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Epidemiology and clinical manifestations of Cushing's syndrome

Epidemiology and clinical manifestations of Cushing's syndrome
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Kathryn A Martin, MD
Literature review current through: Dec 2022. | This topic last updated: Apr 05, 2021.

INTRODUCTION — The symptoms and signs of Cushing's syndrome result directly from chronic exposure to excess glucocorticoid. Establishing the diagnosis is often difficult because few of the symptoms or signs are pathognomonic of the syndrome in isolation. There is a large spectrum of manifestations from subclinical to overt syndrome, depending on duration and intensity of excess steroid production. Furthermore, some of them (such as obesity, hypertension, and glucose intolerance) are common in individuals who do not have adrenal hyperfunction. An important clinical clue to the presence of glucocorticoid excess is the simultaneous development and increasing severity of several of these symptoms.

The major manifestations of Cushing's syndrome will be reviewed here. The diagnosis and treatment of this disorder and Cushing's syndrome during pregnancy are discussed separately. (See "Establishing the diagnosis of Cushing's syndrome" and "Establishing the cause of Cushing's syndrome" and "Overview of the treatment of Cushing's syndrome" and "Diagnosis and management of Cushing's syndrome during pregnancy".)

EPIDEMIOLOGY — Estimates of the incidence of Cushing's syndrome are imprecise and likely underestimate the incidence of iatrogenic Cushing's syndrome, undiagnosed mild hypercortisolism, and the ectopic corticotropin (ACTH) syndrome.

Iatrogenic Cushing's syndrome – More than 10 million Americans receive pharmacologic doses of glucocorticoids each year. Therefore, iatrogenic Cushing's syndrome must be more common than any other cause but is seldom reported. (See "Major side effects of systemic glucocorticoids", section on 'Dermatologic effects and appearance'.)

Cushing's disease – Pituitary ACTH-dependent Cushing's causes 65 to 70 percent of Cushing's syndrome [1]. The reported incidence was 1.2 to 2.4 per million per year in European population-based studies [2,3] and 6.2 to 7.6 per million person-years in the United States [4]. (See "Causes and pathophysiology of Cushing's syndrome", section on 'Cushing's disease'.)

Ectopic ACTH syndrome – Recognized ectopic ACTH syndrome causes 10 to 15 percent of cases. However, its true incidence is probably more common because a number of these patients do not present with catabolic features and are not diagnosed. For example, small cell lung cancer is diagnosed in approximately 8 of 100,000 persons annually, in whom the ectopic ACTH syndrome is diagnosed in approximately 1 percent, approximately 1 per million [5,6]. As ectopic ACTH secretion accounts for only approximately 15 percent of Cushing's syndrome, it is clear that it is underdiagnosed. Other causes of ectopic ACTH syndrome, such as pulmonary neuroendocrine tumors, are reviewed separately. (See "Causes and pathophysiology of Cushing's syndrome", section on 'Ectopic ACTH syndrome'.)

Adrenal tumors – Adrenal carcinoma and adenoma cause a similar number of cases of Cushing's syndrome in most series, together comprising approximately 20 percent of all cases. However, a preponderance of Cushing's syndrome caused by adrenal adenomas has been described in Hokkaido, Japan and in Italy [7,8]. Based on the United States Surveillance, Epidemiology, and End Result (SEER) database, the incidence of adrenal carcinoma from 2000 to 2012 was estimated to be 1.26 per million per year [9]. A population-based study in Denmark reported the incidence of adrenal adenoma and adrenal carcinoma as 0.6 and 0.2 per million per year, respectively [2]. (See "Clinical presentation and evaluation of adrenocortical tumors".)

All other causes of Cushing's syndrome are extremely rare, including Cushing's syndrome due to either bilateral macronodular adrenal hyperplasia or primary pigmented nodular adrenocortical disease, which are discussed elsewhere. Ectopic production of corticotropin-releasing hormone (CRH) is perhaps the most uncommon cause of the syndrome. (See "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia" and "Cushing's syndrome due to primary pigmented nodular adrenocortical disease".)

The incidence of Cushing's syndrome varies by both sex and age. The sex-related distribution of Cushing's syndrome varies with the cause:

Males had a three times greater incidence of the ectopic ACTH syndrome 30 years ago, but the increasing incidence of lung cancer in cigarette-smoking females has narrowed that margin. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Epidemiology'.)

Females are three to eight times more likely than males to develop Cushing's disease [1], approximately three times more likely to have either benign or malignant adrenal tumors, and approximately four to five times more likely to have Cushing's syndrome associated with an adrenal tumor [1,10-12]. The reasons for this preponderance in females are unknown.

