Production of cortisol by the adrenal gland is regulated by the hypothalamic-pituitary-adrenal axis. The hypothalamus produces corticotropin releasing hormone (CRH) in response to light and stressors, such as fever, hypoglycemia, hypotension, pain, and acute illness. CRH stimulates corticotropin production and secretion from the anterior pituitary. Corticotropin is more commonly known as adrenocorticotropic hormone or ACTH. Corticotropin stimulates the adrenal cortex to produce cortisol, aldosterone, and dehydroepiandrosterone sulfate (DHEA).
Primary adrenal insufficiency is rare. The most common causes are autoimmune adrenalitis (90% of all cases) and inherited disorders of adrenal steroidogenesis, such as congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Primary adrenal insufficiency results in deficiency of all adrenocortical hormones, including low levels of cortisol, aldosterone, and the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione. In contrast, corticotropin levels are elevated as a result of decreased negative feedback.
Secondary adrenal insufficiency occurs due to deficient pituitary production of corticotropin. The most common cause of secondary adrenal insufficiency is glucocorticoid therapy. It can also be caused by immune checkpoint therapies that result in hypophysitis. Prolonged corticotropin deficiency results in atrophy of the adrenal cortex and decreased ability to produce cortisol.
Measurement of plasma cortisol collected early in the morning (08:00 a.m.) is the recommended initial test to evaluate for adrenal insufficiency. Guidelines from the European Society of Endocrinology and the Endocrine Society state that an early-morning cortisol measurement greater than 10 µg/dL indicates normal hypothalamic-pituitary-adrenal axis function and has a very low probability representing clinically relevant adrenal insufficiency. Conversely, an early-morning serum cortisol level of less than 5 µg/dL in patients with clinical features concerning for adrenal insufficiency is considered indicative of adrenal insufficiency.
When combined with an early-morning cortisol measurement, corticotropin concentrations help determine the type of adrenal insufficiency. Nearly all patients with primary adrenal insufficiency have elevated plasma corticotropin (usually >100 pg/mL). In contrast, patients with secondary adrenal insufficiency have corticotropin concentrations that are below or at the lower end of the reference range (usually <20 pg/mL).
Another major clinical use for the measurement of corticotropin is to help delineate the cause of Cushing syndrome. In patients with primary adrenal disease, corticotropin levels are suppressed, while in those with a pituitary tumor or ectopic corticotropin producing tumor, levels are elevated. Patients with pituitary tumors usually have ACTH levels up to two times the upper limit of normal, while the majority of patients with ectopic ACTH tumors have higher levels. Because of the diurnal variation in ACTH secretion, levels drawn at 0800 offer the best discrimination between the various forms of Cushing syndrome.
Corticotropin reference range is 15-65 pg/mL.
Specimen requirement is a lavender top (EDTA) tube of blood. Prior to collection, the tubes should be cooled in ice. Following collection, tubes should be mixed and placed immediately in an ice water bath for transport to the laboratory. The laboratory should immediately centrifuge the sample and freeze the plasma.
References
Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.
Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540.
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