Cushing’s Syndrome

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Chapter 8

Cushing’s Syndrome

Harvey Cushing1,2 was the first to codify the symptom complex of obesity, diabetes, hirsutism, and adrenal hyperplasia, and to postulate that the basophilic adenomas found at autopsy in six of eight patients caused the disease that now bears his name. Shortly thereafter, Walters and colleagues3 identified the etiologic contribution of adrenal tumors and the therapeutic role of adrenalectomy. Over the ensuing century, our understanding of the pathogenesis of Cushing’s syndrome has expanded to include ectopic production of adrenocorticotropic hormone (ACTH)4 and corticotropin-releasing hormone (CRH),5 and recognition of bilateral adrenal stimulation by factors other than ACTH.69 Because florid Cushing’s syndrome is ultimately fatal, early diagnosis and treatment have always been important. A plethora of tests have been developed over the years to improve the diagnostic yield. Similarly, the treatment options for Cushing’s syndrome have increased to include medical agents that decrease the secretion or block the activity of circulating cortisol and surgical resection of eutopic and ectopic ACTH-producing tumors. Despite all these advances, Cushing’s syndrome continues to tax endocrinologists and is likely to continue to do so. This chapter reviews the manifestations, causes, approaches to diagnosis, and treatments for this complicated and multifaceted syndrome.

Etiology and Pathophysiology

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 8-1). 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.1719 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 8-2). 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.3133 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.5053 Ectopic cortisol production by an ovarian carcinoma has been reported.54


A pseudo-Cushing’s state may be defined as one in which some or all of the clinical features that resemble true Cushing’s syndrome, and some evidence of hypercortisolism, are present but disappear after resolution of the underlying condition.55 The pathophysiology of these states has not been established. One hypothesis is that these stressful conditions increase the activity of the CRH neuron, resulting in excessive ACTH secretion, adrenal hyperplasia, and increased cortisol production.56 The model predicts only intermittent and modest hypercortisolism because of appropriate corticotroph reduction in ACTH secretion in response to negative feedback by cortisol (Fig. 8-1). This construct presumes also that hypertrophied adrenal glands produce excessive glucocorticoids in response to normal ACTH levels, an assumption that is supported by the blunted ACTH, but not cortisol, response to exogenous CRH in anorexia nervosa,57 depression,58 and obligate athleticism.59


Iatrogenic causes account for most cases of Cushing’s syndrome because of the common therapeutic use of high-dose glucocorticoids. Large series have reported the distribution of endogenous cases as follows: Cushing’s disease (68%), adrenal adenomas (8% to 19%), adrenal carcinoma (6% to 7%), ectopic ACTH syndrome (6% to 15%), and nodular adrenal hyperplasia (2%).55,60 However, a paucity of information is available on the true incidence of these causes. Perhaps the best data come from a population-based study covering the whole of Denmark (population of 5.3 million), which used stringent methods of data collection, aided by the small number of centers treating the disorder.61 The incidences of Cushing’s disease, adrenal adenoma, and adrenal carcinoma were 1.2 per million per year, 0.6 per million per year, and 0.2 per million per year, respectively. The reported incidence of ectopic ACTH syndrome was extremely low (0.1 per million per year). This is probably due (as the authors concede) to the fact that many cases were never recognized, but may be explained in part by a group of patients with ACTH-dependent Cushing’s syndrome (0.5 per million per year) with presumed but unproven pituitary disease. Some of these may well have had ectopic ACTH syndrome. The incidence of ectopic ACTH syndrome most certainly is underestimated in the endocrine literature because most cases reaching endocrinologists are those caused by occult tumors as opposed to those caused by overt malignancy. However, given that Cushing’s syndrome will be present in 3% to 12% of cases of small cell lung cancer,62,63 and that the recent incidence of small cell lung cancer in Europe is approximately 120 per million per year in men and 40 per million per year in women,64 this is by far the most common cause. Other epidemiologic studies have looked at just the incidence of Cushing’s disease and have found rates between 0.7 per million per year in northern Italy65 and 2.4 per million per year in northern Spain.66

Gender and age distribution varies with the cause of Cushing’s syndrome. Adrenal adenomas and Cushing’s disease present much more commonly in women than in men, and adrenal carcinoma is approximately 1.5 times as common as in men.55,60 Nodular adrenal hyperplasia has an approximately equal gender ratio.