The age at presentation varies depending upon the cause of hypercortisolism:

The age at which the ectopic ACTH syndrome develops parallels the development of lung carcinoma, increasing rapidly after age 50 years. Ectopic ACTH secretion due to more benign neuroendocrine tumors (previously termed carcinoids) can occur at earlier ages but is rare in children. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Epidemiology'.)

Cushing's disease occurs mainly in women aged 25 to 45 years. It is unusual in children but still accounts for up to 46 percent of cases of childhood Cushing's syndrome, occurring mostly after puberty [13,14]. In two small studies reporting on approximately 20 prepubertal children, boys were affected more often than girls (18:2), while 36 of 53 adolescents with Cushing's disease were female [13,15-17]. (See "Causes and pathophysiology of Cushing's syndrome", section on 'Cushing's disease'.)

Adrenal tumors have a bimodal age distribution, with small peaks in the first decade of life for both adenomas and carcinomas and major peaks at approximately 50 years for adenomas and 40 years for carcinomas [11,18]. One literature review found that adrenal tumors (benign and malignant) cause 41 percent of all cases of childhood Cushing's syndrome, with primary pigmented nodular dysplasia accounting for approximately 6 percent [14]. Girls are affected slightly more often than boys. (See "Clinical presentation and evaluation of adrenocortical tumors".)

CLINICAL MANIFESTATIONS — The major symptoms and signs of Cushing's syndrome are listed in the table (table 1) and reviewed in detail in this section [19-21].

In adults, signs and symptoms most suggestive of the presence of hypercortisolism include proximal muscle weakness, facial plethora, wasting of the extremities with increased fat in the abdomen and face, wide purplish striae, bruising with no obvious trauma, and supraclavicular fat pads [22-24]. An important clinical clue to the presence of glucocorticoid excess is the simultaneous development or accumulation of new features over time and increasing severity of several of these symptoms.

The clinical manifestations of Cushing's syndrome can be categorized as reproductive, dermatologic, metabolic, cardiovascular, musculoskeletal, neuropsychiatric, and infectious. In addition to the considerable morbidity caused by hypercortisolism, there is also an increase in mortality rates. (See 'Mortality' below.)

Severity of symptoms — When hypercortisolism is severe, its signs and symptoms are unmistakable. However, many of the signs and symptoms of Cushing's syndrome can occur in individuals without hypercortisolism, and not all patients with Cushing's syndrome present with obvious features.

The presence and relative severity of symptoms varies, being determined by the following factors:

The degree and duration of hypercortisolism.

The presence or absence of androgen excess (because hypercortisolism alone causes neither hirsutism nor pustular acne).

The cause of the hypercortisolism (because hyperpigmentation is caused by increased secretion of corticotropin [ACTH]) and androgen excess occurs only in females with adrenal cancer or ACTH-stimulated hyperandrogenism (the adrenal gland being a major source of androgen production in females but not males). Adrenal adenomas generally secrete only glucocorticoids.

Adrenal carcinoma or the ectopic ACTH syndrome can cause tumor-related symptoms that may overshadow the effects of hypercortisolism (such as weight loss instead of weight gain).

In patients with adrenal adenomas, both the degree of hypercortisolemia and many of the clinical manifestations of Cushing's syndrome tend to be less severe in patients >50 years of age [20]. Many patients with incidentally discovered adrenal adenomas have subclinical Cushing's syndrome (mild hypercortisolism without clinical manifestations of Cushing's syndrome, now often referred to as "autonomous cortisol secretion"), but glucose intolerance and hypertension are common [21]. (See "Evaluation and management of the adrenal incidentaloma", section on 'Subclinical Cushing syndrome'.)

Reproductive

Menstrual irregularities — Menstrual irregularities are common in women with Cushing's syndrome. In one series of 45 women with newly diagnosed Cushing's disease, 80 percent had abnormal menstrual cycles, 31 percent had oligomenorrhea, 33 percent had amenorrhea, and the remainder had excess or variable menses [25]. The menstrual abnormalities correlated with increased serum cortisol and decreased serum estradiol concentrations but not with serum androgen concentrations. Because both luteinizing hormone and follicle-stimulating hormone levels are low, the menstrual irregularities appear to be due to suppression of secretion of gonadotropin-releasing hormone by hypercortisolemia [26].

Signs of adrenal androgen excess — Females with some types of Cushing's syndrome (most commonly adrenal carcinoma) have signs of androgen excess [27]. The adrenal glands are the major source of androgens in females [28]. In contrast, the testes are the major source of androgens in males [29]. Thus, males with Cushing's syndrome do not have signs of androgen excess, because cortisol has no androgenic activity [30].

