Cushing's Syndrome

Cushing's syndrome is the clinical state resulting from prolonged exposure to excess glucocorticoid (cortisol). It can arise from exogenous corticosteroid medication or from endogenous overproduction, which is most often driven by an ACTH-secreting pituitary tumour (Cushing's disease) but can also stem from an autonomously secreting adrenal tumour or from ectopic ACTH production. The chronic cortisol excess produces a characteristic combination of metabolic, body-composition, and cardiovascular changes.

Definition

Cushing's syndrome is the constellation of clinical features caused by chronic excess of glucocorticoid hormone, whether from external corticosteroid administration or from endogenous overproduction of cortisol.

Scope

This entry covers the definition of cortisol excess, the distinction between exogenous and endogenous causes, the ACTH-dependent versus ACTH-independent classification of endogenous disease, the consequences of chronic hypercortisolism, and the feedback logic that underlies diagnostic testing. It is a reference topic and does not provide treatment regimens or individualised advice.

Core questions

• Is the cortisol excess exogenous (from medication) or endogenous (from overproduction)?
• If endogenous, is it ACTH-dependent (pituitary or ectopic ACTH source) or ACTH-independent (an adrenal source)?
• How do dynamic tests exploit the normal feedback suppression of cortisol to confirm and localise the excess?

Key concepts

• Glucocorticoid (cortisol) excess
• Exogenous versus endogenous Cushing's syndrome
• ACTH-dependent versus ACTH-independent disease
• Cushing's disease (pituitary ACTH-secreting tumour)
• Ectopic ACTH syndrome
• Loss of cortisol circadian rhythm
• Dexamethasone suppression and other screening tests

Mechanisms

Sustained glucocorticoid excess drives the syndrome's features through cortisol's broad actions on metabolism, fat distribution, blood pressure, bone, and immune function, producing central weight gain, glucose intolerance, hypertension, and skin and muscle changes. In endogenous disease the source determines the ACTH pattern: an ACTH-secreting pituitary adenoma (Cushing's disease) or an ectopic ACTH-producing tumour raises ACTH and adrenal cortisol output (ACTH-dependent), whereas an autonomous adrenal tumour secretes cortisol directly and suppresses ACTH (ACTH-independent). The normal negative feedback by which exogenous glucocorticoid suppresses cortisol secretion is the basis of dexamethasone suppression testing, and the loss of the normal evening cortisol nadir underlies late-night cortisol measurements.

Clinical relevance

Cushing's syndrome matters because untreated chronic cortisol excess is associated with substantial cardiovascular and metabolic morbidity, and because distinguishing its causes determines very different sources of disease. This entry explains the classification and diagnostic logic conceptually; it is not a basis for self-diagnosis or for any specific treatment, which require specialist evaluation.

Epidemiology

Endogenous Cushing's syndrome is rare, with an incidence on the order of a few cases per million per year; among endogenous causes, an ACTH-secreting pituitary adenoma (Cushing's disease) is the most common, followed by adrenal and ectopic ACTH sources. Exogenous Cushing's syndrome from corticosteroid therapy is far more common than the endogenous forms.

Evidence & guidelines

The Endocrine Society has issued clinical practice guidelines on both the diagnosis (Nieman and colleagues, 2008) and the treatment (Nieman and colleagues, 2015) of Cushing's syndrome, and a comprehensive Lancet review (Lacroix and colleagues, 2015) synthesises the causes, evaluation, and consequences of the disorder.

History

Harvey Cushing described the syndrome of cortisol excess in the early twentieth century and linked a subset of cases to pituitary basophil tumours, the form now called Cushing's disease. The later isolation of cortisol and the development of ACTH assays and dexamethasone suppression testing allowed the syndrome's many causes to be distinguished from one another.

Key figures

• Harvey Cushing
• Lynnette Nieman
• André Lacroix

Seminal works

• lacroix-2015
• nieman-2008
• nieman-2015

Frequently asked questions

What is the difference between Cushing's syndrome and Cushing's disease?

Cushing's syndrome is the general state of cortisol excess from any cause, including corticosteroid medication. Cushing's disease is the specific subtype caused by an ACTH-secreting pituitary tumour, which is the most common cause of endogenous (non-medication) cortisol excess.

Why are dexamethasone suppression tests used in Cushing's syndrome?

Dexamethasone normally suppresses cortisol through negative feedback on the pituitary; in cortisol excess this suppression is impaired or follows a pattern that helps confirm the syndrome and point to its source. These are diagnostic tools interpreted by clinicians, not self-administered tests.