postoperative period, so that preoperative treatments for these need to reassessed. Some evidence indicates that deficits in bone mass may be partially reversed after treatment of hypercortisolemia.277,278 Bisphosphonate treatment may induce a more rapid improvement in bone mineral density²⁷⁹ and should be considered (along with calcium and vitamin D supplements) in patients with osteoporosis.

Persistent hypercortisolemia after transsphenoidal exploration should prompt reevaluation of the diagnosis of Cushing’s disease, especially if previous diagnostic test results were indeterminate or conflicting, or if no tumor was found on pathologic examination. Petrosal sinus sampling after transsphenoidal surgery can confirm a pituitary source of ACTH, but the rate of correct lateralization decreases, probably because of alterations in venous anatomy caused by the previous surgery; therefore, the procedure cannot be used routinely to direct a second operative search or decision for hemihypophysectomy.

Treatment options for patients with persistent Cushing’s disease include repeat surgery, radiation therapy, and adrenalectomy. If immediate surgical remission is not achieved at the first exploration, early repeat transsphenoidal surgery may be worthwhile in a significant proportion of patients, at the expense of increased likelihood of hypopituitarism.280,281 The likelihood of remission after repeat surgery is greatest when some or all of the following outcome parameters are present: The diagnosis is correct, as evidenced by previous curative surgery with pathologic confirmation of an ACTH-staining adenoma; the initial exposure or resection was incomplete; or residual tumor is seen on MRI scan without evidence of cavernous sinus invasion. Repeat sellar exploration is less likely to be helpful in patients with empty sella syndrome or very little pituitary tissue on MRI scans. Patients with cavernous sinus or dural invasion identified at the initial procedure are not candidates for repeat surgery to treat hypercortisolism and should receive radiation therapy.

Recovery of the HPA axis can be monitored by measurement of 9:00 am serum cortisol after omission of hydrocortisone replacement. Because recovery after transsphenoidal surgery rarely occurs before 3 to 6 months and is common at 1 year, initial testing at 6 to 9 months is cost-effective.²⁸² If the cortisol is undetectable on 2 consecutive days, then recovery of the axis has not occurred, and glucocorticoid replacement can be restarted. If the cortisol is measurable, adequate reserve of the HPA axis can be assessed with the insulin tolerance test,²⁸³ with a peak cortisol value of >18 µg/dL (500 nmol/L), indicating adequate reserve on modern assays.²⁸⁴ Many centers use the cortisol response to 250 µg synthetic (1-24) ACTH as an alternative means of assessing HPA reserve,^285,286 but some controversy regarding its reliability in this situation has been ongoing.^287,288 If it is used instead of the insulin tolerance test, a 30 minute cortisol of 22 µg/dL (600 nmol/L) is probably more reliable than the traditional cutoff of 18 µg/dL (500 nmol).²⁸⁴ Glucocorticoid replacement can be discontinued abruptly if the cortisol response is shown to be normal.

Where recovery of the HPA axis is only partial on dynamic testing, but the 9:00 am cortisol levels are above the lower limit of the normal range (7 µg/dL [200 nmol/L]), it is reasonable to reduce the hydrocortisone unless symptoms of adrenal insufficiency occur. Patients must continue to be aware of the continuing need for additional glucocorticoids at times of stress or illness and should be given a supply of oral hydrocortisone and an intramuscular injection pack. For patients with detectable but low 9:00 am cortisol levels, the hydrocortisone replacement dose should be adjusted down if weight loss has occurred, and a slightly lower dose may be given. Some centers assess adequate replacement of thrice daily hydrocortisone dosing by measuring serum cortisol at various points throughout the day, ensuring that levels are always sufficient (>1.8 µg/dL; 50 nmol/L) before each dose; this may mean that peak levels after each dose appear to be unphysiologic, but there is a tradeoff between mirroring a normal physiologic rhythm as far as possible and the inconvenience of multiple dosing.