Signs of androgen excess in Cushing's syndrome are most common in women with adrenal carcinomas [10,18]. These tumors usually secrete large amounts of androgenic precursors because they are inefficient at converting cholesterol to cortisol [31,32]. In comparison, signs of androgen excess are usually mild in women with ACTH-dependent Cushing's syndrome and do not occur in women with adrenal adenomas [18].

Androgen excess in affected women can cause the following symptoms:

Hirsutism, which is usually mild and limited to the face but can be generalized. Downy sideburns and increased hair on the upper lip and under the chin are most common (picture 1). The scalp hair often becomes thin, but temporal balding is rare.

Oily facial skin and acne on the face, neck, or shoulders.

Increased libido (however, decreased libido is more common, occurring in 70 percent of patients in one series [33]).

Virilization, including temporal balding, deepening voice, male body habitus, male escutcheon, and clitoral hypertrophy, occurs only in girls or women with extremely high serum concentrations of androgens due to an adrenal carcinoma. Prepubertal males may develop premature puberty (picture 2).

Dermatologic — Many changes in the skin and subcutaneous tissue occur in patients with Cushing's syndrome. Unlike most other symptoms and signs associated with Cushing's syndrome, which can occur alone or in combination in normal subjects and patients with pseudo-Cushing's states, the dermatologic changes characteristic of Cushing's syndrome seldom occur in other subjects [22,34].

Easy bruisability – Loss of subcutaneous connective tissue due to the catabolic effects of glucocorticoid results in easy bruising after minimal, often unremembered, injury (picture 3). Extensive ecchymoses at venipuncture sites are also common, and it is often difficult to maintain intravenous lines without fluid infiltration into the surrounding tissues. As a result, patients with Cushing's syndrome are sometimes thought to have senile purpura or a bleeding diathesis [35].

Striae – Purple striae occur as the fragile skin stretches due to the enlarging trunk, breasts, and abdomen (picture 4). The striae appear as wide, reddish-purple streaks because the increasingly thin skin does not hide the color of venous blood in the underlying dermis. Striae occur most often in younger patients, can be numerous, and are most common on the abdomen and lower flanks; however, they can also occur on the breasts, hips, buttocks, shoulders, upper thighs, upper arms, and axillae [36].

Skin atrophy – The skin usually atrophies, the stratum corneum is thinned, and there is loss of subcutaneous fat to a sufficient degree that subcutaneous blood vessels may be seen [37]. The skin eventually becomes fragile due to these changes and, in extreme cases, peels off after being covered with adhesive tape. Minor wounds heal slowly, and surgical wounds may dehisce. Such changes should be considered in the context of sex and age differences in skin thickness, with healthy men and younger individuals having greater skin thickness.

Fungal infections – Cutaneous fungal infections, especially tinea versicolor, are often found on the trunk. Some patients have fungal infections of the nails, but oral candidiasis is rare.

Hyperpigmentation – Hyperpigmentation is induced by increased ACTH, not cortisol, secretion. ACTH is the principal pigmentary hormone in humans. It acts via binding to melanocyte-stimulating hormone receptors [38]. The degree of hyperpigmentation is dependent upon both the duration and the degree of increase in ACTH secretion.

Hyperpigmentation occurs most often in patients with the ectopic ACTH syndrome, less often in those with pituitary overproduction of ACTH, and not at all in patients with adrenal tumors in whom ACTH secretion is suppressed.

Hyperpigmentation may be generalized but is most conspicuous in areas exposed to light (such as the face, neck, and back of the hands) or to chronic mild trauma, friction, or pressure (such as the elbows, knees, spine, knuckles, waist [belt], midriff [girdle], and shoulders [brassiere straps]) (picture 5A-B). Patchy pigmentation may occur on the inner surface of lips and the buccal mucosa along the line of dental occlusion (picture 6). The hyperpigmentation is less pronounced than in patients with chronic primary adrenal insufficiency.

Acanthosis nigricans also can be present in the axillae and around the neck.

Surgical or traumatic scars that form when plasma ACTH concentrations are markedly elevated are permanently pigmented. In comparison, scars incurred before ACTH hypersecretion or after it is reduced are not pigmented.

Metabolic

Glucose intolerance — Glucose intolerance is common in Cushing's syndrome. It is primarily due to stimulation of gluconeogenesis by cortisol and peripheral insulin resistance caused by obesity, but direct suppression of insulin release also may contribute. (See "Major side effects of systemic glucocorticoids".)

Overt hyperglycemia occurs in only 10 to 15 percent of patients, usually those with a family history of type 2 diabetes mellitus [39]. Diabetic ketoacidosis is rare and, if present, usually indicates unsuspected type 1 diabetes exacerbated by hypercortisolemia.