Ectopic ACTH syndrome is the only cause of the syndrome that is more common in men (other than Cushing’s disease in prepubertal children), although this may change as more women are developing small cell lung cancer. Lung cancer is more common after age 40, and this accounts for the increased mean age of patients with ectopic ACTH syndrome compared with Cushing’s disease, which occurs between 25 and 40 years of age.67 The other major cause of ectopic ACTH secretion, intrathoracic carcinoids, has a peak incidence around 40 years and only a slightly increased male-to-female ratio.68 The age distribution of adrenal cancer is bimodal, with peaks in childhood and adolescence and late in life, although adrenal adenoma occurs most often around 35 years of age.

Clinical Features

Excessive cortisol production has widespread systemic effects67,6972 (Table 8-3). Although the full-blown cushingoid phenotype is unmistakable, the clinical diagnosis may be equivocal for patients with few of the typical characteristics (Fig. 8-2). Some nonspecific features consistent with the diagnosis of Cushing’s syndrome, such as obesity, hypertension, and menstrual irregularity, are common in the general population and may provoke unwarranted and costly screening tests for patients not likely to be affected.

One useful strategy when the diagnosis of Cushing’s syndrome is considered, is to look for evidence of progressive physical changes by examination of serial photographs, especially of individuals photographed at annual events such as holidays, birthdays, or school milestones (Fig. 8-3). Another approach relies on identification of signs and symptoms that correctly classify patients suspected of having the disorder. Truncal obesity, ecchymoses, plethora, proximal muscle weakness, and osteopenia are useful discriminant indices for Cushing’s syndrome, with osteoporosis, ecchymoses, and muscle weakness being the most reliable.69,73,74

Increased deposition of fat, one of the earliest signs, occurs in almost all patients and is reported as increasing weight or difficulty in maintaining weight. The distribution of fat is altered in both men and women, with increased amounts in the visceral compartments75 and subcutaneous sites on the face and neck. Increased intra-abdominal fat results in the truncal obesity described by Cushing in approximately 50% of patients. Increased fat in the face (moon facies), the supraclavicular or temporal fossae, and the dorsocervical area (“buffalo hump”) is uncommon in normal people. When extreme, the supraclavicular fat may present as a “collar” rising above the clavicles (Fig. 8-4); filling of the temporal fossae may prevent eyeglass frames from seating properly. Abnormal fat deposition may occur in the epidural space. Spinal epidural lipomatosis causing neurologic deficit, a rare complication of long-term exogenous steroid use, has been reported in a few patients with endogenous Cushing’s syndrome.76,77 Lumbosacral findings were seen in both men and women, whereas thoracic obstruction was restricted to men. The condition can be diagnosed by magnetic resonance imaging (MRI).78

Loss of subcutaneous tissue results in a variety of skin abnormalities that are unusual in the general population and suggest hypercortisolism. Ecchymoses, often after minimal trauma, and cutaneous atrophy, seen as a fine “cigarette paper” wrinkling or tenting over the dorsum of the hand and elbows, are typical. Cutaneous atrophy is influenced by gender and age, with men and the young having greater skin thickness. Two maxims follow: First, it is useful to compare the patient’s skin with that of a near age- and gender-matched healthy person; and second, skin thickness is relatively preserved in cushingoid women with increased androgen production or preservation of ovarian function (Fig. 8-5).

Facial plethora, especially over the cheeks, also reflects loss of subcutaneous tissue. Although plethora is more obvious in pale Caucasian individuals, it may be present and should be sought in darker-skinned persons. Because erythema may be induced in normal persons by ultraviolet radiation from lamps or sunlight, wind, or medications (including topical drying agents, glucocorticoids, and antipsoriatic treatments), exposure to these agents should be ascertained before plethora is ascribed to endogenous hypercortisolism. A demarcation line, representing collar, sleeve, or shoulder straps, may differentiate exogenous from endogenous causes. Flushing caused by other conditions (e.g., mastocytosis, thyrotoxicosis, vasomotor instability or estrogen insufficiency in women, carcinoid syndrome) also should be considered.

