Adrenal Function

The adrenal cortex has three distinct zones which secrete various hormones under the direct control of specific feedback mechanisms ¹. Cortisol secretion from the adrenal glands’ zona fasciculata is primarily regulated by corticotropin, also known as adrenocorticotropic hormone, or ACTH. ACTH is released from the anterior pituitary in response to hypothalamic neuropeptides and stress ^{1, 2} .

ACTH and cortisol measurements are frequently used in the assessment of adrenocortical function and other disturbances of the hypothalamic-pituitary-adrenal (HPA) axis.

These include the screening and differential diagnosis of Cushing’s syndrome (CS), a large group of signs and symptoms due to prolonged and inappropriately high exposure to glucocorticoids, mainly cortisol ³. Many common signs of Cushing’s such as obesity, high blood pressure, and increased blood glucose are frequently observed today ⁴. In general, normal or high ACTH concentrations indicate pituitary or ectopic sources of ACTH, while low concentrations indicate an adrenal tumour secreting glucocorticoids ⁵. For the initial testing of CS, the Endocrine society recommends the following screening tests⁶: Urine free cortisol (UFC), late-night salivary cortisol, and the dexamethasone suppression test (DST). For UFC, levels below the upper limit of normal are considered a normal response⁷, while a cut-off at <1.8ug/dL is an indication of suppressed serum levels during the DST. Late-night saliva concentrations in healthy subjects should be at <0.1 to 0.2ug/dL⁸.

ACTH and cortisol levels also play a role in the diagnosis of Addison’s disease, a failure of the adrenal gland to produce cortisol. Patients with primary adrenal insufficiency (AI) can be diagnosed based on a combined measurement of early morning serum cortisol and plasma ACTH levels. The Endocrine Society recommends that a peak cortisol <18 µg/dL following a standard-dose corticotropin stimulation test is indicative of adrenal insufficiency ^{1, 6}. Secondary AI most commonly requires dynamic testing such as the insulin tolerance test or the overnight metyrapone test ^1,8,9.

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4. Findling, J. W. & Raff, H. Cushing’s Syndrome: important issues in diagnosis and management. The Journal of clinical endocrinology and metabolism 91, 3746-3753, (2006).
5. Talbot, J. A., Kane, J. W. & White, A. Analytical and clinical aspects of adrenocorticotrophin determination. Annals of clinical biochemistry 40, 453-471, (2003).
6. Nieman, L. K. et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism 93, 1526-1540, (2008).
7. Nieman, L. K. Diagnosis of Cushing’s Syndrome in the Modern Era. Endocrinology and Metabolism Clinics of North America 47, 259-273, (2018)
8. Grimminger ,P et al. Cortisol in saliva in the diagnosis of Cushing’s syndrome: Diagnostic performance of a new automated chemiluminescence immunoassay and the impact of age, sex and BMI. Endocrine Society poster (SUN411), 2016
9. Bancos, I., Hahner, S., Tomlinson, J. & Arlt, W. Diagnosis and management of adrenal insufficiency. The Lancet. Diabetes & endocrinology 3, 216-226, (2015).
10. Arlt, W. & Allolio, B. Adrenal insufficiency. Lancet 361, 1881-1893, (2003).