Poorly controlled hyperglycemia in a person with obesity may be a clue to the presence of Cushing's syndrome. One report, for example, found that 3 percent of such patients had Cushing's syndrome [40]. In a prospective study of 200 individuals with obesity, type 2 diabetes, and no symptoms of Cushing's syndrome, four patients (2 percent) were identified as having occult Cushing's syndrome (three with Cushing's disease and one with an adrenal adenoma) [41]. However, a subsequent study of 201 patients did not identify any with Cushing's syndrome [42]. Thus, it is not recommended to screen diabetic patients unless they have other features of the disorder [23].

Patients with Cushing's syndrome who have hyperglycemia should be treated like any other patient with type 2 diabetes (see "Overview of general medical care in nonpregnant adults with diabetes mellitus"). The hyperglycemia becomes much easier to control and may completely remit if the hypercortisolism is reversed [43].

Increased urinary albumin excretion appears to be common in Cushing's syndrome, and it is reversible. In a study of 13 patients, 80 percent had increased urinary albumin excretion, but neither the presence nor the degree of albuminuria was correlated with blood pressure or fasting plasma glucose concentrations [44]. Kidney biopsies in three patients with microalbuminuria showed normal glomeruli with no evidence of diabetic or hypertensive nephropathy.

Progressive obesity — The most common feature of patients with Cushing's syndrome is progressive, central (centripetal) obesity (picture 7), usually involving the face, neck, trunk, abdomen (picture 8), and, internally, spinal canal and mediastinum [45,46]. The extremities are often spared and may be wasted. Some authors report generalized obesity in a majority of adults with Cushing's syndrome [22].

Children with Cushing's syndrome almost invariably have generalized obesity and growth retardation; the latter may be the first indication of glucocorticoid excess. As a result, any child whose weight rises and height falls in percentile rank as compared with age-matched normal children should be considered to have Cushing's syndrome until proven otherwise (figure 1). These abnormalities both improve after successful treatment of patients whose bones have not yet fused [47].

Fat can also accumulate in the following areas in patients with Cushing's syndrome:

Fat accumulation in the cheeks and the temporal fossae results in a "moon" face that sometimes obscures the ears when a patient is examined from the front (picture 1).

A "buffalo hump" or dorsocervical fat pad is common and is usually consistent with the general degree of obesity (picture 9).

Enlarged fat pads that fill the supraclavicular fossae and obscure the clavicles are one of the most specific signs of Cushing's syndrome [22], although they occasionally occur in exogenous obesity. The bulging, supraclavicular fat pads make the neck appear thick and shortened (picture 1). Retroorbital fat deposition may result in exophthalmos, which is present in up to 5 percent of patients [48,49].

Rarely, fat accumulation in the epidural space leads to neurologic abnormalities, usually in patients with ectopic ACTH secretion or exogenous steroid administration [50].

The degree of fat accumulation in Cushing's syndrome is variable. Patients who diet and exercise rigorously may have little or no weight gain, facial rounding, or central weight redistribution. Other patients with no weight gain still have central weight redistribution. The cause of abdominal fat may be caused by cortisol-induced downregulation of adenosine monophosphate-activated protein kinase (AMPK), which regulates lipid and carbohydrate metabolism [51].

The conversion of cortisone to cortisol also contributes to fat deposition, as shown by a report of the absence of abnormal fat accumulation in a patient with a mutation that prevented this conversion [52].

Patients with Cushing's syndrome have higher serum leptin concentrations than obese subjects with a similar body mass index (BMI) [53]. Leptin secretion does not respond to changes in plasma ACTH or serum cortisol concentrations, but it does appear to vary according to changes in fat mass and peripheral insulin resistance (and therefore serum insulin concentrations), as it does in other obese subjects [54].

Sleep apnea — In one study, sleep apnea was diagnosed in 10 of 22 patients with Cushing's disease or adrenal adenoma [55]. In the same study, patients without sleep apnea showed abnormal sleep architecture and fragmented sleep with shortened rapid eye movement latency, similar to that seen in depression [55]. These abnormalities may contribute to the fatigue that is common in these patients [33].

It is likely that central obesity and possibly myopathy of the muscles that maintain airway patency both contribute to the development of sleep apnea [56]. There are no data regarding reversal after cure of Cushing's syndrome.

Cardiovascular — Patients with endogenous Cushing's syndrome are at increased risk of death from cardiovascular disease, including myocardial infarction, stroke, and thromboembolism [2,3,57]. (See 'Thromboembolic events' below.)

Other common cardiovascular problems in patients with Cushing's syndrome include hypertension and dyslipidemia. In addition, a study of 15 patients with ACTH-dependent Cushing's syndrome reported an increase in markers of subclinical atherosclerosis (coronary calcifications and noncalcified plaque volumes) when compared with controls [57].