Purple striae more than 1 cm in diameter are virtually pathognomonic for Cushing’s syndrome (Fig. 8-6). Although the silvery, healed striae that are typical postpartum are not caused by active Cushing’s syndrome, other pink, less pigmented, and thinner striae may be seen. Although most common over the abdomen, striae occur also over the hips, buttocks, thighs, breasts, and upper arms. The tear in the subcutaneous tissue may be best appreciated by indirect (side) lighting, which throws the striae into relief, or by light stroking of the skin. The violaceous hue is not dependent on ACTH-dependent pigmentation and may be seen in Cushing’s syndrome in association with primary adrenal causes.

Proximal muscle weakness with preservation of distal strength is a hallmark of Cushing’s syndrome. Histologically, this is reflected in profound atrophy of fibers without necrosis.7981 Weakness is best assessed historically by questions related to the use of these muscles: Is there difficulty or weakness in climbing stairs, getting up from a chair or bed without using hand propulsion, or performing activities using the shoulders (e.g., brushing hair, reaching objects in overhead cabinets, changing ceiling light bulbs)? Formal muscle testing is useful. Assess the strength of the hip flexors by asking the patient to get out of a chair without using his or her arms. If this can be done, the patient is asked to rise from a squat. Inability to perform either task, in the absence of hip or lower extremity arthropathy or other myopathic processes, is suggestive of Cushing’s syndrome. Leg extension while seated is a quantifiable test of proximal muscle strength. The number of seconds for which this position is held can be used to judge deterioration or progress after treatment.

Osteopenia is common. A history of fractures, typically of the feet, ribs, or vertebrae, may be one of the only signs of Cushing’s syndrome, especially in men.70,71,82 Avascular necrosis of bone, a rare complication of endogenous hypercortisolism, is more common in iatrogenic hypercortisolism.83,84 It usually occurs in the hips, but we have also seen it in the knees.

Vellous hypertrichosis of the forehead or upper cheeks distinguishes Cushing’s syndrome from the more common causes of hirsutism and may be appreciated only by careful visual and tactile inspection (Fig. 8-7). Excessive terminal hair on the face and body, and acne—pustular, reflecting increased androgens, or papular, reflecting pure glucocorticoid excess—may be present.85 Severe hirsutism and virilization are uncommon and suggest adrenal carcinoma.

Most patients experience emotional and cognitive changes (including increased fatigue, irritability, crying, and restlessness, depressed mood, decreased libido, insomnia, anxiety, impaired memory, concentration, and verbal communication) and changes in appetite. These changes correlate with the degree of hypercortisolism.86 Irritability, characterized as a decreased threshold for uncontrollable verbal outbursts, may be one of the earliest symptoms. Global impairment in neuropsychological function correlates well with the performance of seven serial subtractions and recall of the names of three cities—bedside tests that can be used by the clinician to quantify this symptom complex.87 Approximately 80% of patients meet strict criteria for a major affective disorder—50% with unipolar depression and 30% with bipolar illness.88,89 Although the quality of the depressed mood ranges from suicide attempts to sadness, the time course is characteristically intermittent, rarely lasting longer than 3 days, in contrast to the constant dysphoria reported by depressed patients without Cushing’s syndrome.86 A minority of patients are manic. The improvement in neuropsychiatric findings after treatment of Cushing’s syndrome, coupled with similar features in patients treated with exogenous steroids, and the association of hypercortisolism with poor cognitive performance in depressed patients suggest glucocorticoid excess as a cause.90,91

Hypertension is present in approximately 80% of patients, and although hypertension is also common in the general population, its presence in patients younger than 40 years of age, especially if difficult to control, may alert one to the syndrome. Hypertension usually resolves with treatment of the Cushing’s syndrome but may persist, possibly as the result of microvessel remodeling and/or underlying essential hypertension.92

The association of hypercortisolism and fungal infections of the skin, such as mucocutaneous candidiasis and pityriasis versicolor, with poor wound healing is a common feature. Wound dehiscence occurs less often but is an important consideration in patients who are treated surgically without medical pretreatment.

Patients with marked hypercortisolism (plasma cortisol >43 µg/dL [1200 nmol/L], UFC >2000 µg/day [5520 nmol/day]) are at risk for two potentially catastrophic events: perforation of the viscera and severe infection, either bacterial or opportunistic, such as Pneumocystis carinii, aspergillosis, nocardiosis, cryptococcosis, histoplasmosis, and Candida.9395 Classic clinical signs, such as loss of bowel sounds and fever, may be absent in peritonitis, and the typical leukocytosis of hypercortisolism may not increase further. Thus, the threshold of suspicion for opportunistic infection and a surgical abdomen must be low in patients with severe hypercortisolism.

