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Screening for Cushing syndrome
Diagnosis of Cushing syndrome in patients presenting with symptoms or signs suggestive of the disease
Cortisol levels are regulated by adrenocorticotropic hormone (ACTH), which is synthesized by the pituitary in response to corticotropin-releasing hormone (CRH). Cushing syndrome results from overproduction of glucocorticoids as a result of either primary adrenal disease (adenoma, carcinoma, or nodular hyperplasia) or an excess of ACTH (from a pituitary tumor or an ectopic source). ACTH-dependent Cushing syndrome due to a pituitary corticotroph adenoma is the most frequently diagnosed subtype; most commonly seen in women in the third through fifth decades of life.
CRH is released in a cyclic fashion by the hypothalamus, resulting in diurnal peaks (elevated in the morning) and nadirs (low in the evening) for plasma ACTH and cortisol levels. The diurnal variation is lost in patients with Cushing and these patients have elevated levels of evening plasma cortisol. The measurement of late-night salivary cortisol is an effective and convenient screening test for Cushing syndrome.(1) In a recent study from the National Institute of Health, nighttime salivary cortisol measurement was superior to plasma and urine free cortisol assessments in detecting patients with mild Cushing syndrome.(2) The sensitivity of nighttime salivary cortisol measurements remained superior to all other measures. The distinction between Cushing syndrome and pseudo-Cushing states is most difficult in the setting of mild to moderate hypercortisolism. Subtle increases in salivary cortisol at the midnight cortisol (cortisol of nadir) appear to be 1 of the earliest abnormalities in Cushing syndrome.
7 a.m.-9 a.m.: 100-750 ng/dL
3 p.m.-5 p.m.: <401 ng/dL
11 p.m.-midnight: <100 ng/dL
Cushing syndrome is characterized by increased salivary cortisol levels, and late-night saliva cortisol measurements may be the optimum test for the diagnosis of Cushing. It is standard practice to confirm elevated results at least once. This can be done by repeat late-night salivary cortisol measurements, midnight blood sampling for cortisol (CORT / Cortisol, Serum), 24-hour urinary free cortisol collection (CORTU / Cortisol, Free, 24 Hour, Urine), or overnight dexamethasone suppression testing. Upon confirmation of the diagnosis, the cause of hypercortisolism, adrenal versus pituitary versus ectopic adrenocorticotropic hormone production, needs to be established. This is typically a complex undertaking, requiring dynamic testing of the pituitary adrenal axis and imaging procedures. Referral to specialized centers or in-depth consultation with experts is strongly recommended.
Acute stress (including hospitalization and surgery), alcoholism, depression, and many drugs (eg, exogenous glucocorticoids, anticonvulsants) can obliterate normal diurnal variation, affect response to suppression/stimulation tests, and cause elevated cortisol levels.
Cortisol levels may be increased in pregnancy and with exogenous estrogens.
Midnight salivary cortisol assay cannot diagnose hypocortisolism or Addison disease because of the limited sensitivity of the assay method.
Using this assay, we determined that late-night salivary cortisol is in the range of 100 ng/mL to 6,000 ng/dL (2.76-166 nmol/L) for clinically confirmed Cushing patients (N=11).
Normal values are based on 36 donors-ages 0 to 8 years, 46 donors-ages 9 to 17 years, and 102 donors-ages >17 years.
1. Raff H, Raff JL, Findling JW: Late-night salivary cortisol as a screening test for Cushing's syndrome. J Clin Endocrinol Metab 1998;83:2681-2686
2. Papanicolaou DA, Mullen N, Kyrou I, Nieman LK: Nighttime salivary cortisol: a useful test for the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 2002;87:4515-4521