Two late but unrelated conundrums may arise: the questions of recurrence and permanent lack of recovery of the axis. Patients who articulate that Cushing’s syndrome has returned are often correct, even before physical and biochemical evidence is unequivocal. Assessment is warranted in a patient with these complaints or with recurrent physical signs characteristic of the hypercortisolemic phase. If this is to be done on an outpatient basis, UFC can be measured initially on dexamethasone 0.5 mg/day, if not yet weaned from glucocorticoids. Measurement of late-night salivary cortisol after omission of the afternoon dose of hydrocortisone also may be useful. However, ideally, assessment of a cortisol circadian rhythm can be done on an inpatient basis after the hydrocortisone has been stopped completely. If the UFC result is increased, evaluation of hypercortisolism should proceed. If recurrent Cushing’s disease is diagnosed, the therapeutic options are the same as for persistent disease. It should be remembered when investigating recurrence that long-standing ACTH stimulation by a pituitary adenoma causing macronodular adrenal hyperplasia subsequently may involve autonomous cortisol production.²⁸⁹

If the UFC result is subnormal or low, the patient should be questioned about the actual dose of glucocorticoid that has been taken. Often, patients take additional hydrocortisone, either because they discover that this decreases the symptoms of glucocorticoid withdrawal, or because they have increased the dose “for stress,” often without following strict guidelines. These patients have a suppressed axis and a very slow regression of cushingoid features because of exogenous hypercortisolism. They require education and support along with reduction in the daily dose of hydrocortisone to recommended levels. The patient who has a subnormal cortisol response to ACTH 2 years after transsphenoidal surgery (in the absence of overreplacement) may proceed to life-long ACTH deficiency.

Adrenalectomy

Resection of the affected adrenal gland(s) is the treatment of choice only for non–ACTH-dependent hypercortisolism of adrenal origin, or when a specific surgical approach to ACTH-dependent causes is not feasible. In adrenal adenomas, the cure rate is 100% when performed by experienced adrenal surgeons.²⁹⁰ Surgery is the mainstay of treatment for adrenal cancer; more aggressive surgical approaches probably account for the increase in life span reported in this disease.^85,291 This approach may require multiple operations to resect primary lesions, local recurrences, and hepatic, thoracic, and, occasionally, intracranial metastases. Adjuvant medical treatment with mitotane and other chemotherapeutic agents is discussed later.

The mortality and morbidity of traditional open adrenalectomy via an anterior or posterior incision range from 1% to 20% in various series, probably reflecting differences in the severity of Cushing’s syndrome and the presence of associated conditions, such as cardiovascular disease.184,246 Apart from resection of suspected carcinoma, these approaches have been supplanted by laparoscopic resection, which has low mortality and morbidity when done by an experienced surgeon.²⁹² Glands as large as 7.5 cm may be removed through this approach²⁹³ (see Chapter 15). Serum cortisol levels become undetectable after successful adrenalectomy. Early failure to achieve hypocortisolism usually is related to incomplete resection of the gland(s). Recurrence, especially in the ACTH-dependent forms of Cushing’s syndrome, may be related to regrowth of adrenal cells in the surgical bed, or to growth of adrenal rest tissue.

Bilateral adrenalectomy as a second line of treatment for Cushing’s disease has the advantage of providing rapid resolution of hypercortisolism and has no risk of hypopituitarism, in contrast to radiation therapy. Adrenalectomy may be chosen over radiation therapy by young patients who desire fertility, who have concerns about radiation-induced hypopituitarism and loss of reproductive function. Its disadvantages include perioperative morbidity and mortality and the life-long requirement of glucocorticoid and mineralocorticoid replacement therapy. In addition, patients with Cushing’s disease have a risk for developing Nelson’s syndrome, which may occur more frequently if adrenalectomy is performed at a younger age, and if a pituitary adenoma is confirmed at previous pituitary surgery.259,294 Regular pituitary MRI and monitoring of ACTH levels are mandatory in these patients.²⁹⁵ Prophylactic pituitary radiotherapy appears to reduce the risk for developing Nelson’s syndrome from 50% to 25%,²⁹⁶ but no consensus has been reached on this topic.