Cardiovascular risk — One study estimated cardiovascular risk in 49 patients with active Cushing's syndrome according to World Health Organization (WHO)/International Society of Hypertension (ISH) criteria. Eighty percent of patients had a high or very high risk: 85 percent were hypertensive, 47 percent were diabetic, and 41 percent were obese [58]. Thus, aggressive treatment of these factors is warranted.

Although markers of cardiovascular risk, including lipid profiles, waist-to-hip ratios, and carotid artery intima medial thickness, improve in patients cured of their Cushing's disease, they may not normalize, suggesting that cured patients continue to have excess cardiovascular risk (possibly due to residual abdominal obesity and/or insulin resistance) [59,60].

Patients with subclinical Cushing's syndrome due to an adrenal incidentaloma may also have excess cardiovascular risk [61-63]. (See "Evaluation and management of the adrenal incidentaloma", section on 'Subclinical Cushing syndrome'.)

Hypertension — The pathogenesis of hypertension in Cushing's syndrome is multifactorial and not fully understood; however, the following factors may be important [64,65]:

Increased peripheral vascular sensitivity to adrenergic agonists [66].

Increased hepatic production of renin substrate (angiotensinogen); based on this observation, one consensus paper suggests that angiotensin-converting enzyme (ACE) inhibitors should be considered the first-line treatment of hypertension in Cushing's syndrome patients [67].

Activation of renal tubular type 1 (mineralocorticoid) receptors by cortisol (this mechanism applies mainly to patients with severe hypercortisolism, which is usually due to ectopic ACTH secretion) [68,69].

It is also possible that cortisol has a direct cardiotoxic effect [70].

Treatment of hypertension in patients with Cushing's syndrome does not differ from that of patients with primary hypertension (formerly called "essential" hypertension). However, blocking mineralocorticoid activity with spironolactone may be particularly effective in patients with very high serum cortisol concentrations, especially those with hypokalemia. The hypertension usually becomes easier to control and may entirely disappear when the Cushing's syndrome is treated [71].

Severe hypertension and hypokalemia are more prevalent in patients with ectopic ACTH [72]. The high serum cortisol concentrations overwhelm the ability of the kidneys to convert cortisol to cortisone, resulting in activation of mineralocorticoid receptors as described above. Hypokalemia may also result from adrenal hypersecretion of mineralocorticoids, such as deoxycorticosterone and corticosterone [73]. (See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)", section on 'Ectopic ACTH syndrome'.)

Thromboembolic events — An increase in venous thromboembolism (VTE) risk has been reported in most studies of patients with Cushing's syndrome [22,74-77]. In a systematic review of 15 studies, the risk of postoperative VTE ranged from 0 to 5.6 percent (with one outlier of 20 percent) [78]. In two of the studies, the risk of VTE not related to surgery was reported to be 1.9 and 2.5 percent. Based upon the 6 to 9.7 years of follow-up in these studies, this corresponded to an incidence of 2.5 to 3.1 per 1000 person-years [78], much higher than the estimated incidence in an age- and sex-matched population (VTE incidence for 40-year-old women = 0.3 per 1000 person-years) [79].

In a multicenter cohort study of patients with Cushing's syndrome published after the systematic review (n = 473; 360 with ACTH-dependent pituitary Cushing's syndrome, 113 with ACTH-independent adrenal disease), VTE rates not related to surgery were higher than reported in the systematic review, while postoperative rates were in a similar range [80]:

Prior to treatment, 17 patients with Cushing's syndrome (4 percent) had a VTE, for an incidence rate of 12.9 per 1000 person-years.

The frequency of postoperative VTE (within three months after transsphenoidal surgery for ACTH dependent or adrenalectomy for ACTH independent) was 3.4 and 0 percent, respectively [80]. The 3.4 percent postoperative risk in those with ACTH-dependent disease (12 events in 350 patients) translates to an incidence of 141 per 1000 person-years. No episodes of postoperative VTE were seen in a control group of 185 patients undergoing pituitary surgery for nonfunctioning adenomas.

The risk is possibly due to glucocorticoid-induced increases in plasma concentrations of clotting factors, especially factor VIII and von Willebrand factor complex, and decreases in fibrinolytic activity [74-76]. Elevated serum homocysteine concentrations, which appear to be associated with an increased risk of cardiovascular disease and venous thrombosis, have been reported in patients with Cushing's syndrome [81]. (See "Overview of homocysteine".)

Clinical features that appear to contribute to the excess risk of thromboembolism include obesity and surgery [78]. Another study that examined factors in 20 of 176 patients who developed venous thromboembolism found risk factors of age ≥69 years, reduced mobility, acute severe infections, previous cardiovascular events, midnight plasma cortisol level more than 3.15 times the reference range, and shortened activated partial thromboplastin time (aPTT) [82].

