We searched MEDLINE from January, 2000, to October, 2005. We used search terms “Cushing's” OR “Cushing's” AND “Syndrome”. We selected publications from this 5-year period, but our search also included other commonly referenced and highly regarded older publications known to us, and those that we judged appropriate. Several review articles or book chapters were included because they provided comprehensive overviews beyond the scope of this Seminar.
SeminarCushing's syndrome
Section snippets
Epidemiology and prognosis
Patients with incompletely controlled Cushing's syndrome have a five-fold excess mortality, lending urgency to its ascertainment,4 although this rate might not necessarily apply to patients with the subtle clinical and biochemical phenotype being increasingly diagnosed. Depending on the population studied, incidence of the disorder ranges from 0·7 to 2·4 per million population per year.4, 5, 6 New data, however, suggest that Cushing's syndrome is more common than had previously been thought. In
Causes of Cushing's syndrome
Endogenous Cushing's syndrome is more common in women than men and is divided into corticotropin-dependent and corticotropin-independent causes (table 1). Overall, corticotropin-dependent causes account for about 80–85% of cases, and of these, 80% are due to pituitary adenomas (Cushing's disease), with the remaining 20% or so due to ectopic corticotropin syndrome.10, 11, 12 Ectopic corticotropin secretion most usually takes place with small-cell carcinoma of the lung and bronchial carcinoid
Pathogenesis
Although Cushing's disease is the most common form of endogenous Cushing's syndrome, little is known about the underlying pathogenesis of these pituitary tumours.14 In general, corticotrope tumours show especially low expression of the cyclin-dependent inhibitor p27,15 overexpression of cyclin E,16 and a high Ki67 expression indicative of high proliferative activity. Preponderance of reproductive-aged women might suggest a role of oestrogen, and there is a male predominance in prepubertal
Clinical features of Cushing's syndrome
Table 2 summarises clinical features of Cushing's syndrome. These are variably present in any given patient and can differ in a cyclic way, causing diagnostic difficulty. The diagnosis is being increasingly considered in patients with metabolic syndrome, who might have mild features of slow onset, and diagnosis can be a substantial diagnostic challenge. Signs that most reliably distinguish Cushing's syndrome from obesity are those of protein wasting—presence of thin skin in the young, easy
Biochemical diagnosis of hypercortisolaemia
Diagnostic assessment is usually prompted by clinical suspicion, but in certain groups of patients without classic clinical features, screening might be warranted, such as in poorly controlled and hypertensive diabetic patients and men with unexplained osteoporosis (figure 1). Biochemical confirmation of the hypercortisolaemic state must be established before any attempt at differential diagnosis: failure to do so will result in misdiagnosis, inappropriate treatment, and poor management.
Establishing the cause of Cushing's syndrome
Once a diagnosis of Cushing's syndrome is established, the next step is to establish cause, which is best done in major referral centres (figure 2). Investigation will vary depending on availability of biochemical tests and imaging methods. The first step is to measure concentrations of corticotropin in plasma. Concentrations consistently lower than 1·1 pmol/L (5 pg/mL) indicate corticotropin-independent Cushing's syndrome and attention can be turned to imaging the adrenal gland with CT.
Medical therapies to lower cortisol
Metyrapone, ketoconazole, and mitotane can all be used to lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland.2, 19 Metyrapone and ketoconazole are enzyme inhibitors and have rapid onset of action, but frequently control of hypercortisolism is lost with corticotropin oversecretion in Cushing's disease (known as escape). These drugs are not usually effective as the sole long-term treatment of the disorder, and are used mainly either in preparation for surgery or as
Conclusions
Diagnosis and management of Cushing's syndrome remains a considerable challenge. Our understanding of the pathogenesis has advanced, but mainly with respect to the very rare causes of Cushing's syndrome, although the underlying pathogenesis of the most common cause—Cushing's disease—remains to be elucidated. Cushing's syndrome can be present in up to 2% of patients with poorly controlled type 2 diabetes, and has great implications for screening of this at-risk population. Measurement of
Search strategy and selection criteria
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