In the postoperative period after bilateral adrenalectomy, the hydrocortisone dose is maintained at approximately twice the replacement dose, and saline 0.9% is given intravenously until the patient can take oral medications. This provides sodium and sufficient mineralocorticoid activity until fludrocortisone 100 µg/day can be given by mouth. Serum cortisol measurement done to confirm adequacy of resection is assessed while the patient receives dexamethasone 0.5 mg/day and fludrocortisone. The patient then is switched back to hydrocortisone and fludrocortisone and must be advised regarding adrenal insufficiency, as previously discussed. The dose of fludrocortisone is adjusted according to the patient’s blood pressure, exposure to heat, and salt intake; the usual dose is 100 µg/day but ranges from 50 to 400 µg. A normal plasma renin activity measurement provides evidence of adequate mineralocorticoid replacement and can be used to gauge therapy.

After unilateral adrenalectomy, the components of the HPA axis gradually recover after surgical cure of Cushing’s syndrome. The time to recovery may be as short as 3 months and as long as 2 years.268,282 The duration of recovery may be shorter in patients with mild hypercortisolism and in those with recurrence, and longer after resection of an adrenal adenoma.

Surgery for Ectopic Adrenocorticotropic Hormone Syndrome

If an ectopic ACTH-secreting tumor is localized and amenable to surgical excision, such as in a lobectomy for a bronchial carcinoid tumor, the chance for cure of Cushing’s syndrome is high. However, if significant metastatic disease is present, surgery is unlikely to be of benefit. If the source of ACTH cannot be localized, or if metastatic disease precludes surgery, alternative treatment for hypercortisolism must be chosen. For the patient with occult disease, medical therapy allows interval tumor surveillance with the goal of eventual tumor resection. Because some tumors remain occult for as long as 20 years, this may not prove practical for all patients, and adrenalectomy is appropriate when the patient cannot tolerate the cost, medical side effects, or psychological effects of long-term medical therapy and monitoring. Long-term medical therapy also may be the treatment of choice for the patient with widely disseminated disease who is not a good surgical candidate for adrenalectomy. Bilateral adrenalectomy is the treatment of choice for any patient requiring rapid correction of hypercortisolism or when hypercortisolism cannot be controlled with medical therapy, when previously effective medical therapy must be discontinued because of significant medical side effects or intolerance, or when a severely hypercortisolemic patient is unable to take oral medications or etomidate.

Pituitary

The role of radiation therapy to the pituitary gland in Cushing’s disease is usually adjunctive in those who have failed transsphenoidal surgery, but it is also a good primary option for patients who cannot undergo surgery, and for those having a bilateral adrenalectomy for whom the risk for Nelson’s syndrome is deemed great.

Conventional Radiotherapy

Conventional pituitary radiotherapy is delivered at a total dose of 4500 to 5000 cGy (rad) in 25 fractional doses over 35 days through a three-field (opposed lateral fields and vertex field) technique. Nowadays, this usually is based on stereotactic conformal field planning to optimize the tumor dose and to minimize radiation to other areas. This approach ensures that the daily dose to neural tissue does not exceed 180 cGy and avoids the complications of optic neuritis and cortical necrosis associated with larger total and fractional doses.²⁹⁷ The latent onset of action of radiotherapy means that adjunctive medical therapy usually is instituted before or at the time of treatment. The therapeutic response is assessed at least with annual monitoring, with weaning of medical treatment if possible. When conventional radiotherapy is used as primary treatment for Cushing’s disease, remission is achieved in only 40% to 60% of adult patients.^{259,298–300} The response is even worse if a lower dose of radiation (2000 cGy) is used.³⁰¹ More usually, conventional radiotherapy is used in the setting of failure to cure after transsphenoidal surgery. In this regard, it performs rather better, with reported remission rates as high as 83%.^299,302 After conventional radiotherapy is given, remission usually starts by 9 months after treatment, and most patients are in remission within 2 years, although this can take much longer.³⁰³