Prophylactic postoperative anticoagulation may reduce the risk of thromboembolic complications. This was illustrated in a retrospective study of 307 patients with Cushing's syndrome; postoperative prophylactic anticoagulation with heparin and/or warfarin appeared to reduce the risk of thromboembolic complications (14 of 232 patients [6 percent]) compared with a historical control group that was not anticoagulated (15 of 75 patients [20 percent]) [75]. Although further studies are needed to confirm its benefit, postoperative anticoagulation prophylaxis seems warranted at present for nonambulatory patients. In the absence of further studies, we would not recommend postoperative anticoagulation in patients who are ambulatory.

We also encourage our hospitalized patients to get out of bed during the day and to walk for 15 to 20 minutes two or three times a day, if possible.

Other — Hypercortisolism may also be associated with heart failure and dilated cardiomyopathy:

One series reported heart failure in almost one-half of patients older than 40 years [83], but in our experience, it is rare. Dependent edema can also occur, although the mechanism is not well understood. It should not be caused by excess mineralocorticoid activity, due to the phenomenon of aldosterone escape [84].

Dilated cardiomyopathy occurs rarely in Cushing's syndrome but it is generally reversible [85]. In one literature review, it was associated with Cushing's disease in approximately one-quarter of the patients and with adrenal adenomas in the remainder [85], but it has also been reported in a single patient with ectopic ACTH secretion [86]. It is characterized by cell hypertrophy and myocardial fibrosis [87].

Bone health/musculoskeletal

Proximal muscle wasting and weakness — Weakness and proximal muscle wasting are common in Cushing's syndrome, being induced by the catabolic effects of excess glucocorticoid on skeletal muscle (picture 10). As a result, many patients cannot rise from a squatting position without assistance; patients with more severe disease may be unable to climb stairs or get up from a deep chair. The catabolic effects of cortisol are amplified by physical inactivity [88] (see "Glucocorticoid-induced myopathy"). In a number of studies, muscle wasting and weakness were uncommon in patients with pseudo-Cushing's syndrome [34,48,49,89]. However, in one study of 23 patients with pseudo-Cushing's syndrome and 32 with Cushing's syndrome, the incidence of weakness was similar in the two groups (approximately 30 percent) [90].

Hypokalemia, due to decreased renal conversion of cortisol to cortisone by 11-beta hydroxysteroid dehydrogenase type II, allowing for cortisol to exert mineralocorticoid effects, can accentuate the weakness in patients with severe hypercortisolism [69]. On the other hand, a high-protein diet and exercise may improve or mitigate muscle wasting and increase strength.

Bone loss — Osteoporosis is common in patients with Cushing's syndrome. It is caused by decreased intestinal calcium absorption, decreased bone formation, increased bone resorption, and decreased renal calcium reabsorption [91,92]. It can be demonstrated by densitometry of the lumbar vertebrae, even in young patients. Pathologic fractures may occur, often resulting in severe skeletal pain. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

The following skeletal abnormalities may be seen:

A study of 80 patients with Cushing's syndrome showed a 76 percent prevalence of osteoporosis [93]. Multiple fractures were more common in patients with ectopic ACTH secretion.

Pathologic rib and long-bone fractures [94].

Osteonecrosis (aseptic necrosis) of the femoral heads and rarely the humeral heads, usually only with chronic, high-dose glucocorticoid therapy [95]. Osteonecrosis of the femoral head has been described in few patients with Cushing's syndrome [96] and, rarely, it may be the presenting manifestation of Cushing's syndrome [97]. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults".)

Low back pain is very common and is attributed to osteoporosis, vertebral compression, muscle wasting, and the lordotic posture resulting from weight gain.

Lower-extremity insufficiency fractures, particularly of the feet, were reported in 10 women, five of whom had mild disease [98].

Increased bone resorption can also lead to hypercalciuria and renal calculi [99]. Hypercalcemia is very rare.

Bone mineral density improves in adults and children after successful treatment of Cushing's syndrome [21,100]. One study of 17 adults found normal bone mineral density in the spine and hip when measured on average at 8.6 years after cure of Cushing's syndrome [101]; others have reported normalization within five years in children [102].

Subclinical hypercortisolism — Even patients with mild chronic hypercortisolism, such as women who have adrenal incidentalomas causing slightly increased cortisol secretion but no other clinical manifestations of Cushing's syndrome (ie, subclinical Cushing's syndrome), may have increased bone turnover, decreased bone mineral density, and vertebral fractures [103]. (See "Evaluation and management of the adrenal incidentaloma", section on 'Subclinical Cushing syndrome'.)