Libido is decreased uniformly in men and to a lesser extent (44%) in women,70 in whom increased libido may indicate excess androgen production by an adrenocortical carcinoma. Menstrual irregularities, amenorrhea, and infertility are common and may be the presenting complaints.96 Impotence is common.


The cardinal laboratory findings in endogenous Cushing’s syndrome reflect overproduction of glucocorticoids. Although morning plasma cortisol values may be normal, an increased nighttime nadir blunts or obliterates the normal diurnal rhythm.9799 This increase in mean 24-hour plasma values is reflected in increased levels of free, or unbound, cortisol in urine100 and saliva.101 The capacity of corticosteroid-binding globulin for cortisol is exceeded at a serum cortisol value of approximately 20 µg/dL (≈600 nmol/L). At this point, the excretion of free cortisol increases dramatically in direct proportion to the increased unbound circulating cortisol values.

Hypokalemic metabolic alkalosis usually is observed when daily urine cortisol excretion is greater than 1500 µg (4100 nmol), and thus mainly in cases of ectopic ACTH syndrome.102 This probably represents a mineralocorticoid action of cortisol at the renal tubule due to saturation of the enzyme 11β-hydroxysteroid dehydrogenase type 2, which inactivates cortisol to cortisone.103 However, although a common feature of ectopic ACTH secretion, it also may occur in approximately 10% of patients with Cushing’s disease. Serum albumin is inversely correlated with cortisol levels, but this is of clinical significance only at very high cortisol levels, and it reverses with treatment for Cushing’s syndrome.104 Drastic reductions in serum albumin should alert the physician to the possibility of concomitant pathology such as infection. Circulating elevated glucocorticoids increase clotting factors, including factor VIII, fibrinogen, and von Willebrand factor, and reduce fibrinolytic activity, resulting in a fourfold risk of thrombotic events.105107 Lipid abnormalities show increases in very–low density lipoprotein, low-density lipoprotein, high-density lipoprotein, and consequently total cholesterol and triglycerides. These changes probably are caused by a direct cortisol effect of increased hepatic synthesis of very low–density lipoprotein without altered clearance.108,109

Cushing’s syndrome is characterized by insulin resistance and hyperinsulinemia, with frank diabetes mellitus occurring in 30% to 40% of patients, and glucose intolerance in a further 20% to 30%.110,111 A recent study has suggested that as many as 2% of overweight, poorly controlled patients with diabetes may have occult Cushing’s syndrome if fully investigated.112 In the absence of clinical suspicion, the yield is probably lower.113

Patients with Cushing’s disease show accelerated cardiovascular disease, including increased carotid artery intima-media thickness and atherosclerotic plaques on Doppler ultrasonography.114 This increased risk is maintained even as long as 5 years after cure of the hypercortisolemia is attained.115 It also is likely that glucocorticoids have a direct pathogenic effect on the myocardium.

Hypercortisolism suppresses the thyroidal, gonadal, and growth hormone axes. Thyrotropin-releasing hormone and thyroid-stimulating hormone release is disturbed, and particularly the nocturnal surge of thyroid-stimulating hormone is lost, resulting in reduced total thyroxine, total triiodothyronine, and free triiodothyronine levels compared with controls.116 Others have found no differences in free thyroxine or free triiodothyronine levels but have shown a significantly increased prevalence of autoimmune thyroid disease in patients treated for Cushing’s syndrome.117,118 In both men and women, low levels of luteinizing hormone, follicle-stimulating hormone, and gonadal steroids consistent with hypogonadotropic hypogonadism are common and correlate with the degree of hypercortisolemia.119,120 In addition, the coexistence of polycystic ovarian syndrome in Cushing’s syndrome may be more common than was previously thought.96 Hypercortisolemia causes reduced growth hormone (GH) secretion during sleep and blunted GH response to stimulation tests.121

The prevalence of osteoporosis as assessed by dual-energy x-ray absorptiometry is approximately 50% in adult Cushing’s syndrome.122 It appears more common in adrenal Cushing’s syndrome than in Cushing’s disease, and this may relate to the protective effect of increased adrenal androgens in the latter.123

The accentuated visceral fat distribution characteristic of Cushing’s syndrome can be marked when visualized by computed tomography (CT),75 and the liver frequently (20%) is steatotic on imaging.124