Hypopituitarism is the most common side effect of pituitary radiotherapy, with growth hormone deficiency occurring in 36% to 68% of treated adults.265,302 Gonadotropin and thyroid-stimulating hormone deficiency is seen less commonly. The risk for optic neuropathy is low and probably is less than 1% as long as low-dose fractions are used³⁰⁴ (200 cGy). Similarly, the occurrence of brain necrosis is exceedingly rare.³⁰⁵ The issue of secondary tumors remains contentious; although meningiomas and gliomas have been reported after pituitary radiotherapy, it is not clear whether the incidence is significantly greater than the background risk for developing such tumors in patients who already have one intracranial tumor and have undergone careful surveilllance.³⁰⁴

Stereotactic Radiosurgery

In stereotactic radiosurgery, concentrated beams of high doses of radiation are aimed precisely at the mapped discrete lesion, delivering very high doses to the tumor and relatively low doses to normal surrounding tissue. A number of techniques can be used to do this: using narrow beams from multiple gamma cobalt sources (gamma knife), using heavy charged particles (proton or helium beams), or using a single beam from a linear accelerator that is arced around the target (X-knife, SMART, Linac). The advent of high-resolution MRI for mapping has facilitated this therapy. Usually, only a single therapy dose is required, and this is biologically more effective than delivery of the same dose in fractions.³⁰⁶ This technique also may be used to deliver radiation to the entire pituitary gland when a specific target is not known after surgery or MRI examination.

Probably the technique most widely used currently for Cushing’s syndrome is the gamma knife. As adjunctive therapy after failed transsphenoidal surgery, it probably is no better than conventional radiotherapy.³⁰⁷ Radiosurgery of the pituitary gland using proton beams has similar efficacy.³⁰⁸ Linear accelerator radiotherapy for Cushing’s disease is less well described, but success has been reported in small numbers of patients.³⁰⁹

As with conventional radiotherapy, the main side effect is hypopituitarism, and although the perceived risk of damage to adjacent structures such as the optic chiasm is less, additional studies and longer follow-up are needed. Some centers use it mainly for salvage of difficult recurrent tumors, for example, in the cavernous sinus or in Nelson’s syndrome, whereas others have suggested it as an alternative to conventional radiotherapy in adenomas smaller than 30 mm with a minimal distance from the optic chiasm of 2 to 3 mm.³⁰⁵

Interstitial Radiotherapy

Two centers have used interstitial irradiation (yttrium-90 or gold-198 implants) as primary therapy for Cushing’s disease.310,311 Remission rates in these cohorts were high (75% to 77%), although some required a second implant. The principal side effect was hypopituitarism.

Other Tumors

No significant evidence suggests that radiotherapy improves overall survival in adrenocortical carcinoma, although sporadic reports indicate that it may be helpful adjuvant treatment to radical surgery in selected cases.312,313 Local radiotherapy after surgical resection of an ectopic ACTH-secreting source may be beneficial, particularly in nonmetastatic thoracic carcinoid tumors.^314,315

Agents Inhibiting Steroidogenesis

The oral inhibitors of adrenal steroidogenesis are the most commonly used medical agents as treatment for Cushing’s syndrome; of these, metyrapone, ketoconazole, and mitotane are the most effective. Aminoglutethimide³¹⁶ is no longer available, and trilostane³¹⁷ is now rarely used. Etomidate is the only available agent that can be given parenterally. We usually would recommend partial inhibition of cortisol production (adjusted adrenal blockade) with frequent monitoring to identify a dosing regimen that maintains eucortisolism while avoiding adrenal insufficiency or excess. However, in some patients, particularly those with variable cortisol production, it can be difficult to achieve this. In these cases, full adrenal blockade with glucocorticoid replacement to avoid symptoms of adrenal insufficiency (a block-and-replace regimen) may be advocated. In all forms of treatment, patients and their physicians must be alert to the signs and symptoms of adrenal insufficiency.