Neuropsychologic changes and cognition — A number of neuropsychologic symptoms may occur, including insomnia, depression, and memory loss. Symptoms of psychiatric disease occur in over one-half of patients with Cushing's syndrome of any etiology and are, therefore, presumably caused by excess cortisol [48,104,105]. Some patients have psychiatric illness as the presenting symptom [105]. (See "Glucocorticoid effects on the nervous system and behavior", section on 'Behavior'.)

Depression occurs in up to 86 percent of patients with Cushing's syndrome [33,106,107]. Most have the increased appetite and weight gain that is usually associated with atypical depression [106]. Rarely, however, anorexia and weight loss predominate as is common in melancholic depression [108]. Severely depressed patients may also be suicidal [48,104].

On the other hand, some patients appear euphoric or manic, particularly early in the course of the illness. Children tend to be overachievers, often ranking near the top of their class [109].

The most common psychologic symptoms are [33,48,104-106]:

Emotional lability

Depression (37 to 86 percent of patients)

Irritability (86 percent)

Anxiety (up to 80 percent)

Panic attacks (up to 30 percent)

Mild paranoia and mania are less common [33]

After correction of the hypercortisolism, resolution of the psychiatric symptoms is variable [110-112] (see "Glucocorticoid effects on the nervous system and behavior", section on 'Correction of hypercortisolism'):

In one study of 33 patients with Cushing's syndrome, important psychopathology (predominantly atypical depression) was present in 55 percent before treatment compared with 24 percent one year after successful treatment [110]. There was also a significant improvement in overall mood score. However, important psychopathology developed after treatment in 4 of 17 patients who had no prior psychiatric symptoms, and one of the four became suicidal.

Other data suggest that Cushing's disease has adverse effects on mood and social functioning that persist after surgical cure [112,113]. This was illustrated in a follow-up report of 114 patients with pituitary tumors who had undergone successful pituitary surgery. The 15 patients with treated Cushing's disease had significantly worse scores on measures of psychosocial well-being and psychosocial functioning compared with patients with other tumors (nonfunctioning adenomas, macroprolactinomas, acromegaly) in whom the scores were similar [112].

In adults, learning, cognition, and memory (especially short-term memory) are impaired by hypercortisolism [114,115]. Bedside assessment of these attributes may be useful in assessing the presence of hypercortisolism [116].

Hypercortisolism is also associated with a decrease in hippocampal volume and a general reduction in brain volume [114,117]. In one study, the degree of impaired memory was associated with a decrease in hippocampal volume [118]. Brain volume increases but does not always return to normal after cure of the hypercortisolism [117]. (See "Glucocorticoid effects on the nervous system and behavior", section on 'Loss of brain volume'.)

In patients with Cushing's disease in remission, cognitive function may improve but not return to baseline [119,120]. In a study of 24 patients studied before and after treatment, some, but not all, had an improvement in cognitive and memory function [119]. Improvements in the ability to remember a list of unrelated words was associated with an increase in hippocampal volume.

One study of 11 children found a decline in intelligence quotient (IQ) and cognitive performance at one year after curative surgery, in the absence of psychopathology, despite reversal of cerebral atrophy [121].

Infection and immune function — Glucocorticoids inhibit immune function, thereby contributing to an increased frequency of infections [122]. In parallel with this, there may be thymic atrophy [123]. Infection accounted for 21.6 percent of deaths in one study of 311 patients with Cushing's disease [124]. Nevertheless, opportunistic infections with organisms of low pathogenicity occur only in patients with severe hypercortisolemia, such as those with ectopic ACTH syndrome [125]. In one study, patients with serum cortisol concentrations above 40 mcg/dL (1100 nmol/L), urinary cortisol excretion greater than 2000 mcg/day (5500 nmol/L), or urinary 17-hydroxycorticosteroid (17-OHCS) excretion greater than 35 mg/g creatinine (96 micromol/g creatinine) were likely to have severe infections [126]. Bacterial infections were most common (74 percent), but opportunistic pathogens or both (42.1 and 13.8 percent, respectively) were frequent and should be considered when giving empiric antibiotic coverage to such patients [126].

The mechanism by which glucocorticoid excess predisposes to infection is poorly understood. One mechanism may be a fall in circulating CD4 cells and decline in natural killer cell activity [127]. Perhaps the major effect is that glucocorticoids inhibit the synthesis of almost all cytokines, apparently by inducing the synthesis of I kappa B alpha, a protein that traps and thereby inactivates nuclear factor kappa B [128,129]. The latter protein is an activator of cytokine genes and mediator of the inflammatory action of tumor necrosis factor.