Clinical Spectrum

The typical patient with Cushing’s disease presents at midlife complaining of the gradual development of symptoms, although males tend to present at an earlier age and with more severe clinical consequences.125 Hypokalemia, virilization, and extremely high cortisol excretion (>10-fold normal) are distinctly uncommon and should alert the physician to an alternative cause. The clinical presentation of pituitary corticotroph macroadenomas, apart from visual field changes caused by suprasellar expansion, is not unique. By contrast, invasive pituitary adenomas present at a slightly younger age; cavernous sinus and dural involvement may result in cranial neuropathies and facial neuralgia.126,127 Only a few case reports attest to cerebrospinal or extracranial metastasis of ACTH-producing pituitary tumors.128

Nelson’s syndrome is characterized by the development of hyperpigmentation and high ACTH levels after bilateral adrenalectomy for Cushing’s disease. Tumor growth after adrenalectomy has been attributed to the relative resistance of these tumors to physiologic glucocorticoid suppression.

An abrupt onset of severe Cushing’s syndrome should prompt an evaluation for ectopic ACTH secretion. This variant of ectopic ACTH secretion classically presents as a paraneoplastic syndrome in the context of a known malignancy. The features were captured in the initial formulation of Liddle4: weight loss, hypokalemia, weakness, and diabetes. However, Cushing’s syndrome caused by less obvious ectopic ACTH secretion often presents in the more classic way with weight gain and striae and can be difficult to differentiate clinically from Cushing’s disease. It is patients with this syndrome who most often present a diagnostic dilemma. They tend to have UFC excretion in the range seen in pituitary disease and may not show hypokalemia, hyperpigmentation, or the other findings typical of severe classical ectopic ACTH secretion.

Adrenocortical carcinomas are inefficient producers of cortisol and tend to evince Cushing’s syndrome when the tumor is large (>6 cm), if at all. Abdominal pain or a palpable mass suggests this cause. Feminization in a man or virilization and increased libido in a woman, indicating involvement of the zona reticularis, suggest adrenal cancer or macronodular adrenal disease, which is rarer. The typical patient with PPNAD is a child or young adult who may present with an intermittent course or a family history of associated signs: Lentigines may be the initial clue to this cause. By contrast, patients with the massive macronodular variant of ACTH-independent Cushing’s syndrome tend to be older than 40 years.

Diagnosis and Differential Diagnosis

The diagnosis of Cushing’s syndrome rests on the demonstration of both physical and biochemical features of glucocorticoid excess. Thus, the diagnosis is unequivocal in a typical patient, with many of the physical features discussed earlier in the setting of UFC levels more than fourfold above normal.129 However, many of the signs of hypercortisolism, such as obesity, hypertension, glucose intolerance, mood changes, menstrual irregularity, and hirsutism, are common in the general population. Similarly, mild glucocorticoid excess is seen in affective disorders,130 strenuous exercise,59 alcoholism and alcohol withdrawal states,131 renal failure,132 and hypoglycemia. Diagnostic strategies for distinguishing between these pseudo-Cushing’s states and true Cushing’s syndrome are discussed later.

Glucocorticoid resistance is characterized by an abnormal glucocorticoid receptor number or binding, which causes compensatory increases in ACTH and excessive glucocorticoid production to maintain normal glucocorticoid-mediated effects at the target tissues. The diagnosis should be considered in the hypokalemic, hypertensive, hypercortisolemic patient without typical glucocorticoid-mediated signs of Cushing’s syndrome.133


When a careful history and physical examination reveal clinical features that could be consistent with the syndrome, exogenous glucocorticoid use must be excluded (Table 8-4). In addition to inquiring about the use of oral, rectal, inhaled, injected, or topical glucocorticoid administration, it is important to evaluate the use of “tonics,” herbs, and skin bleaching creams, which may contain glucocorticoids. In the absence of exogenous glucocorticoids, biochemical confirmation of the diagnosis of Cushing’s syndrome is needed. It is important to remember that the urgency for diagnosis and treatment of Cushing’s syndrome is greatest when the symptoms are severe. In milder cases, the patient may be best served by waiting until the diagnosis is clear. Periodic reevaluation with urine screening tests and documentation of body habitus with photographs may reveal progression.

Initial Screening Tests

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