Glucocorticoid Receptor Antagonists

Mifepristone (RU 486), the antiprogesterone antagonist that is marketed as an abortifacient, is also a competitive antagonist of glucocorticoid and androgen receptors. The major drawback is the lack of biochemical markers to monitor overtreatment, and its long half-life and minimal agonist activity leave the patient open to hypoadrenalism.³⁶³

Agents That Modulate ACTH Release

A number of agents, including the serotonin antagonists cyproheptadine³⁶⁴ and ritanserin,³⁶⁵ the dopamine agonists bromocriptine³⁶⁶ and cabergoline,³⁶⁷ and sodium valproate,³⁶⁸ have been examined in Cushing’s disease. The precise mechanism of action of many of these agents is incompletely understood, although most seem to reduce ACTH secretion through an effect on the hypothalamic-pituitary axis. Their efficacy in Cushing’s disease seems to be variable between individual patients; therefore, we do not recommend their routine use. However, more recent data on the use of cabergoline suggest that this drug may be more effective than was previously realized.

Somatostatin Analogues

Long-acting somatostatin analogues such as octreotide and lanreotide are used widely in the therapy of various neuroendocrine tumors, and somatostatin receptors have been demonstrated on corticotroph adenomas, in addition to ectopic sources of ACTH.³⁶⁹ Octreotide appears to inhibit ACTH release in Nelson’s syndrome but rarely in patients with Cushing’s disease, and this has been postulated to be due to somatostatin receptor downregulation from the circulating hypercortisolemia.³⁷⁰ In ectopic ACTH-secreting tumors, octreotide has produced a prolonged (>3 months) reduction in ACTH and hypercortisolemia in approximately 70% of published cases, but this high rate of response may be due to selective reporting. Preoperative assessment with pentetreotide scintigraphy may help predict which tumors might respond to treatment. Octreotide treatment produces a temporary response in GIP-dependent Cushing’s syndrome but is unhelpful in other causes of ACTH-independent Cushing’s syndrome.³⁷¹ So far, little experience has been reported with use of the sustained-release preparations in treating Cushing’s syndrome. Much interest surrounds somatostatin analogues with a broader spectrum of activity for somatostatin receptor subtypes. Such an agent, pasireotide (SOM230; Novartis, Basel, Switzerland), has been shown in vitro to reduce human corticotroph proliferation and ACTH secretion,³⁷² and early results in vivo are encouraging.^373,374 Additional clinical studies are ongoing.

Thiazolidinediones

Rosiglitazone, a peroxisome-proliferator–activated receptor-γ (PPAR-γ) agonist, at suprapharmacologic doses has been shown in vitro and in animal models to suppress ACTH secretion and corticotroph tumor size.³⁷⁵ However, a number of clinical trials of the thiazolidinediones rosiglitazone and pioglitazone in patients with Cushing’s syndrome have generally been disappointing, with only short-term benefit seen in occasional patients even at high doses.^376–380

Potential Novel Medical Agents

In the rare cases of Cushing’s syndrome due to AIMAH and aberrant receptor expression, specific receptor antagonists have proved useful at least in the short term, and further investigation is needed.³⁸¹ Retinoic acid has been found to inhibit ACTH secretion and cell proliferation both in vitro in ACTH-producing tumor cell lines and cultured human corticotroph adenomas and in vivo in nude mice³⁸² and dogs.³⁸³ The potential antisecretory and antiproliferative activities of this agent in Cushing’s syndrome have not to our knowledge been investigated further in man.