Inhibition of cytokine release has another clinically important effect with regard to infection; the associated reduction in inflammatory and febrile responses to bacterial infection may make these infections difficult to detect.

The increased susceptibility to infection occurs despite a glucocorticoid-induced rise in the circulating neutrophil count. The granulocytosis is partly due to decreased margination and partly to increased circulating granulocyte colony-stimulating factor [130].

Ophthalmologic findings — Increased intraocular pressure, cataracts, and central serous chorioretinopathy occur rarely as a result of endogenous Cushing's syndrome and are more common with exogenous glucocorticoid administration, in particular, topical steroids [96,131-133].

Mortality — Cushing's syndrome is associated with considerable morbidity and increased mortality [2,134].

In a meta-analysis of seven studies, patients with Cushing's disease in whom initial surgical cure was not obtained had excess mortality compared with the general population, while patients with initial remission did not [135].

In contrast, mortality was twice as high (hazard ratio [HR] 2.3) before treatment in a mixed group of 343 patients with benign Cushing's syndrome of adrenal or pituitary origin compared with controls; the mortality rate in 186 patients remained elevated, despite cure, during long-term follow-up (HR 2.31) [122]. Mortality risk was the same in adrenal Cushing's and pituitary Cushing's. Increases in potential causes of mortality were seen, including VTE (HR 2.03), stroke (HR 1.91), and myocardial infarction (HR 4.38).

In a retrospective cohort study of patients who had been cured of hypercortisolism for at least 10 years at study entry, an increased risk of overall mortality was observed compared with the general population, particularly from cardiovascular disease [134]. However, median survival from cure was still excellent (approximately 40 years).

Side effects of exogenous glucocorticoids — Although endogenous cortisol hypersecretion is relatively rare, many clinicians care for patients receiving prolonged, often high-dose, glucocorticoid therapy for autoimmune disorders, such as vasculitis, systemic lupus erythematosus, and rheumatoid arthritis; for allergic disorders, such as asthma; and to prevent transplant rejection. These patients have a relatively high frequency of serious glucocorticoid-induced side effects, which are reviewed separately. (See "Major side effects of systemic glucocorticoids".)

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Beyond the Basics topics (see "Patient education: Cushing's syndrome (Beyond the Basics)")

SUMMARY

Iatrogenic (exogenous) Cushing's due to pharmacologic doses of glucocorticoids is likely the most common cause of Cushing's syndrome, followed by pituitary corticotropin (ACTH)-dependent Cushing's syndrome. (See 'Epidemiology' above.)

Cushing's syndrome caused by benign and malignant adrenal tumors accounts for approximately 20 percent of endogenous Cushing's syndrome cases. (See 'Epidemiology' above.)

Ectopic ACTH secretion causes up to 15 percent of endogenous Cushing's syndrome. Approximately 1 percent of patients with small cell lung cancer have ectopic ACTH syndrome. Hypercortisolism may not be recognized in these patients, because of weight loss and paraneoplastic syndromes. (See 'Epidemiology' above.)

The presence and relative severity of symptoms varies, being determined by the following factors (see 'Severity of symptoms' above):

The degree and duration of hypercortisolism.

The presence or absence of androgen excess (because hypercortisolism alone causes neither hirsutism nor pustular acne).

The cause of the hypercortisolism (because hyperpigmentation is caused by increased secretion of ACTH) and androgen excess occurs only in females with adrenal cancer or ACTH-stimulated hyperandrogenism (the adrenal gland being a major source of androgen production in females but not males). Adrenal adenomas generally secrete only glucocorticoid.

Adrenal carcinoma or the ectopic ACTH syndrome can cause tumor-related symptoms that may overshadow the effects of hypercortisolism (such as weight loss instead of weight gain).

In adults, signs and symptoms most suggestive of the presence of hypercortisolism include proximal muscle weakness, facial plethora, wasting of the extremities with increased fat in the abdomen and face, wide purplish striae, bruising with no obvious trauma, and supraclavicular fat pads. Other symptoms are described above (table 1). (See 'Clinical manifestations' above.)

An important clinical clue to the presence of glucocorticoid excess is the simultaneous development or accumulation of new features and severity of multiple symptoms consistent with Cushing's syndrome. (See 'Clinical manifestations' above.)

Some of the most common manifestations of Cushing's syndrome, such as obesity, hypertension, and glucose intolerance, are less suggestive of the presence of hypercortisolism as they are also common in individuals who do not have adrenal hyperfunction. (See 'Clinical manifestations' above.)

In addition to the considerable morbidity caused by hypercortisolism, there is also an increase in mortality rates. (See 'Mortality' above.)

DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

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Topic 143 Version 24.0

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