Cushing's syndrome refers to the clinical manifestations induced by chronic exposure to excess
glucocorticoids. There are three pathological conditions that can result in the chronic overproduction of endogenous
cortisol in man: the most frequent is
Cushing's disease where
adrenocorticotropic hormone (
ACTH) is overproduced by a pituitary
corticotroph adenoma, rarely
ACTH can be produced in an 'ectopic' manner by a non-pituitary tumour, finally
cortisol can be directly over-secreted by one or (rarely) the two adrenals that have become tumourous, either benign or malignant. The positive diagnosis of
Cushing's syndrome requires that chronic
hypercortisolism is unequivocally demonstrated biologically, using 24-h urinary
cortisol, late-evening plasma or salivary
cortisol, midnight 1-mg or the classic 48-h-low-dose
dexamethasone suppression test, etc., all with essentially the same diagnosis potencies. The search for the responsible tumour then relies on the assessment of the corticotroph function, and imaging: suppressed
ACTH plasma levels indicate an 'adrenal' Cushing, and the responsible unilateral adrenocortical tumour is always visible at computed tomography (CT) scan, whereas its benign or malignant nature may be difficult to diagnose before surgery. Imaging can suspect bilateral 'adrenal' Cushing, when the two adrenals are small, as in the primary pigmented nodular adrenal dysplasia associated with
Carney complex, or enlarged, as in the
ACTH-independent macronodular adrenocortical hyperplasia. Measurable or increased
ACTH plasma levels indicate either
Cushing's disease or the
ectopic ACTH syndrome. When the dynamics of the corticotroph function (high-dose
dexamethasone suppression test, the CRH test) are equivocal, and/or the imaging is non-contributive, it may be difficult to distinguish between the two. This is the situation where sampling
ACTH plasma levels in the inferior petrosal sinus may be necessary. The best treatment option of
Cushing's disease is when the responsible
corticotroph adenoma can be entirely removed by the trans-sphenoidal approach, with sufficient skill to preserve the normal anterior pituitary function. When it fails, all other options directed towards the pituitary (
radiation therapies), or the adrenals (medications or surgery), have numerous side effects. There is at present no recognised efficient medical treatment towards the
corticotroph adenoma -still an
orphan disease.